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The enormity of the zinc deficiency problem and available solutions; an overview
⁎Corresponding authors. shamsalig@yahoo.com (Shams Tabrez Khan), mrshaik@ksu.edu.sa (Mohammed Rafi Shaik)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
The societal cost of micronutrient deficiency (MND) or the “hidden hunger” is in millions of dollars/year, reducing the GDP of some countries by as much as 11%. Zn is an important micronutrient for both plants and animals. An estimated 17% of the world population, or around 1.1 billion people, are at the risk of zinc (Zn) deficiency. The deficiency has been related to adverse pregnancy outcomes, stunted growth, premature deaths, immune system dysfunctions, neuro-behavioral disorders, and recently with the failure to recover from COVID-19. These health risks associated with Zn deficiency have compelled FAO and WHO to recommend Zn fortification of diet. Correcting Zn deficiency is a challenge due to several reasons. Close to half of the agricultural soils are Zn deficient, and chemical Zn fertilizers are costly and ineffective. Developing Zn-rich crops through plant breeding and genetic engineering is challenging. Zn-dense diet is costly and cannot be implemented in the low-income region most affected by Zn deficiency. Lack of consensus among regulatory bodies on defining and diagnosing Zn deficiency in plants and Humans. Awareness and other sociocultural issues. Among the most important available solutions are zinc biofortification of the cereal crops, use of zinc biofertilizers, development of Zn-efficient crops with reduced phytate content. The use of Zn supplements, dietary modification, and diversification, especially with fish, are proposed as the most accessible and affordable solutions. Awareness programs in areas suffering the most from Zn deficiency are required. Despite the suggestions from FAO and WHO, global efforts to combat Zn deficiency matching those for combating diseases like HIV are not in place. Coordinated efforts of the international community, especially policy-makers, agricultural scientists, dieticians, physicians, and others, are required to address the issue of hidden hunger.
Keywords
Zn deficiency
Crops
Zn transporters
Malnutrition
Phytomicrobiome
Zn fertilizers and biofertilizers
Zn biofortification
Dietary diversification
Phytate
- MND
-
Micronutrient Deficiency
- FAO
-
Food and Agriculture Organization
- WHO
-
World Health Organization
- HIV
-
Human Immunodeficiency Virus
- GDP
-
Gross Domestic Product
- PGP
-
Plant Growth-Promoting
- EDXRF
-
Energy-dispersive X-ray fluorescence spectrometry
- LA-ICP-OES
-
Laser ablation Inductively Coupled Plasma-Optical Emission Spectrometry
- AE
-
Acrodermatitis enteropathica
- DALYs
-
Disability adjusted Life years
- DTPA
-
Diethylene Triamine Penta-Acetic Acid
- IZiNCG
-
International Zinc Nutrition Consultative Group
- SIREM
-
Systematically induced root metabolite exudation
- HEDTA
-
Hydroxy-EDTA
- CAS
-
Chrome azurols
- DMA
-
2′-deoxymugenic acid
- UNICEF
-
United Nations Children's Fund
- GDP
-
Gross domestic product
Abbreviations
1 Introduction
By 2050 world population is expected to grow by 25%, adding another 2 billion people adding to the increasing burden of food demand (Schroeder et al., 2013). The problem is further aggravated by the shrinking area under cultivation, urbanization, and climate change (Satterthwaite et al., 2010; Zabel et al., 2014). The issues are even more pressing in low-income countries, forcing farmers to resort to extensive agricultural practices to meet the food demand. With extensive agricultural practices and the advancement of technology, food availability has slightly improved, but the nutritious quality of the products has deteriorated (Haddad et al., 2016). Consequently, malnutrition still affects every third person, i.e., around 2 billion people worldwide, primarily affecting children. MND result in serious health consequences like diminished physical and cognitive abilities, stunted growth in children and account for half of all the children's deaths under 5 years of age (Bailey et al., 2015).
Additionally, MNDs have also been linked to modern-day health problems such as obesity and the inability to recover from COVID-19, further adding to the societal cost of malnutrition (Asfaw, 2007). Low-income countries, mainly in Africa and Asia suffer the most from MND, where people are mainly dependent on Zn poor cereal-based staple diets like wheat and rice (Kumssa et al., 2015; Wessells and Brown, 2012). Even in high-income countries, the population suffers from MND due to the reduced nutritive value of the diet and dietary habits. MNDs can be attributed to various reasons like dependency on mineral poor diets such as cereal-based diets, affordability, and food beliefs and taboos. The MNDs incur a high societal cost, including production losses, direct medical cost, and cost due to disability-adjusted life-years (DALYs). Fe and Zn deficiency has been estimated to reduce the Gross Domestic Product (GDP) of some developing countries by 2–11% (Darnton-Hill et al., 2005). It is also estimated that addressing MNDs may save 35 trillion dollars for the world economy (Dimkpa and Bindraban, 2016).
The enormity of Zn deficiency and its health and economic consequences have compelled scientists and regulatory bodies (FAO and WHO) to suggest various remedies to combat this problem. Different countries in the world and sections of society suffer from Zn deficiency due to different reasons. Strategies have to be chosen by carefully identifying the prevailing reasons for the deficiency. The most prevalent reason is the low dietary Zn intake, which can be improved by including Zn-dense food, Zn supplements, or Zn biofortification of the food. Improving the dietary intake of economically weaker sections of the society, mainly in Asia and Africa, is one of the biggest challenges as the economically poor sections of the society in these countries cannot afford Zn-rich food to meet daily requirements. Two approaches have been at least partially successful in addressing the issue of Zn deficiency in these regions. First, the use of fertilizers for the Zn fortification of crops, and second the development of Zn dense cereals producing crops through breeding programs or genetic engineering. The unacceptability of genetically modified crops, chemical pollution caused by fertilizers, cost and social unacceptability of genetic engineering programs, and many other concerns have to be considered. Zn fertilizers can help correct soil Zn deficiency up to some extent, which is one of the primary reasons for low Zn content in cereals. The threat of chemical pollution and the residual effect of the fertilizers require alternative and eco-friendly approaches to correct soil Zn deficiency. The use of microbial inoculants is one such approach. Microbial inoculants not only improve the Zn status of the crops but can also improve soil fertility through other plant growth-promoting (PGP) activities. Further research and involvement of policymakers and health workers are required to address the problem of MND (Ritchie et al., 2018).
This review discusses the enormity of the Zn deficiency problem with reference to the impact on agriculture and human health in the light of recently published literature. The review also discusses the available and future remedies suggested by various groups.
2 Enormity of Zn deficiency problem
2.1 Zinc, the metal of life
Nutrients supporting life are grouped into two categories based on the amounts in which they are required, namely macronutrients and micronutrients. Micronutrients are required in very small amounts but are vital for life, playing irreplaceable roles in growth and metabolism. Since many of the micronutrients cannot be synthesized by living organisms, a balanced supply of these is required on a regular basis. Without which good health and survival will be seriously affected (Haddad et al., 2016). A total of twenty-five nutrients, including Zn, cobalt, copper, manganese, molybdenum, and selenium, are identified as micronutrients required for maintaining the life process both in animals and plants, including human beings (Chellan and Sadler, 2015). With an atomic number of 30 and an atomic weight of 65.37, Zn is a vital transition metal for the living world.
Some scientists argue that Zn is the most important micronutrient after macronutrients N, P, and K. The first report highlighting the importance of Zn for living organisms was on Aspergillus niger in 1869. Following which several seminal studies have recognized the role of Zn in all forms of life. The relative concentration of free Zn ions in the cytoplasm and organelles of various living cell systems ranges between ≤103 to ≤109 mol/L (Fabris, 1994). It is a constituent of about 3000 proteins contributing to their catalytic activity (Metalloenzymes; e.g., carbonic anhydrase) and structure (Metalloproteins; e.g., protein kinases, alcohol dehydrogenases). Zn is found in all six classes of enzymes, including hydrolases, lyases, ligases/isomerases, oxidoreductase, and transferases. These enzymes catalyze life's most important functions like DNA replication, repair, translation, inter and intracellular signaling, maintenance of membrane integrity, and photosynthesis (Andreini et al., 2006). Some of these proteins help in Zn transport itself, maintaining its homeostasis in the cells (Kambe et al., 2015). Zn also plays a crucial role in cell growth and differentiation. In humans, its role in immunity, neurotransmission, and proper functioning of the brain is becoming increasingly evident (Frederickson et al., 2005). It also strengthens the defense against oxidative stress and the synthesis, storage, and release of insulin. Zn is equally essential for proper plant growth playing important roles in plant physiology and metabolism. It is involved in various crucial metabolic processes, from photosynthesis to chlorophyll synthesis, plant reproduction, and autophagy. Its role in grain yield, seed development, protection against plant pathogens and herbivores are also reported (Cabot et al., 2019). Therefore, Zn is correctly referred to as a “metal of life”.
2.2 Zinc and plants
2.2.1 Role of Zn in plant health
The concentration of Zn varies from plant to plant, tissue to tissue, cell to cell, and even from compartment to compartment within a cell. The Zn content of plants varies between 30 and 100 mg/kg of dry matter. It is present both as protein-bound Zn and free Zn2+ ion. However, what proportion of Zn is found as free Zn2+ and what proportion of Zn exists in the protein-bound Zn is unknown (Broadley et al., 2007). In most crops, Zn concentration in the leaf required for adequate growth is in the range of 15–20 mg Zn/kg of leaves (Broadley et al., 2007). At the same time, Zn concentration in various compartments of leaf cells varies from 74 to 3205 µg/g dry weight (Frey et al., 2000).
Some vital Zn-dependent enzymes include DNA and RNA polymerases, histone deacetylases, splicing factors, and other important enzymes of mitochondria and chloroplasts (Pilon et al., 2009). It is key to various vital metabolic and physiological functions in plants, such as carbohydrate metabolism, including photosynthesis, chlorophyll synthesis, sucrose, and starch synthesis. It plays an essential role in lipid and nucleic acid metabolism, gene expression, gene regulation, protein synthesis, and maintenance of membrane integrity (Hänsch and Mendel, 2009; Segal et al., 2003). In maize, it is found to be involved in forming functional 80S ribosomal complex and functioning of tRNA synthetases (Pilon et al., 2009). It plays a role in chloroplasts' functioning, such as in repairing photosystem II by turning over photo-damaged D1 protein. Zn-dependent hydrolytic activities also occur in the cytoplasm, lysosomes, and the apoplastic spaces within the plant cells. Zn metalloproteases destroy many signal peptides. Zn regulates plant growth by being a cofactor of various plant growth hormones like auxin.
A high concentration of Zn in pollens indicates towards its role in reproduction. This is also supported by the important role of Zn binding proteins in the tapetum (Kapoor et al., 2002). Zn is a cofactor of the Carbonic anhydrase enzyme, which also helps in increasing the CO2 content of the chloroplast consequently increasing the activity of Rubisco (Salama et al., 2006). It is also involved in signal transduction via mitogen-activated protein kinases. The role of Zn in various physiological processes has been summarised in detail in the books authored by Brown et al. and Alloway (Alloway, 2008; Brown et al., 1993).
2.2.2 Zn deficiency in plants
Since Zn is vital to the growth and reproduction of plants, its deficiency has varying degrees of consequences depending on the susceptibility of the plants to Zn deficiency. Some plants are highly susceptible to Zn deficiency like beans, corn, grapes, maize, rice, and sorghum. In contrast, some are mildly sensitive, like potatoes, tomatoes, sorghum, and sugar beets. Crops like oat, carrot, and pea are less susceptible to Zn deficiency (Noulas et al., 2018; Westermann, 1991). Different genotypes or varieties of the same crop may vary in their ability to assimilate Zn (Mishra et al., 2019). For example, durum wheat is more sensitive to Zn deficiency than bread wheat. The concentration of Zn in plants and plant organs can be estimated using various methods like histochemical methods (dithizone, Znon), flame atomic absorption spectrometry (AAS), ultrasound-assisted sequential extraction, energy-dispersive X-ray fluorescence spectrometry (EDXRF), and Laser ablation Inductively Coupled Plasma-Optical Emission Spectrometry (LA-ICP-OES) (Cakmak et al., 2010; Leśniewska et al., 2016; Paltridge et al., 2012). Since these currently used techniques require expensive instrumentation and expertise, easy to use methods/kits for on-site determination of Zn concentration in the plant tissues are highly desirable. The concentrations determined using different techniques can give different concentrations based on their effectiveness. So far, there is no general definition of critical deficiency concentration, defining Zn deficiency in plants (Lindsay, 1972). The critical deficiency concentrations determined in various studies, particularly the values for some important cereal crops, are listed in Table 1 (Alloway, 2008). Young leaf blades have been used customarily to determine the Zn status of the plants, and a concentration of 20 mg Zn/kg is considered a lower critical concentration. A Zn concentration of 15 mg/kg has been suggested as the critical value for grains. For various crops, different values are suggested; a value of 10 mg Zn/kg and 43 mg Zn/kg is considered critical for wheat and soybean, respectively (Alloway, 2008).
Cereals/Grains
Reference tissue
Concentration (mg/kg)
Senstivity to Zn Deficiency
Reference
Range
Average
Spring Wheat
Youngest tissues
15–70
14
Low
(Brennan and Bolland, 2002)
Durum Wheat
Youngest tissue
15–70
20
Low
(Brennan and Bolland, 2002)
Rice
Leaf-blade
20–25
–
High
(Reuter and Robinson, 1997; Singh, 1984)
Maize/Corn
–
20–70
–
High
(Noulas et al., 2018)
Barley
Leaf blade
–
20
Medium
(Genc et al., 2002)
Pearl Millet
–
–
18
–
(Alloway, 2008)
Oat
Top Leaves
–
5–20
Low
Zn is involved in carbohydrate, protein, and DNA metabolism. As a structural component of the ribosome, Zn deficiency affects ribosome structure, consequently influencing transcription and translation. This results in a decreased protein content and accumulation of amino acids in Zn-deficient tissues (Kitagishi and Obata, 1986). The deficiency mainly affects metabolism in shoot meristems and pollen tubes, where Zn concentration are 5–10 times higher than in mature leaf blades. Zn deficiency also increases the breaking down of RNA through increased RNase activity (Pandey et al., 2002). Permeability of plasma membrane also increases under Zn deficient conditions. The symptoms of mild to moderate Zn deficiency are not very apparent. In contrast, plants show characteristics and easily detect symptoms under severe Zn deficiency.
Some of the most common symptoms include stunted growth affecting root, shoot, stem, seed, and fruit formation. The typical symptoms associated with leaves are mottling and bronzing, which results from interveinal chlorosis and the development of purple or bronze tints and is more noticeable on middle-aged leaves. Leaves become smaller in size, and leaf lamina curls inwards, called the little leaf and goblet leaves, respectively. It also results in the necrosis of the root apex, and stems become thin with characteristic shortened internodes. Fruit and seed formation is reduced significantly; some studies also report the reduction of dry matter (Table 2). Once these symptoms appear, it becomes challenging to manage the Zn deficiency. Therefore, it is essential to timely screen the crops for such deficiency, at least for crops sensitive to Zn deficiency, and to develop the methods for the same. Some recent studies have reported methods for predicting Zn deficiency in plants. As Zn deficiency causes redox imbalance in roots and shoots even before the appearance of visible symptoms, it can be used as a marker for predicting deficiency (Höller et al., 2014). Zn deficiency also enhances NAD(P)H-dependent superoxide radical production in plasma membrane vesicles isolated from bean plant roots (Pinton et al., 1994). Another study has demonstrated that Zn deficiency induces DNA damage which causes abnormal development of leaves. And when the DNA damage was alleviated, the malformation of leaves was controlled (Sotta et al., 2019). Early and late Zn deficiency responsive genes in rice have also been identified using transcriptome analysis (Bandyopadhyay et al., 2017). These genes are involved in root system architecture, photosynthesis, metal transport, phyto-siderophore biosynthesis, and ROS scavenging. The same study demonstrates that Zn-deficient seedlings secrete more oxalates for Zn mobilization and an increased ROS activity in Zn-deficient leaves. Zn-deficient wheat roots are also known to increase the secretion of the exudates (Zhang et al., 1989). In the roots of Zn-deficient maize, the accumulation of lipids, oxalic acid, and tannins have been reported (Alloway, 2008). Since such biochemical markers will be helpful in the timely management of Zn deficiency, it is important to identify and standardize such markers. Other approaches like machine learning using images can help the scientific community to understand the real-time situation. Awareness programs among stakeholders and farmers about the significance of Zn deficiency are also required.
Crop
Deficiency Symptoms
Reference
Wheat (Triticum aestivum L.)
Small leaves, curved upwards, interveinal chlorosis, necrotic spots
(Alloway, 2008; Cakmak et al., 1996)
Rice (Oryza sativa L.)
Leaf midrib chlorotic at the base. Brown spots on older leaves. Browning of leaves. Stunted growth and reduced tillering.
(Alloway, 2008; Mori et al., 2016; Wissuwa et al., 2006)
Maize/Corn (Zea mays L.)
White to yellow chlorosis of leaf, Stunted plants with short internodes, Whitetips
(Alloway, 2008; Mattiello et al., 2015)
Barley (Hordeum vulgaris L.)
Uniform chlorosis of leaves, drying up and decreased tip growth
(Alloway, 2008)
Oat (Avena sativa L.)
Bronzing & Necrosis of leaves
(Alloway, 2008)
Pearl Millet (Pennisetum glaucum L.)
Chlorosis of leaves, margins with red lines, bleached white patches on leaves
(TANU)
2.3 Zinc and human health
Although the availability of food has improved, the nutritional quality of the food has declined. The status of micronutrients in food is a matter of global concern having health and economic burdens. >800 million people around the globe are undernourished, and more than two billion people are known to suffer from one or more chronic MNDs (Kumssa et al., 2015). One such micronutrient is Zn, and its use for medicinal purposes is known since 2000 BCE. An Egyptian papyri from 2000 BCE (for example, the Smith Papyrus1) mentions the use of Zn in skin cream. Since then, Zn has been identified as one of the most important micronutrients. Many reviews underlining the importance of Zn for life have been published (Alloway, 2001; Cakmak et al., 1996).
2.3.1 Role of Zn in metabolism and physiology
Zn plays a crucial role in metabolism, being a constituent of all six different enzyme classes. It is estimated that the human body contains about 2.6 g of Zn. Its concentration in different tissues varies; the highest concentration is present in skeletal muscles accounting for 60% of the total body Zn (Hess et al., 2007). At the same time, blood plasma contains only 0.1% of the total body Zn (Hambidge et al., 1986; Hess et al., 2007). It can be present as a protein-bound Zn or as a free Zn ion, although excess free Zn in body tissues (100–500 mg/dL) is toxic (Choi and Koh, 1998). As far as protein-bound Zn is concerned, it alone constitutes 10% of the human proteome contributing to their structure or catalytic activity (Andreini et al., 2006). In addition to enzymatic catalysis, Zn plays an important role in gene regulation, intra-, and intercellular signaling, stabilization of membranes, and apoptosis (Cai et al., 2015; Chellan and Sadler, 2015; Choi et al., 2017). The role of Zn fingers in the regulation of transcription and their role in health and disease needs a special mention here (Cassandri et al., 2017). Zn also influences hormone production, secretion, and sexual development (Bjorndahl and Kvist, 2011; Li, 2014). It enhances the immune system and is involved in the proper functioning of the brain and nervous system (Frazzini et al., 2018; Fukada et al., 2019; Gammoh and Rink, 2019; Portbury and Adlard, 2017). Its role in the stabilization of circadian cycle proteins has also been established (Schmalen et al., 2014). Table 3 lists some of the important physiological processes involving Zn.
Zinc Function
Examples
Reference
Constituent of Enzymes
Structural
Zn fingers, Zn ribbons
(Lemaire et al., 2009a)
Catalytic factor
In all six categories of enzymes
Oxidoreductases
Alcohol dehydrogenase
(Vallee and Williams, 1968)
Hydrolases
Alkaline Phosphatases
(Bosron et al., 1975)
Lysases
Carbonic anhydrase
(Christianson and Fierke, 1996)
Isomerases
Phosphomannose isomerase
(Bangera et al., 2019)
Transferases
Sulfur transferase
(Selbach et al., 2014)
Ligases
tRNA Synthetase
(Sankaranarayanan et al., 2000)
Role in Signalling
Intercellular
GABA mediated synaptic transmission
(Sensi et al., 2011)
Intracellular
Zn wave/intracellular second messenger.
(Yamasaki et al., 2007)
Physiological functions
In the functioning of brain & CNS
GABA Synaptic transmission
(Sensi et al., 2011)
Apoptosis regulation
(Webb et al., 1997)
Immunity
Both innate and cellular immunity
(Rink and Haase, 2007), (Bonaventura et al., 2015)
Reproductive Health
(Bjorndahl L, Kvist U, 2011)
Pregnancy
(Chaffee and King, 2012)
Antioxidant
(Brieger et al., 2013)
Circadian cycle
(Schmalen et al., 2014)
Endocrine system
(Baltaci et al., 2019)
Anti-Inflammation
(Prasad, 2014)
2.3.2 Prevalence of Zn deficiency and its markers
An estimated 1.1 billion people or 17.3% of the total world population, mainly in Africa, Asia, the Andean region, and Central America, are at the risk of Zn deficiency due to inadequate dietary supply (Fig. 1) (Brown, K.H. et al., 2004a). However, the toxicity of excess Zn and the inability of humans to store extra Zn necessitates maintaining healthy Zn homeostasis in the body either through diet or Zn supplements. This healthy Zn homeostasis is vital for the proper functioning of cells, organs, and various systems, including the immune and nervous systems. Several detailed reviews on the significance of Zn in human health have been published (Bonaventura et al., 2015; Frederickson et al., 2005; Roohani et al., 2013). The Zn deficiency is a great health concern and has been linked to several diseases and health problems detailed below, primarily affecting newborns and young children. This not only results in financial losses but also causes loss of lives. Losses due to Zn deficiency are so evident and rampant that international organizations like FAO and WHO have recommended Zn fortification of diet (Bailey et al., 2015; Kaur et al., 2014). It is imperative to timely detect the Zn deficiency using economic and standard, easy to use, and quick methods. Scientists are developing such methods for easy, quick, and economical detection of Zn deficiency (Wieringa et al., 2015). Various indicators/markers of Zn deficiency/status have been used, such as Zn concentration in plasma, blood cells, hair, and urine (Brown, K. et al., 2004). But the plasma Zn concentration is a widely accepted marker of Zn deficiency. The normal human blood serum contains 800 ± 200 μg/dL of Zn, which may vary with age, sex, and other factors (Li, 2014). However, other unrelated conditions may influence plasma Zn concentrations. For example, long-term fasting and pregnancy increase and decreases Zn concentration, respectively (Aggett and Favier, 1993). The lower cut-off value of the Zn ranges from 50 to 70 μg/dL for various age groups (Table 4). Severe Zn deficiency is rare, but mild-to-moderate Zn deficiency is widespread, affecting 7.5–29.6% of the total population in different parts of the world, especially affecting children and pregnant women (Brown, K. et al., 2004; Wessells and Brown, 2012). Imp Note: The age groups and values are adjusted to provide a simplified overview.
The global prevalence of Zn deficiency. Nation wise Zn status based on inadequate dietary Zn and childhood growth stunting.
Age, Sex, health condition
RDI (mg/day)
Physiological requirement (mg/day)
Percent Absorption
Lower cut off serum Zn Conc. (mg/dl)
Fasting
Non-Fasting
Children
6 Months-3 years
1.5–2.5
0.53–0.84
33.8–35.9
–
0.0065
3–8 years
3–4
0.83–1.2
Adults
9–13 years
6
1.4–2.1228.9–30.3
10–15 years Male
6
1.82
0.0074
0.007
15–18 years Male
1.97–3.37
10–15 years Female
6
1.55
33.9
0.007
0.0066
15–18 years Female
1.54–3.02
Health Condition
Pregnancy
7–13
2.27–5.02
–
0.0056
0.0056
Lactation
11–14
2.89–4.52
–
–
–
2.3.3 Consequences of Zn deficiency in humans
Undernourishment and MND are associated with >6% of global mortality and morbidity burdens (Kumssa et al., 2015). About 4.4% of the childhood deaths, mainly in Africa, Asia, and Latin America, are due to Zn deficiency (Fischer Walker et al., 2009). Zn deficiency is associated with anorexia, cognitive dysfunction, childhood mortality, hypogonadism, impaired immune function, the prevalence of diarrhea, pneumonia, stunted growth, and skin disorders (Kaur et al., 2014). Premature and small-for-gestational-age infants and preschool children, especially of less than 2 years of age, constitute the most vulnerable group (Chaffee and King, 2012). The role of Zn in various diseases like atherosclerosis, age-related degenerative neurological disorders like Alzheimer's, autoimmune diseases, diabetes, diarrhea, and several malignancies has been established as has been recently published in many reviews (Chasapis et al., 2012; Kaur et al., 2014; Roohani et al., 2013). Some of the diseases are discussed below, and a list of these diseases is summarised in Table 5.
Disease
Reference
Infant and Birth related problems
Low birth weight, Small for gestation
(Wang et al., 2015)
Adverse pregnancy outcomes
(Chaffee and King, 2012; Kaur et al., 2014)
Stillbirth, infant mortality
(Jurowski et al., 2014; Smith et al., 2017)
Children
Diarrhoea in children
(Folwaczny, 1997)
Pneumonia in children
(Barnett et al., 2010; Eijkelkamp et al., 2019)
Cognitive dysfunction in children
(DiGirolamo and Ramirez-Zea, 2009)
Other Problems
Brain and Nervous System
(Frederickson et al., 2005; Nuttall and Oteiza, 2014)
Alzheimer and Parkinson’s
(Adani et al., 2020)
Hypersensitivity
(Seo et al., 2017)
Acrodermatitis enteropathica
(Gray et al., 2019)
Atopic dermatitis
(Satria et al., 2019)
Breast Cancer
(Jouybari et al., 2019)
Pancreatic cancer
(Li et al., 2007)
Liver diseases like Hepatitis C
(Mohammad et al., 2012)
Diabetes
(Ohta et al., 2019)
2.3.3.1 Role of Zn in pregnancy and diseases of children
MNDs, especially Zn deficiency, may affect pregnancy outcomes and early child development (Britto et al., 2017; Flynn et al., 1981; Wang et al., 2015). Zn affects pregnancy as it involves the metabolism of various hormones like androgen, estrogen, progesterone, and prostaglandins (Chaffee and King, 2012; Favier, 1992). Zn deficiency during pregnancy can cause atonic bleeding, inefficient labour, preterm birth, maternal morbidity, and an increased risk to the fetus. In a study involving 39 developed countries like Sweden and the Netherlands, Zn intervention was found to reduce preterm birth by 5% (Chang et al., 2013). Mortality due to preterm birth is much higher in other parts of the world (Black et al., 2016). Infants from mothers who received Zn during pregnancy show reduced risk of acute diarrhea, dysentery, and impetigo, diseases that claim the lives of about 9% of infants (Black et al., 2016; Osendarp et al., 2001). Other studies found a significant effect of the breast milk Zn concentration on the weight of neonates (Doneray et al., 2017). The Zn deficiency in children during breastfeeding is also called acquired Zn deficiency. A detailed account of the different roles of Zn in pregnancy and child health has been reviewed and published earlier (Kaur et al., 2014).
2.3.3.2 Zn and nervous system
The mammalian brain contains a significant amount of Zn, found as free, protein-bound, and vesicular Zn. Protein-bound Zn is one of the main pools of Zn in the forebrain. While vesicular Zn mainly exists in glutamatergic neurons accounting for 5–15% of the total brain Zn (Marger et al., 2014). Zn plays a crucial role in neuronal function and signaling, as has been recently demonstrated (Frederickson et al., 2005). Zn2+ transporters are involved in the development of the nervous system, neurulation, and neuronal differentiation (Chowanadisai et al., 2013). The role of Zn in memory impairment is also documented as Zn transporters like ZnT3 are known to regulate presynaptic Erk1/2 signaling and hippocampus-dependent memory (Sindreu et al., 2011). Evidence indicates that Zn plays a key role in the physiology and pathophysiology of brain function. Many studies have demonstrated a positive association between Zn intake or status with one or more measures of cognitive function. Zn imbalances may cause brain disorders like Alzheimer's and Parkinson’s disease, which many authors have reported and reviewed (Adani et al., 2020; Frederickson et al., 2005).
2.3.3.3 Role of Zn in immunity
Zn plays an important role in immunity, and imbalances in its concentration affect the immune system's functioning, especially cell-mediated immunity. Detailed reviews highlighting various roles of Zn in immunity have been recently published (Kaur et al., 2014; Prasad, 2008). Low Zn status is known to decrease the response to vaccination and disturbs the functioning of innate immune cells (Haase and Rink, 2009). In a survey, a low Zn status has also been related to higher levels of IgE, a hypersensitivity-associated antibody, showing that low levels of Zn may be involved in hypersensitivity (Seo et al., 2017). The role of Zn in the development and function of T regulatory cells involved in the prevention of auto-immune diseases has also been described (Hogstrand et al., 2009).
2.3.3.4 Role of Zn in skin diseases
Acrodermatitis enteropathica (AE) is a skin disease involving Zn deficiency characterized by dry skin and skin blisters. AE is a genetic disorder wherein a change in Zn binding membrane protein occurs due to the mutation in its gene (Nistor et al., 2016). The gene “SLC39A4” encoding hZIP4 Zn transport protein, is found to be involved in this disease in humans (Küry et al., 2002). Another skin disease, atopic dermatitis (AD), is a hypersensitive skin disease which results in Zn deficiency. In some cases, the co-occurrence of both AE and AD diseases has also been reported (Gray et al., 2019; Satria et al., 2019). Zn helps in wound repair by augmenting the migration of keratinocytes (Lansdown et al., 2007). And a Zn-binding protein, MG53, is also found to be involved in membrane repair, facilitating injury repair (Cai et al., 2015).
2.3.3.5 Zn status and metastasis
Metastasis and its progression are also influenced by impaired Zn homeostasis. The overexpression of Zn transporter ZnT1 leading to impaired Zn homeostasis is documented in at least five different cancer types (Lehvy et al., 2019). Decreased serum Zn was found in breast, prostate, kidney, liver, and lung cancer. In another study, lowered serum Zn concentrations have been shown to increase the risk of breast cancer and its onset in women (Jouybari et al., 2019). Studies have described the underlying molecular mechanism demonstrating the involvement of Zn transporters, Zn channel protein ZIP7, and an antiapoptotic kinase CK2 in cancer (Hogstrand et al., 2009; Taylor et al., 2012). In another study, the involvement of Zn transporter ZIP4 (SLC39A4) in human pancreatic cancer was demonstrated (Li et al., 2007). Although the molecular mechanism is not yet well-understood, Zn is shown to protect against prostate cancer (Kolenko et al., 2013).
2.3.3.6 Zn and diabetes
Zn plays an important role in the pathogenesis of diabetes, functioning of β-cells, glucose homeostasis, and insulin's action (Ranasinghe et al., 2015). It is found to be involved in the synthesis of insulin and determining its conformational integrity (Fukunaka and Fujitani, 2018; Norouzi et al., 2017). Proinsulin, a Zn-containing hexamer, is readily converted into insulin hexamer, an active form of enzymes (Emdin et al., 1980). The recently published structure of an integral membrane proteins Adiponectin receptor that controls glucose and lipid metabolism contains Zn-binding sites (Vasiliauskaité-Brooks et al., 2017). Low Zn concentration is known to influence the maturation of insulin-producing cells (Ohta et al., 2019). The crystallization of insulin in mice is also known to be affected by the expression of Zn transporter ZnT8. However, it was not found to be involved in the homeostasis of normal glucose concentration (Lemaire et al., 2009b). The literature published so far remains inconclusive about the role of Zn in diabetes.
2.3.3.7 Role of Zn in miscellaneous health conditions
Recently, the role of Zn in various other health conditions and diseases, like cardiac health, hepatitis, obesity, and pneumonia, have been documented (Barnett et al., 2010; Kaur et al., 2014). Low Zn status has been regarded as a risk factor for pneumonia in the elderly (Barnett et al., 2010). Zn intervention alleviated recurrent diarrhea and pneumonia in children, consequently reducing child mortality (Hambidge, 2006; Lassi et al., 2016). It has been suggested that the Zn can be used as a low‐cost adjunct for anti-viral therapy for the hepatitis C virus (Read et al., 2018). In contrast, the studies have found that the Hepatitis C virus replicase contains a Zn-binding domain (Tellinghuisen et al., 2005). Scientific evidence on the role of Zn and Zn transporters in various health conditions is being published by various groups highlighting the role of Zn as a metal of life. Recently the role of Zn in the fight against COVID-19 has been demonstrated (Sethuram et al., 2021). A list of various diseases caused by Zn deficiency is given in Table 5.
2.4 Cost of Zn deficiency
As detailed above, Zn is vital for both humans' and plants' growth, development, and reproduction. And hence, its deficiency results in decreased crop productivity and several plants diseases causing significant economic losses on a global scale (Figs. 2 and 3). Growth retardation, diseases, and mortality caused by Zn deficiency in humans also result in significant economic losses and loss of life, as discussed below in detail.
A glimpse of the economic burden of Zinc and other micronutrient deficiency on the global economy.
2.4.1 Losses of crop yield and plant productivity
Since Zn is essential for the growth and reproduction of plants, its deficiency results in losses of crop productivity. The use of Zn helps control these losses and increase crop productivity (Cakmak et al., 1996). Nevertheless, few studies have estimated the actual scale of financial loss to crop productivity due to the Zn deficiency. One such study demonstrated that Zn deficiency causes a loss of up to 30% in cereal grains, without any obvious visual symptoms of stress (Noulas et al., 2018). While, another study by Cakmak et al. estimated that the use of Zn fertilizers increased the yield of wheat grain in Central Anatolia, Turkey, by >600% returning benefits of about 100 million US$ annually (Cakmak, 2008). Zn fertilizers increased the grain yield in Punjab, India, worth an additional benefit of >800 M US$ annually (Joy et al., 2017; Prasad et al., 2013). These studies demonstrate that millions of dollars are lost annually due to the loss of agricultural productivity caused by Zn deficiency. Therefore, if Zn deficiency is corrected, it will increase agricultural benefits and help the world achieve food security.
2.4.2 Economic burden of Zn deficiency in humans
MNDs in general and Zn deficiency in particular results in the loss of millions of dollars annually as extra medical cost and claims millions of lives, primarily affecting children. For some nations, it can reduce gross domestic product by as much as 11% (Hicks et al., 2019). It is estimated that in China, the economic burden due to the diseases caused by malnutrition is at around 66 billion US$ annually (Linthicum et al., 2015). Malnutrition in Cambodia is estimated to incur a loss of >400 million US $ annually (Bagriansky et al., 2014). The economic burden of MNDs is mainly due to the losses in productivity, increased medical costs, and DALYs. The societal cost of MNDs among 6- to 59-month-old children in Pakistan was estimated to be 3222 million US$ in production losses, 46 million US$ in medical costs, and about 3.4 million US$ in DALYs (Wieser et al., 2017). One study demonstrated that about 3 billion US$ could be saved annually by averting roughly 58,000 preterm births through Zn intervention (Chang et al., 2013). The costs of micronutrient deficiency are 5 times higher in poor households than in wealthy households (Wieser et al., 2017). These studies suggest billions of dollars can be saved annually by simply managing the MNDs in general and Zn deficiency in particular. It is also estimated that the cost of managing these deficiencies is much lower than the benefits that can be earned from successfull management of deficiencies.
2.5 Reasons of Zn deficiency
Several factors cause Zn deficiency in plants and humans. These include edaphic factors like Zn-deficient soil and factors associated with plants like the Zn efficiency and its sensitivity to the Zn deficiency. The low Zn content of the plants directly affects the Zn status in humans as plants are primary producers and an essential part of the diet. Zn poor diet is one of the primary reasons for Zn deficiency in humans. Malabsorption of Zn due to age and other factors also causes the deficiency. This section discusses how these factors affect Zn availability in plants and humans and how these factors are related (Fig. 3).
Major reasons of Zn deficiency associated with soil, plants and humans contributing to the global zinc deficiency.
2.5.1 Reasons for Zn deficiency in plants
Several factors cause Zn deficiency in plants. These include the Zn status of soil, physicochemical characteristics of the soil, inefficiency of plants to accumulate Zn, transport of Zn to various plant parts, especially to the edible parts. These reasons are discussed below.
2.5.1.1 Zn deficiency in soil
The earth's crust is made up of two types of rocks, namely igneous and sedimentary rocks containing 48–100 and 20–200 mg/kg of Zn, respectively (Mertens and Smolders, 2013). Franklinite (ZnFe2O4), Hopeite (Zn3(PO4)2 4H2O), Smithsonite (ZnCO3), Zincite (ZnO), and Zinkosite (ZnSO4) are some of the generally found zinc minerals in the soil. Zinc in the soil is present as three different pools: exchangeable pool (ions bound to soil particles), water-soluble pool, and organically bound pool (chelated or complexed with organic matter). Some proportion of the Zn may also bind to clay and other soil particles in an in-exchangeable form. The usual range of total Zn in soils is 10–300 mg/kg with a mean value of 50 mg/kg (Sharma et al., 2013). Zn is generally present in the earth's crust in a concentration of 67 mg/kg (Rudnick and Gao, 2003). A detailed summary of Zn concentration in various soils is given in Table 6 (Kabata-Pendias, 2010; Mertens and Smolders, 2013). Zn, which is available to plants, is either in exchangeable ionic form (Zn2+) or organically complexed Zn. Different extraction methods are used to estimate Zn in ionic or free form/water-soluble form. These include diethylene triamine pentaacetic acid (DTPA), Mehlich, and HCl methods, and based on these methods, different definitions for critical deficiency are in use. These also vary with the soil type (Table 7). Soils containing less than 0.5 mg of DTPA extractable Zn/kg of soil are classified as Zn deficient soils (Mertens and Smolders, 2013). Some studies define critical deficiency in the range of 0.6 to 2.0 mg/kg depending on the extraction method (Singh and Singh, 2005). The presence of insoluble forms of Zn in agricultural soil is one of the most important reasons for Zn deficiency in plants. The deficiency of Zn in the soil is a global problem as it results in the deficiency of this micronutrient in various food chains affecting humans. One-third of the world's soil is Zn deficient. Various researchers and international organizations like FAO, IZiNCG, and WHO, have highlighted the issue of Zn deficiency in soil (Brown, K.H. et al., 2004b; Gibson et al., 2016; Kumera et al., 2015). Countries in Asia like China, India, Indonesia and Turkey, Sub-Saharan Africa and the north western region of South America have the most Zn deficient soils. A survey of 3500 soil samples from 29 developing countries has shown that most of the Zn-deficient soils were found in in Iraq (57% of samples), Turkey (35%) and Pakistan (20%) (Sillanpää, 1982). No such detailed surveys have been published since then. Recent surveys of sub-Saharan Africa also have shown that Zn deficiency predominates the studied soil samples (Kihara et al., 2020). An Indian survey of 256,000 soil and 25,000 plant samples have shown that 48.5% of the soils and 44% of the plant samples are Zn deficient (Fig. 4) (Arunachalam et al., 2013). The incidence of low Zn was particularly higher in Maharashtra, Karnataka, and Haryana (Arunachalam et al., 2013). .
S.No.
Country
Zn Concentration (mg/kg soil)
Soil Type
Mean
Range
1
USA
50
10–300
2
China
99
37–491
Gleysols
Australia
2–180
3
34
4–41
Alkaline soil
5–36
Calcerous soil
England and Wales
97
–
35
–
Sandy soil
4
65
–
Coarse loamy
90
–
Fine silty soil
106
–
Clayey soil
France
17
–
Sandy soil
40
–
Silty soil
5
63.5
–
Loam
98
–
Clayey soil
132
–
Very Clayey
–
Poland
37
–
sandy soil
6
60
–
Loess soil
75
–
Loam
Germany
27.3
–
Sandy soil
7
59.2
–
Loam/Silt
76.4
–
Clay
8
Sweden
65
–
9
Japan
89
–
Agricultural soil
10
India
59
20–89
Arid/Semi-arid
52
22–74
Humid/sub-humid tropics
69–76
Vertisols
24–30
Oxisols
11
Brazil, Parna
73
–
12
Philippines
63–135
Rice soils
13
Vietnam
102
40–485
14
Indonesia
33–174
15
Thailand
45
5–158
S. No.
Zn Conc mg/kg of soil
Method
Soil type
Reference
1.
0.5–1.0
DTPA
–
(Cox, 1987)
2.
1.1
Mehlich
–
(Cox, 1987)
3.
0.1
HCl
–
(Cox, 1987)
4.
0.13
DTPA
Sub-Terranean
(Brennan and Gartrell, 1990)
5.
0.55
DTPA
Sand
(Brennan and Gartrell, 1990)
6.
0.55
DTPA
Clay
(Brennan and Gartrell, 1990)
7.
0.6
AAS
Latosol
(de Almeida et al., 2020)
The predominant Zn deficiency in Indian soil. Percent soil samples exhibiting Zn deficiency in various states of India.
2.5.1.2 Presence of Zn in insoluble/unavailable forms
The presence of insoluble Zn complexes or secondary minerals in the soil also significantly contributes to Zn deficiency. These insoluble forms of Zn include Zn carbonate (ZnCO3), Zn oxide (ZnO), and Zn sulfide (ZnS). Smithsonite (ZnCO3), sphalerite (ZnS), Zincite (ZnO), franklinite (ZnFe2O4), willemite (Zn2SiO4), and hopeite (Zn3(PO4)2·4H2O) are the secondary minerals containing insoluble Zn in soil. Studies claim that the insoluble form of Zn constitutes > 90 % of soil Zn, which is not available to plants, while exchangeable, water-soluble Zn constitutes only a fraction (4 × 10−10−4 × 10−6 M) (Gupta et al., 2016).
2.5.1.3 Edaphic factors
Various edaphic factors like pH, salinity, and soil texture affect the solubility and bioavailability of Zn to plants. Since Zn2+ are held on the surface of clay particles, clayey and silty soils tend to contain more plant-available Zn than sandy loam or sandy soils. The median Zn concentration in sandy soils was estimated to be 17 mg/kg of soil, while in clayey soil, the concentration was 132 mg/kg (Mertens and Smolders, 2013). At the same time, Silty and loamy soils were found to contain 40 and 64 mg/kg of Zn (Alloway, 2009). Soil alkalinity (pH > 6.5) reduces the Zn uptake by plants. Therefore, calcareous and sandy soils with alkaline pH tend to contain less plant-available Zn. Unfortunately, 30% of the arable lands worldwide are alkaline (Cakmak and Kutman, 2018). Even if Zn fertilizers like Zn sulfate are added to Zn deficient soils, the added fertilizers are often transformed back into insoluble compounds like Zn(OH) and Zn(OH)2 at the alkaline pH. Under highly reduced conditions like in paddy fields, Zn sulfate may also get converted into ZnS (Alloway, 2008). High levels of phosphorus can also adversely affect the availability of Zn to plants due to the formation of calcium phosphate (apatite), which changes soil pH.
2.5.1.4 Zn sensitivity and Zn efficiency of plants
Plants vary in their sensitivity to Zn deficiency; some are more sensitive to Zn deficiency than others. This ability of plant species, genotypes, or cultivars to optimally grow and produce good yield under Zn-deficient conditions is referred to as Zn efficiency of the plant (Alloway, 2008; Hacisalihoglu and Kochian, 2003). Zn-efficient genotypes can efficiently absorb the Zn from soils to support optimal growth and good grain yield. The increased absorption of Zn may be due to the better physicochemical behavior of the root and the change in the root structure. Extensive, long, and fine roots tend to absorb more nutrients from the soil. Roots also increase the Zn absorption through the secretion of Zn-chelating siderophores (Cakmak et al., 1998). Along with increased absorption, Zn efficient cultivars may have developed a better mechanism for utilizing and distributing absorbed Zn to various cell compartments and tissues. Such genotypes may also have a system in place to maintain Zn-dependent enzymes such as carbonic anhydrase and Cu/Zn superoxide dismutase. Zn content of the grains is a highly desirable and altogether different genetic trait. Since grains are used as a staple food, cultivars that have high Zn content should be preferred. Cakmak reported that wheat developed through crosses of local landraces exhibits high Zn efficiency (Cakmak et al., 2010). On the contrary, cultivars or genotypes that are not Zn efficient will be associated with loss of productivity and decreased Zn content.
2.5.1.5 Climatic conditions
Lower temperatures also reduce the Zn uptake by plants mainly due to reduced microbial activity in soil and conversion of organically bound Zn to available forms. Low temperature indirectly affects Zn uptake as it can also affect other biogeochemical processes (Alloway, 2008; Liu et al., 2019; Xue et al., 2012). For example, phosphorus-induced Zn deficiency is more severe at low temperatures.
2.5.1.6 Interference by other nutrients
High phosphate level in the soil decreases plant Zn uptake, resulting in low Zn content of many crops worldwide (BARROW, 1987). The underlying mechanism is not very well understood. The soil's nitrogen content is also known to affect Zn availability to plants. Nitrogen increases protein formation, consequently increasing the synthesis of Zn-protein complexes in the root. These complexes sometimes are not translocated to other parts of the plant (Alloway, 2008). On the contrary, an increased Zn uptake due to nitrogen-mediated change of soil pH has been demonstrated (Liu et al., 2018). Transcriptomic studies have shown an upregulation of N-homeostasis genes in the stems of Zn-deficient plants (Bouain et al., 2019).
2.5.1.7 Soil microbiome/rhizobiome
The soil microbiome not only plays a role in the nutrient uptake by plants but also in fixing various nutrients from the environment for the plants. Microbes provide these nutrients to plants in a sustainable and eco-friendly manner. These microorganisms often referred to as plant growth promoting rhizobacteria (PGPR), are engaged in various metabolic activities to promote plant growth in addition to nitrogen fixation. Plant-associated microorganisms exclusively carry out several of these activities. With the increasing knowledge of microbiome using high throughput sequencing and omic approaches, the multifarious role of microbes in sustaining plant productivity and health is becoming increasingly evident (Berg et al., 2017). Some recent reports show that certain plant symbionts even engineer the plant-associated microbiome or so-called phytomicrobiome through changes in root exudates, signaling, and modification of rhizospheric soil (Uroz et al., 2019). Plant-associated microbes not only control phytomicrobiome but also are involved in root-root signaling, resulting in systematically induced root metabolite exudation or SIREM (Korenblum et al., 2020). This signaling activity occurs over a much longer distance than previously thought, as demonstrated for glycosylated azelaic acid, a SIREM signaling molecule (Korenblum et al., 2020). Microorganisms can promote Zn availability to plants through the solubilization of insoluble Zn in soil. These Zn solubilizing microorganisms can also promote plant growth through other PGP activities (Kamran et al., 2017; Kumar et al., 2019a). Unfortunately, even for Zn, chemical fertilizers are more readily available than biofertilizers. Lack of awareness among farmers and the unavailability of commercial microbe-based fertilizers have further complicated the problem. Regular and extensive use of chemical fertilizers inherently cause a number of problems jeopardizing the soil health and its status as a renewable resource (Wu et al., 2019).
2.5.2 Causes of Zn deficiency in humans
Various reasons contribute to the Zn deficiency in humans, the most important being inadequate dietary intake, malabsorption, impaired utilization, and increased losses during digestion.
2.5.2.1 Inadequate dietary intake
One of the main reasons for Zn deficiency is inadequate dietary intake. The recommended dietary intake varies with age group, sex, and special health conditions like pregnancy. Inadequate dietary intake can be related to various reasons ranging from affordability to food beliefs and taboos. Typical human Zn intake is in the range of 14–30 mg/kg. In a detailed study, the FAO national food balance sheet of 188 countries was used to estimate Zn intake (Wessells and Brown, 2012). It was concluded that an estimated 17.3% of the global population is at risk of inadequate Zn intake, while in the South-Asia, this value was much higher, with 30% of the population at the risk of Zn deficiency. In another investigation, 1.1 billion people were found to be at the risk of Zn deficiency mainly due to inadequate dietary supply, and 90% of those at risk were from Africa and Asia (Kumssa et al., 2015). Even in developed countries like the United States, the elderly were at increased risk of Zn deficiency (Maret and Sandstead, 2006). The percentage of countries at risk of Zn deficiency has improved from 35% in 1992 to 26% in 2011. The primary source of Zn were animal products in the Americas, Australia, Europe, North Africa, and New Zealand. Cereals served as the main source of Zn in other parts of the world. Whole-grain cereals, lean red meat, pulses, and legumes provide the highest concentrations of Zn, 25–50 mg/kg of raw weight. As phytate interferes with the absorption of Zn its high concentration, high phytate to Zn ratio in cereals and vegetables was identified as a reason of Zn deficiency (Gibson, 2012; Raboy, 2001). Therefore, animal-based food is a better source of absorbable Zn than plant-based diet (Gibson et al., 2018). Wide spread vegetarianism in countries like India needs alternative ways of supplementing Zn. Certain subgroups of population with high growth rates and tissue synthesis for example infants and toddlers require higher Zn intake (Krebs et al., 2014).
2.5.2.2 Malabsorption of Zn
Dietary Zn is primarily absorbed in the small intestine, mainly the duodenum and jejunum. With the help of specific transport proteins like DMT1 (divalent metal-ion transporter-1) and Zn transporters like ZnT-1, it enters the circulation portal, making it available to other tissues. About 70% of the Zn in circulation is found as albumin-bound Zn. Therefore, factors that alter serum albumin concentration can also affect the availability of Zn to other tissues (Brown, K.H. et al., 2004b). The excess Zn is excreted through gastrointestinal secretion, sloughing mucosal cells, and integument. Malabsorption of Zn also results in the loss of dietary Zn, adding to the problem and requiring an even higher Zn intake (Gibson et al., 2016). Due to this malabsorption and other factors, only 25–93% of Zn from the diet can be absorbed (Abbaspour, 2013). The malabsorption and the loss occurs due to the reasons like age, diseases, or interference by various components of the diet itself. A well-known genetic disorder Acrodermatitis which affects 1 person per 500,000, also results in Zn deficiency. It is an autosomal recessive mutation of the SLC39A4 gene on chromosome 8q24.3, encoding Zn transporter Zip4. It results in the malabsorption of Zn in the diseased person (Weedon, 2010). Components of food, including high-fat content, type of protein (animal or plant), fibers, phytates, and other metals, may interfere with the absorption of Zn (Bel-Serrat et al., 2014; Jurowski et al., 2014; Lönnerdal, 2000). Several studies have highlighted the fact that phytate found in a plant-based diet interferes with Zn absorption (Gibson, 2012). Studies have shown that the higher the phytate content lower the absorption of Zn.
3 Strategies for combating Zn deficiency
Since Zn deficiency is a multifaced problem, it requires a set of strategies to deal with the problem at different levels (Fig. 5).
Various strategies that can be used for combating Zn deficiency in humans and plants.)
Adapted from Khan and Malik (2022.
3.1 Improving the Zn status of the crops/plants
Since plants are primary producers, the Zn deficiency in plants will cause a deficiency in the subsequent food chain. One of the main reasons for this deficiency in plants is the poor Zn status of agricultural soil, as one-third of the global soil has inadequate Zn. Secondly, Zn is often present as insoluble Zn, unavailable to plants. Thirdly various edaphic factors also influence the bioavailability of Zn, like alkaline pH and sandy texture of the soil. Therefore, it is of immense importance to correct the Zn status of the plants and crops through strategies targeting specific problems.
3.1.1 Biofortification using Zn fertilizers: One of the strategies to alleviate Zn deficiency in soil is the use of Zn fertilizers
3.1.1.1 Types of Zn fertilizers
Zn fertilizers can be classified into four categories based on their chemical nature: inorganic, organic, natural organic, and synthetic chelates (Hergert et al., 1984; Khan et al., 2018). Zn oxide (ZnO), Zn carbonate (ZnCO3), Zn sulfate (ZnSO4), Zn nitrate (Zn(NO3)2), and Zn chloride (ZnCl2) are some of the inorganic Zn fertilizers (Alloway, 2008). The most commonly used inorganic forms are ZnSO4 and ZnO. The inorganic complexes provided more than one nutrient like ammoniated ZnSO4, and ammoniated ZnCl2 provides Zn and nitrogen. Superphosphate is another such formulation that contains Zn as an impurity (Alloway, 2009). Natural organic complexes are produced by reacting metallic salts with other organic materials. These organic materials include citrate or by-products from industries like the wood and pulp industry. Lignosulfonates, phenols, and polyflavonoids are some of the other commonly used by-products. These organic complexes can also be obtained by complexing Zn with amino acids. Synthetic chelates of Zn are formed by combining a chelating agent such as Ethylene Diamine Tetra-acetic Acid (EDTA), Diethylene Triamine Penta-Acetic Acid (DTPA), and Hydroxy-EDTA (HEDTA) with Zn ion. The di-sodium salt of Zn-EDTA (Na2Zn-EDTA) is the most commonly used chelate. Plants uptake these synthetic chelates 2–5 times more easily than the simple ZnSO4.
3.1.1.2 Rates and methods of fertilizer application
The choice of method of application and rate of fertilizer application depends on the type of fertilizer, soil characteristics, and crop species. Crops sensitive to Zn deficiency, calcareous soils, and soils having alkaline pH require higher fertilizer application rates (Alloway, 2008). Different fertilizer application methods include seed treatment, spray on topsoil, foliar spray, and banding in the seedbed. For rice, the seedling roots can be dipped in fertilizer before planting. The most commonly used method is the soil application. Many studies suggest that foliar application is better than soil application (Kopittke et al., 2019). Since foliar applications bypass adverse factors of soil hindering absorption by root, it is also known to result in better accumulation in grains. ZnSO4 is typically applied at rates ranging from 5 to 25 kg Zn/ha (Cakmak, 2008; Cakmak and Kutman, 2018; Liu et al., 2020). However, an application rate of less than 10 kg/ha is recommended, which can be added to NPK fertilizer both in granular and liquid forms (Mortvedt and Gilkes, 1993). For foliar spray, a 5 times lower concentration than that of soil application is recommended (<1 kg/ha). The solution for spray typically contains 2–5 g Zn sulphate heptahydrate (ZnSO4·7H2O) per liter (Boonchuay et al., 2013; Cakmak et al., 2010). Chelated forms of Zn, such as Zn-EDTA being expensive, are used as foliar spray only for high-value crops (Alloway, 2008). Timing of the fertilizer application is also an important factor for effective accumulation in cereal grains. One study has shown that the highest increase in Zn content of the grains was observed with the foliar application around the flowering time (Cakmak et al., 2010). A 44% increase in grain Zn content with Zn fertilizers was observed in oats (Shivay et al., 2013). In barley use of Zn fertilizer increased the grain Zn concentration, and with the highest test concentration of fertilizer, the Zn content of grains even doubled (Gonzalez et al., 2019).
3.1.1.3 Zn nanomaterials as Zn fertilizers
As global production and consumption of nanomaterials is increasing, their possible use as nanofertilizer for improving plant mineral nutrition is also being explored (Faizan et al., 2018). Nanoform of nutrients may have advantages over bulk form, such as greater penetrability, higher activity at lower doses, and slow release (Khan, 2020). Nano formulations of many micronutrients and macronutrients have been synthesized and studied, including nitrogen, potassium, Mg, and Zn (Faizan et al., 2018; Kopittke et al., 2019; Sturikova et al., 2018). Various forms of Zn nanomaterials like Zn oxide nanoparticles, Zn nitrate, and Zn hydroxide nitrate nanocrystals ranging in size from 35 to 100 nm have already been tested for crops like wheat, maize, peanut, and tomato. Studies have shown that the foliar spray of ZnO and ZnSO4 nanomaterials increased the Zn content in the grains significantly without affecting the yield (Zhang et al., 2018). Forty-two percent higher yield in maize was obtained when the foliar spray of ZnO nanoparticle (400 mg/L) was used (Subbaiah et al., 2016). The same treatment was found to increase the Zn content of the grains significantly.
3.1.1.4 Benefits of Zn fertilization
Several studies have verified that Zn fertilization increases Zn content in the edible parts of the plant, increases grain yield, and improves overall plant growth (Aghili et al., 2014; Phattarakul et al., 2012). Cakmak has reviewed that Zn fertilization increases the grain yield up to 5.7% in studies undertaken in China, India, Pakistan, and Zambia (Cakmak et al., 2010; Rashid et al., 2019). Another study carried out in China, India, Kazakhstan, Mexico, Pakistan, Turkey and Zambia, reports a 5% increase in the grain yield and an up to 90% increase in grain Zn content following Zn fertilization (Zou et al., 2012). Similarly, with foliar spray of ZnSO4·7H2O, an increase of 42.4% in rice grain Zn was observed (Yuan et al., 2013). Another study reports an increase of 32–37% in grain Zn content following the use of Zn fertilizer under optimal conditions (Fang, Y. et al., 2008; Phattarakul et al., 2012). In some studies, an increase in grain yield of about 5 % was also observed (Phattarakul et al., 2012). Some studies estimated that Zn fortification of wheat and rice in India could save as many as190,000 lives (Tarafdar et al., 2014). Zn fertilizer applied to soil increased maize yield by 4.2–16.7% and the grain Zn content by 24.3–74.9% (Liu et al., 2020). These increased yields can add billions of US dollars to the world economy. Table 8 lists some studies demonstrating an increase in grain yield and grain Zn content following Zn fertilization.
Species/Cereal/Variety
Variety
Zn fertilization
% Increase in grain Zn content
Ref.
Method
Dose
Wheat
Triticum aestivum L.
Cerek-79
Soil
23 kg/ha
90
(Yilmaz et al., 1997)
Foliar
0.40%
33
(Yilmaz et al., 1997)
Baldo
Soil
45 kg/ha
20
(Yilmaz et al., 1997)
Triticum durum Desf.
kunduru-1149
Soil
23 kg/ha
190
(Yilmaz et al., 1997)
PDW 291
Foliar
5.35 kg/ha
122
(Dhaliwal et al., 2019)
Rice
Oryza sativa L.
Wuyunjing 7
Foliar
0.9 kg/ha
20
(Fang, J. et al., 2008)
Foliar + Soil
9.3
73
(Phattarakul et al., 2012)
Pearl Millet
Pennisetum americanum L.
HHB 67
Foliar
10 mg/L
11
Oat
Avena sativa L.
Kent
Soil
5 kg/ha
45
(Shivay et al., 2013)
Maize
Zea mays L.
FHY-421
Soil
54 kg/ha
40
(Kanwal et al., 2010)
3.1.1.5 Challenges associated with the use of Zn fertilizers
Zn fertilizers are not cost-effective, as the added fertilizer is often converted back to insoluble forms which are not bioavailable to plants. Other problems associated with the fertilizers are the residual effect of added Zn, concomitant uptake of other metals, and toxicity concerns. The cost of Zn fertilization is mainly due to the cost of fertilizer application which can be minimized by adding it either with fertilizers or with the pesticides for application. Synthetic chelates like Zn-EDTA are very effective but are 5–10 times more expensive and are currently being used only for precious crops. It is important to check the Zn concentration in the soil before Zn fertilization because only a fraction of added Zn is taken up by plants, and the remaining Zn added to soil shows the residual effect for up to 10 years (Brennan, 2001). Very often, Zn fertilizers added to soil get transformed into unavailable forms like Zn(OH), Zn(OH2), and Zn(PO3)4 due to the factors like alkaline soil pH and high phosphorus content of the soil (Takkar and Sidhu, 1979). A high concentration of Zn (typically 500 mg/kg) is considered toxic for plants. However, the concentration toxic to plants varies from crop to crop based on the sensitivity. A soil Zn concentration of >81 and 60 mg/kg is considered toxic for maize and wheat, respectively (Takkar and Mann, 1978). Another problem associated with Zn fertilization can be the increased accumulation of other undesirable metals like cadmium in grains (Köleli et al., 2004). These problems can be simply avoided by avoiding the overdose of Zn fertilizers and a regular check of Zn status in soil.
3.1.1.6 Zn biofertilizers for Zn biofortification of crops
Inorganic Zn fertilizers are associated with several problems inherent to chemical fertilizers discussed above. Microbe-based biofertilizer is considered an effective alternative to replace chemical fertilizers for meeting the nutritional requirement of plants in a sustainable manner. Conventionally, microbial inoculants are used mainly for nitrogen fixation in agriculture. It is estimated that microorganisms alone fix 50–70 × 106 tons of nitrogen annually into the agricultural soil systems (Herridge et al., 2008). Metagenomics and next-generation sequencing approaches have revealed a much greater interplay of plant and microorganism at work, which can be exploited to maximize agricultural benefits (De-la-Peña and Loyola-Vargas, 2014). The complex nature of the interaction can be understood from the fact that as many as 30,000 different prokaryotic species can be associated with the rhizosphere of a plant. And the plants secrete hundreds of chemicals (auxins, sesquiterpene lactones, Glomalin and PGs) to regulate this complex interplay (De-la-Peña and Loyola-Vargas, 2014; Mendes et al., 2011). Studies have demonstrated that plants secrete compounds to recruit specific microorganisms for their benefit. Sometimes even the plant symbionts engineer the plant–microbe interaction by modifying root exudates (Uroz et al., 2019), which may also affect the neighbouring plant through root to root signaling (Korenblum et al., 2020). The PGPR activities of the prokaryotes can be grouped as biofertilizers (microbes that either fix nutrients or increase their bioavailability to plants), biopesticides (microorganisms that repel or outcompete plant pathogens), and phytostimulators (microorganisms that manipulate the hormonal signaling of plants) (De-la-Peña and Loyola-Vargas, 2014; Jacoby et al., 2017). Biofertilizers promote plant growth by making nutrients available for plants such as nitrogen and phosphorus and by producing other plant growth promoting substances. Conventional examples of biofertilizers include Allorhizobium sp., Azotobacter sp., Rhizobium sp., Trichoderma and Pseudomonas fluorescens based inoculants. Biofertilizers are being produced at industrial scale and are being widely used in fields. In India alone it is estimated that 37997.61–40324.21 metric tonnes of biofertilizer are produced annually (Yadav and Chandra, 2014).
3.1.1.7 Zn solubilizing microorganisms as biofertilizers
Due to extensive agricultural practices, soil is becoming increasingly deficient in micronutrients. The addition of macronutrients to agricultural soil is routine, but micronutrients are mostly neglected due to various reasons, including economic feasibility. This practice results in a gradual depletion of micronutrients in the soil. Microorganisms in addition to providing certain macronutrients, can also promote the uptake of micronutrients by plants and can serve as a source of micronutrients (Bouain et al., 2019; Dinesh et al., 2018; Jacoby et al., 2017; Treeby et al., 1989). Zn, one of the most important micronutrients, is often present in the soil as insoluble Zn (smithsonite; ZnCO3, sphalerite; ZnS, Znite; ZnO, franklinite; ZnFe2O4, and willemite; Zn2SiO4), which is not readily available to plants. Some microorganisms have the innate capacity to convert this fixed form of Zn to labile Zn, making it available for plants. These microorganisms are referred to as Zn solubilizing microorganisms. Several in-vitro studies have demonstrated the ability of bacteria and fungi to solubilize Zn using an agar plate or in liquid medium assays (Table 9). Bacterial genera capable of solubilizing Zn are members of Gammaproteobacteria, Actinobacteria, and Firmicutes and include Acinetobacter sp., Bacillus sp., Burkholderia sp., Curtobacterium sp., E. cloacae, Gluconacetobacter sp., Pseudomonas sp., Plantibacter sp., Pantoea dispersa, Rhizobium sp. and Streptomyces sp. (Table 9). Solubilization of Zn phosphate by endophytic fungi like Beauveria caledonica is also reported (Fomina et al., 2004). Many reported strains are not sufficiently identified and characterized (Table 9). Other strains not mentioned here because these strains were not very effective Zn solubilizers as reported in respective studies. It is challenging to define effective Zn solubilizers as different methods are used, and there is no consensus on the definition of effective Zn solubilizers. Measuring the zone of solubilization on agar plates is one of the most widely used methods. It is suggested that a strain which forms a zone of solubilization with a diameter of ≥18 mm will be considered as an effective Zn solubilizer. However, how these strains behave in soil and various other parameters should be included in the definition of effective Zn solubilizers for their possible use as biofertilizers. PGPR Activities: Lip, Lipase; Cell, cellulase, IAA, Indole acetic acid production; Sid, Siderophore production, Phos; Phosphatase, PS; Phosphate solubilization, NH3; Ammonia solubilization, Amy; Amylase, AF; Antifungal activity. “*” Zn solubilization tested by other methods.
Organism
Identification
Zn solubilization (mm)
PGPR Activities
Ref.
basis
ZnO
ZnCO3
Zn3(PO4)2
Bacteria
Acinetobacter sp.
Polyphasic
*_
PS, Sid, IAA
(Rokhbakhsh Zamin et al., 2011)
Bacillus sp. AZ6
*_
–
(Hussain et al., 2020)
Burkholderia cenocepacia KNU17BI2
16S
25.2
19.6
–
PS, NH3, IAA, Sid, AF
(Tagele et al., 2019)
Burkholderia contaminans KNU17BI3
16S
22.4
21.8
–
PS, NH3, IAA, Sid, AF
(Tagele et al., 2019)
Burkholderia lata ZnSB2
16S, biochemical
15.3
19.3
11.8
NH3, PS, Amy
(Dinesh et al., 2018)
Curtobacterium sp. Strain 81
16S, MALDI-TOF
*_
–
(Costerousse et al., 2018)
Enterobacter cloacae PBS-2
16S
1
1
0.5
–
(Kamran et al., 2017)
Gluconacetobacter diazotrophicus
–
23
28
12
Nematicidal
(Saravanan et al., 2007)
Pantoea dispersa strain EPS-6
16S
11
10
4
Lip, Cell, IAA
(Kamran et al., 2017)
Plantibacter sp. Strain 5
16S, MALDI-TOF
22.4
–
(Costerousse et al., 2018)
Pseudomonas aeruginosa (CMG 823)
API test kit
+
–
+
(Fasim et al., 2002)
Pseudomonas fragi strain EPS-1
16S
9
8
3
Phos, IAA, Sid
(Kamran et al., 2017)
Pseudomonas fluorescens 3a
Biochemical
*–
–
(Di Simine et al., 1998)
Pseudomonas sp. Strain 24
16S, MALDI-TOF
Sid
(Costerousse et al., 2018)
Rhizobium sp. LHRW1
–
18
10
6
–
(Kamran et al., 2017)
Serratia sp. (TM9)
(Idayu Othman et al., 2017)
Streptomyces sp. Strain 68
16S, MALDI-TOF
*_
Sid
(Costerousse et al., 2018)
Fungi
Beauveria caledonica
(Fomina et al., 2004)
Mycorrhizal fungi
+
+
Martino et al., 2003
3.1.2 Mechanism of Zn solubilization by microorganisms
Microorganisms employ different mechanisms for the solubilization of Zn. The most widely reported mechanisms are acidification based on cation exchange and siderophore production (Eshaghi et al., 2019; Saravanan et al., 2011). Acid-producing Zn solubilizers produce organic acids in the soil to sequester Zn cation by decreasing the pH of nearby soil. Such bacteria are known to produce organic acids such as citric acid, gluconic acid, 5-ketogluonic acid, and oxalic acid. The decrease in soil pH considerably increases Zn mobility. It was demonstrated that a decrease in pH by 1 unit increases the availability of Zn by 100 times (Havlin, 2005). Strains listed in Table 9 are known to produce various organic acids, others were shown to produce siderophores, and some strains produce both. To facilitate micronutrient uptake, many microorganisms produce siderophores like catecholate (enterobactin), carboxylates (rhizobactin), and hydroxamates (Pyoverdine) (Ahmed and Holmström, 2014). Most of the studies on Zn solubilizing microorganisms have reported only qualitative and quantitative production of siderophores using Chrome Azurols (CAS) agar assay and no details on the type of siderophores are available. In one report, the production of both hydroxamate- and catechol-type siderophores has been demonstrated using Csaky and Arnow assays (Rokhbakhsh Zamin et al., 2011).
3.1.3 In-vivo studies on Zn solubilizing microorganisms and impact on yield
Many in-vivo studies have evaluated the impact of Zn solubilizing microorganisms based on microbial inoculants on the growth and productivity of plants. These studies were done in various experimental setups using jars, pots, or experimental fields on wheat, rice, maize, and soybean. Various parameters were used to assess the change in vegetative growth and productivity, such as shoot and root lengths, dry weight, and Zn content. Although the most important parameter is the grain yield and grain Zn content, only a few studies report these parameters as far as cereals are concerned. When Zn solubilizing Acinetobacter and Burkholderia were used with ZnCO3 for rice cultivation, the mean dry matter yield/pot, tillers/plant, and a number of panicles/plants improved. Pseudomonas fragi was found to increase the root dry weight, its Zn content, and Zn content in grains (Kamran et al., 2017). Seed yield and Zn content of both wheat and soybean increased significantly when strains of B. cereus were used under microcosm conditions. (Khande et al., 2017). Almost similar results were obtained using the strains of Bacillus aryabhattai in another study (Ramesh et al., 2014). Zn contents of maize shoot and grain increased by 52% and 46%, respectively, with Zn solubilizing Bacillus sp. AZ6 strain. In short-term pot culture experiments, with seed bacterization with Pseudomonas P29 significantly enhanced total dry mass and Zn uptake significantly (Goteti et al., 2013). Interestingly, the use of Zn biofertilizer treatment was shown to decrease the phytate content of the grains, however, the mechanism is not known yet (Hussain et al., 2020).
3.1.4 Commercial production of Zn solubilizing biofertilizers and application
Commercial preparation of Zn biofertilizers requires choosing efficient strains. In addition to having the ability to solubilize Zn effectively, these strains should also survive in the soil and outcompete the soil microbial flora. These fertilizers can be formulated as solid or liquid by mixing with suitable sterile carrier material. Carriers generally used for biofertilizer preparation include naturally occurring materials like charcoal, peat, lignite, or vermiculite (Malusá et al., 2012). The carrier is chosen based on various desirable characteristics suited for biofertilizer production, such as buffering capacity, moisture-holding capacity, and free of any toxicity to inoculant strain. The suitability of the carrier with the inoculant strain should be determined to ensure its survival with the carrier for a longer shelf life of the product. Once the biofertilizer is formulated, it should be subjected to quality control. Some of the important parameters used for the quality control of Zn biofertilizers are listed in Table 10. These include parameters like viable counts of the inoculant, which generally ranges from 108-109. The biofertilizer should be free of any other contaminant strain even at a dilution of many folds, usually up to a dilution of 105. Methods of application vary from crop to crop and the type of fertilizer. The powdered form of fertilizers is generally applied as seed coatings by mixing with adhesives like gum arabica. The granular form of fertilizer can be applied directly to the soil with the seed and liquid form is generally sprayed. Some Zn solubilizing bacterial-based biofertilizers available in India are listed in Table 11, and a web grab of the products is shown in Fig. 6. Disadvantages of biofertilizers include the requirement of aseptic conditions for production, shorter shelf life and sensitivity to extreme environmental conditions like heat and dryness. But the advantages of using biofertilizers outweigh its disadvantages. Therefore, it is evident from the literature that a number of bacteria can serve as Zn biofertilizers in soil. However, isolation of more effective Zn solubilizers from various environment is required. Proper cataloging of such strains should be ensured for their on-demand retrieval and long-term use. Further systematic and large-scale studies are required to better understand the impact of these fertilizers. Studies are also required to estimate the actual global consumption of such fertilizers. Awareness programs among farmers to explain the benefits of these fertilizers are urgently needed. Such programs should demonstrate that these fertilizers are low-cost, economical, and sustainable options to eradicate plant Zn deficiency grown both in Zn deficient soils and in soils where Zn is available as insoluble Zn. Policymakers and agricultural scientists should work hand in hand to promote these fertilizers for obtaining long-term benefits.
S. No.
Parameter
Standard requirement
Inoculant Strain related Paramters
1
Zn solubulization efficiency of inoculant strain
Zone of Zn solublization should be at least 10 mm in diameter on a 3 mm thick Zn solubilization agar plate
2
Viable cell count
The cell count in biofertilizer should be 5 × 107 cells/g of powder or granule or 1 × 108 cells/ml of liquid
3
Contamination check
No contamination at even at a dilution of 105
Carrier related Parameters
4
Carrier base
Dry carrier or base like charcoal, humus and peat can be used, or liquid carrier can also be used
5
pH
pH should be in a range of 6.5–7.5 for powder or granules and 5.0 – 7.5 for liquid carrier
6
Particle size of carrier
Powdered material should pass through 0.15–0.212 mm IS sieve
7
Moisture content
30–40% by weight
Product
Company
Organism
CFU Counts (/g or /ml)
BioZn
Special Biochem Pvt. Ltd.
Unknown Bacteria
5 × 108
BioZn
Criyagen Agri & Biotech Pvt. Ltd.
Thiobacillus thioxidans
NA
Kish Zn
FISHFA Biogenecis
Unknown Bacteria
2.5 × 109
Samridhi Zn Solubilizing Liquid Bio Fertilizer
Jaipur Bio Fertilizers
Unknown Bacteria
1 × 108
SUN BIO ZN BAC
–
Unknown Bacteria
2 × 109
Utkarsh Znoz
Utkarsh Agrochem
Microorganism
NA
Zinc Solubilizing Bacteria (ZSB)
Green Farms
Unknown Bacteria
1 × 108
Web grab of some zinc solubilizing bacteria-based biofertilizers available in Indian market.
3.1.5 Zn mobility from soil to grains
Zn uptake and its translocation from roots to other parts like leaves and grains are complex. Keeping in view these problems, Oslen and Palmgren correctly chose the title of their review as “Many rivers to cross: the journey of Zn from soil to seed”(Olsen and Palmgren, 2014). It involves the uptake from soil by the root epithelial cells, where Zn crosses the cell wall and membrane to reach into the cell protoplasm (Symplast), at the cellular level, many mechanisms facilitate the import, trafficking, sequestration, and export to maintain an intracellular Zn concentration that is not low and not quite high to cause toxicity in a process referred to as homeostasis (Fig. 7). All the living cells need to maintain this homeostasis for optimal cellular functioning. The translocation from root epithelial cells to various parts of the plants and grains will involve its movement through a continuum of symplast (from one cell to another) and it may also have to pass through the dead spaces between the cells (apoplast). Metal carrier or channel proteins are involved in the uptake from the soil into the cell (symplast), and the process is mainly passive, which does not require energy due to the negative membrane potential (Kochian, 1993; Olsen and Palmgren, 2014). In contrast, the biggest bottleneck is the transport through the apoplast or dead spaces between the cells (Palmgren et al., 2008).
Transport of Zn from soil to various parts of plants before finally reaching to grains.
Adapted from Khan and Malik (2022).
Zn is taken up by roots primarily as Zn2+ ion from the soil solution, which is translocated in the plants either as bound to organic acids, Zn2+, or Zn(OH)2. Two mechanisms promote the uptake of Zn2+ in the rhizosphere. One through root exudation of various low molecular weight organic anions including organic acids (oxalate) and metal chelators (phytosiderophores or phytometallophores) (Hoffland et al., 2006). These compounds form complexes with Zn and transport them to the outer face of the root-cell plasma membrane. The second mechanism is the mobilization through acidification of rhizosphere using plasma membrane H+-ATPases, proton pumps. The increase in the proton concentration in rhizospheric soil results in the release of divalent metal ions tightly bound to soil particles through cation exchange. Upon reaching the plasma membrane, Zn2+ binds to proteins with a high affinity to Zn and is transported into the cells. These proteins include metal transporters of the ZIP family and are thought to be the primary uptake systems for Zn in plants. The information on ZIP proteins and other proteins involved in Zn transport has been reviewed by Palmgren and colleagues, Solen and Palmgren, and Ishimaru and colleagues (Olsen and Palmgren, 2014; Palmgren et al., 2008). Zn then enters into xylem parenchyma cells through diffusion and is actively transported out of the symplast into the dead xylem using ATP-dependent heavy metal pumps. From the xylem it is transported into the leaves from shoot through vessel-associated cells in the leaves. Metal ions are remobilized and are exported from leaves into the fruit via the phloem to the fruit. The Zn is subsequently taken up into the developing seed by specialized metal transport proteins. Zn ions leave the symplast twice during translocation from the root into the grain, first, when it is transported from root cells into the xylem, also called xylem loading, and second, when the Zn is transported from phloem into the fruit, called phloem unloading). Among the two processes, the latter is the bottleneck. Therefore, one of the problems is that the movement of Zn from soil to the root surface which can be facilitated by root exudates or by adding siderophore and acid-producing microbial inoculants. Another problem is the translocation of Zn in the plants and its accumulation into the seeds. The problem can be improved through developing Zn efficient varieties of the plants.
3.1.6 Developing Zn efficient varieties through breeding and molecular biology approaches
Developing Zn efficient plant varieties producing Zn dense grains is one of the approaches to address the problem of Zn deficiency. Plant breeding is a low-cost approach to develop such varieties. The breeding programs are mainly being carried out on five main crops (beans, cassava, maize, rice, and wheat) for improving micronutrient deficiency (iron, Zn, and β-carotene). The breeding generally includes the selection of parents with desirable traits, which is followed by the long-term crossing and back-crossing between the selected parents. And finally, the stability of the desirable traits in the offspring variety obtained through these crosses under various soil and climatic conditions is checked. If found successful, a variety can be adapted for cultivation. For example, parent varieties with high Zn efficiency should be selected to produce varieties with Zn dense grains. Various varieties of plants are known to have different grain Zn content. In maize, the grain Zn content of different varieties was found to vary by 50% of the mean value. Breeding approaches have been successfully used to increase the Zn content of the grains. A variety of wheat having improved Zn content was developed under one such program at the Waite Agricultural Research Institute of the University of Adelaide, Australia, and it is being used successfully (Bouis, 2003). Maize inbreds exhibiting 32–78% more grain Fe and 14–180% more grain Zn were developed in a similar program at the International Institute of Tropical Agriculture, Nigeria (Menkir, 2008). A several-fold increase in grain Fe and Zn of disomic hexaploid bread wheat has also been reported (Velu et al., 2014). An iron- and Zn-biofortified Pearl Millet ICTP-8203 was developed in India and has been tested for treating Zn and iron deficiency (Huey et al., 2017).
Genetic engineering can also be used to develop plant varieties yielding Zn dense grains. In this approach, genes that in one way or other improve the ability of the plant to assimilate more Zn in grains or control factors that limit the Zn uptake by plant or control substances like phytate that interfere with the absorption of Zn by humans are targeted. Various genes have been identified, for example, It has been demonstrated that a stress-related NAC gene that regulates senescence improves grain Zn and iron content in wheat (Uauy et al., 2006). Transgenic plants with high grain Zn content have been successfully engineered. Trijatmiko expressed rice nicotianamine synthase (OsNAS2) and soybean ferritin (SferH-1) genes, which resulted in a high Zn and Fe concentration in the endosperm (Trijatmiko et al., 2016). In another study of transgenic rice plants with the ability to produce nicotianamine and 2′-deoxymugenic acid (DMA), a metal chelator was developed for increased metal uptake. The resulting rice plants accumulated up to two times more Zn and four times more iron in their endosperm, significantly improving their nutritional quality (Banakar et al., 2017). When the ferritin gene from soybeans was expressed in indica rice cultivar, plants exhibited higher ferritin levels and were found to contain a 1.54-times higher concentration of Zn and 2.54 times higher concentration of iron (Paul et al., 2014). Although an increased concentration of iron was targeted in this study, it also improved the Zn content of the grains. Molecular tools were also used to minimize grain phytate content as the higher phytate, or phytic acid concentration of grain interferes with the Zn absorption in the human intestine. Therefore, when the gene for phytate was inhibited using RNAi, it was found to reduce the phytic acid levels in the cereal grains. This reduced phytate content improved Zn absorption in the human intestine (Kumar et al., 2019b). Studies discussed above have successfully demonstrated that molecular biology approaches can be used to develop cereals with high Zn grain concentration. However, social acceptability, stability of the trait, and the possibility to lose naturally occurring varieties are some concerns associated with the use of genetically engineered plant varieties. Therefore, the social acceptability of crops developed through breeding programs is still higher than those developed through genetic engineering.
3.2 Strategies for alleviating Zn deficiency in humans
As discussed earlier primary reasons for Zn deficiency in humans include inadequate dietary intake, malabsorption of the Zn in the intestine, and special health conditions. This deficiency can be corrected through long-term dietary programs or short-term Zn supplementation programs for vulnerable groups like children, the elderly, and expecting mothers.
3.2.1 Solutions for inadequate dietary intake
An estimated 30% of the world population, or 1.1 billion people around the globe, are at the risk of Zn deficiency mainly due to the dependency on Zn poor diet. The recommended daily intake of Zn is 14 and 8 mg/day for men and women, respectively. These requirements cannot be met through the type of diet in the most affected regions. The populations in South Asian countries like India, Pakistan, and Sri Lanka have the lowest daily intake of Zn globally (Wuehler et al., 2005). Dependency on the inherently Zn poor cereals-based diet, low income, and widespread vegetarianism are some reasons for Zn deficiency's prevalence. Some of the currently used solutions to improve the diet's Zn status are dietary diversification and modification, Zn fortification of diet and reducing phytate content of the diet to improve its absorption in the intestine.
3.2.1.1 Dietary diversification
Diversification of diet targeting increased Zn uptake involves intake of Zn dense diet or food components that enhance Zn status of the diet or enhance its absorption in the intestine. Inclusion of Zn dense food, primarily animal proteins such as fish and meat, is highly recommended (Gupta, 2016; Hicks et al., 2019; Wuehler et al., 2005). Sulphur amino acids like cysteine and methionine produced during the digestion of animal proteins enhance Zn absorption significantly. Diversifying diet with red meat, fruits, and vegetables has been shown to reduce 6–10% mortality, compared with a reference diet in 2050 (Springmann et al., 2016). However, food diversification cannot be effectively implemented due to rampant poverty, food beliefs, and taboos in most affected regions. It has been recently pointed out that fish is probably one of the most suitable foods for solving the global micronutrient deficiency problem (Hicks et al., 2019; Wuehler et al., 2005). And at least a good supply of dried fish is probably feasible and economically viable (Gibson and Hotz, 2001). Furthermore, a cereal-based diet can be enriched with fish meals. The inclusion of 24 g of whole dried fish Usipa with bones increases Zn intake by 152% and can also alleviate Ca deficiency. Studies suggest that using a variety of cereals instead of one cereal can also improve the Zn content of the diet (Smith et al., 2019). Dairy products like milk and cheese can also serve as a good source of Zn, especially for children having low acceptability for fish and meat. The addition of spices and other Zn-dense herbs can also improve the Zn content of the diet. The addition of inexpensive materials like watermelon seeds with rice or wheat is also one of the economically feasible options. The use of fermented food reduces the food's phytate content and, hence, can enhance the Zn absorption in the intestine (Lönnerdal, 2000). It is the organic acids found in fermented food which promotes Zn absorption in the intestine.
3.2.1.2 Zn fortification of diet
Zn fortification of diet is also a possible option to improve the Zn intake. Zn can be added to salt and cereal flours. Many studies have examined the overall effect of the Zn fortification program on nursing mothers and children and have documented an improvement in health and serum Zn content (Das et al., 2013). Some countries have even made it mandatory to fortify food with Zn. For example, in Indonesia, the flour used for noodles is fortified with Zn (Brown et al., 2010; Kimura, 2013). Similarly, in Latin America the government encourages the Zn fortification of cereal flours (Brown et al., 2010).
3.2.1.3 Reducing phytate content to enhance Zn absorption
The Phytate content of the food is a significant factor as it interferes with Zn absorption in the intestine. Typically diet with a phytate: Zn molar ratio of>15 is considered a diet with low Zn bioavailability, like a diet high in unrefined cereal grains. The food with a phytate: Zn molar ratio of less than 10 is considered a diet with moderate Zn bioavailability such as Lacto‐ovo, ovovegetarian diet, or a mixed diet containing animal and/or fish protein. At the same time, diets low in cereal fiber are considered as high Zn bioavailability diets. Such diets generally have a phytate: Zn molar ratio of less than 5 (SAMMAN, 2007). Several methods can be used to reduce the phytate content of the diet. These include soaking of cereals in water, use of fermented food, germination of cereals to increase phytase activity, and the use of modified milling practices (Gibson and Hotz, 2001). Soaking reduces the phytate content through two mechanisms. Firstly, the water-soluble phytate like potassium or sodium phytate constituting 10–97% of total phytate, which is lost during soaking. Secondly, soaking the dry grains increases the overall enzymatic activity in the grains, including endogenous phytases (Gibson and Hotz, 2001). Soaking cereals and legumes like pulses is an effective method for reducing the phytate content in the grains. Germination also increases the endogenous enzymatic activity, including that of the phytases, and hence can help reduce the phytate content in the grains. The addition of germinated cereals to ungerminated cereals can also reduce the overall phytate content. The use of modified milling practices can also help in reducing the phytate content as phytic acid that is localized in the outer aleurone layer (e.g., wheat, rice, sorghum) or in the germ (e.g., maize) can be reduced by modifying milling practices (O’Dell et al. 1972). Careful milling can also reduce the dietary fiber content, which may enhance Zn absorption to some degree. For legumes like peas and beans, the cotyledons and not the seed coat contain the most phytate. Therefore, removing the coat will not solve the problem and will increase the phytate content. Fermented food also enhances Zn absorption in the intestine mainly due to two reasons. First, during fermentation, organic acids are produced that reduce the phytate content of the food (Eshaghi et al., 2019). The second is dry matter loss during fermentation as microbes degrade carbohydrates and protein (Nkhata et al., 2018). Animal proteins also play an important role in increasing the Zn absorption in the intestine, as detailed above.
3.2.1.4 Use of Zn supplements
Another solution for alleviating Zn deficiency is the use of Zn supplements. Supplementation refers to the consumption of chemical or pharmaceutical formulations of Zn not consumed as food. Chemical forms of Zn like Zn acetate, Zn carbonate, Zn chloride, Zn citrate, Zn gluconate, and Zn lactate can be used as Zn supplements. The choice will depend on parameters like water solubility, intragastric solubility, cost, and palatability. For example, compounds that have better water solubility are easily absorbed. Doses of different supplements are calculated based on a person's daily requirement, age, and health condition. Supplementation programs are beneficial for treating deficiency in the vulnerable population such as children and pregnant women within a shorter time period. Pregnant women require a comparatively higher daily intake that will be especially important for the fetus. Children also require regular Zn intake for proper growth and mental development and to sustain high growth rates. And very often, Zn requirements cannot be met, even with fortification or diversification of diet. Furthermore, children may not readily accept Zn-dense diets such as fish or meat. It is a practice now to recommend iron and folic acid supplements during pregnancy. The importance of Zn is also being realised and is being accepted globally by the scientific community and regulatory bodies like WHO and FAO. Strategies should be developed to monitor the Zn deficiency in vulnerable groups for a timely recommendation of Zn supplements. Supplementation programs can be of two types, preventive supplementation and therapeutic supplementation.
Preventive supplementation is referred to as the recommendation of Zn supplements for the vulnerable group to avoid any health condition caused by Zn deficiency. Zn intervention trials have shown the positive effect of Zn supplements (Bhutta et al., 1999; Bhutta et al., 2013; Lind et al., 2003; Wessells et al., 2018). These studies have confirmed the obvious benefits of preventive Zn supplementation programs for preventing diarrhea in young children (Wessells and Brown, 2012; Wuehler et al., 2005). However, the doses used vary from study to study and need standardization. International Zinc Nutrition Consultative Group IZiNCG currently recommends a dietary Zn intake in a range of 3–5 mg/d for 6–47 months old children and an upper limit range of 6–8 mg/d. Studies are required to confirm the efficacy and safety of these recommended doses. In expecting mothers, a 14% reduction in premature delivery was observed with preventive Zn supplementation (Hess and King, 2009). Zn supplementation in pregnancy was found to reduce the risk of preterm delivery in a study based on 17,000 women but did not affect the low birth weight (Ota et al., 2015; Wilson et al., 2018). In India, a reduction of 68% in mortality of small-for-gestation infants was observed in a study (Aggarwal, 2005). Zn supplement mediated improvement in the birth weight of the children, however is still highly debatable. The use of Zn supplements to cure a health condition caused by Zn deficiency is called therapeutic supplementation. Diarrhea in children is one of the most common health conditions which can be treated using Zn. Therapeutic Zn supplementation effectively decreased the duration of diarrhea among children in many trials (Bajait and Thawani, 2011).
Interestingly it was reported that children show reduced incidence of illness and a better weight gain at least two months following the use of supplements. UNICEF and WHO have recommended the therapeutic supplementation of Zn to manage episodes of diarrhea. Several low-income countries have already started using these guidelines. Another vulnerable group is elderly people, wherein Zn deficiency is now known to play a role in psychiatric and neurodegenerative disorders associated with old age. Recently published data suggest that Zn ions can be used to manage these disorders (Grabrucker et al., 2011).
4 Future directions
Joint global efforts by health workers, policymakers, and scientists are required to deal with the problem of Zn deficiency. International consensus is required on various issues related to Zn deficiency. Definition of Zn deficiency, daily recommended intake, doses for various age groups, and different health conditions must be defined clearly and with international consensus as different organizations define these parameters differently. Long-term dietary strategies must be designed for improving the Zn status of deficient populations through agricultural interventions. It is of immense importance to convince farmers of returns on investments through awareness programs. Such programs are also required for a vulnerable group of the population and primary health care workers. Various approaches have been recommended for improving dietary Zn, including diversification of diet to include Zn dense food like animal proteins or other ingredients like Zn rich spices. Many strategies can be implemented immediately, like including fish in the diet, addition of animal protein flour to a conventional cereal-based diet. However, affordability and acceptability are the major bottlenecks. It is of paramount importance to increase the Zn content of the cereal grains as the population suffering the most from Zn deficiency is mainly due to the dependency on a cereal-based diet. The amount of bioavailable Zn in a cereal-based diet can be improved by using a combination of cereals and soaking them before use. Breeding programs and molecular biology approaches have been used to develop plant varieties with Zn dense grains. However, the prevalence of Zn deficient soil requires Zn efficient varieties and strategies to improve the soil Zn status. Agronomic Zn biofortification programs can also help to improve the grain's Zn content. Improvement both in grain yield and grain Zn content has been reported following the use of Zn fertilizers. Some countries are already making policies to promote the use of Zn fertilizers, for example, Indian government is providing subsidies on Zn fertilizers to promote its use.
Nevertheless, problems inherent with the use of chemical fertilizers like soil pollution cannot be overlooked. Therefore, a better approach can be the use of microbial inoculants having obvious advantages over chemical formulations. The use of such inoculants-based Zn fertilizers has not been explored to its full potential yet. Effective Zn solubilizers with additional plant growth-promoting activities must be isolated and formulated as biofertilizers and tested in fields for their robustness and reproducibility.
Certain vulnerable groups such as children, the elderly, and expecting mothers will often require Zn supplementation as dietary diversification programs cannot achieve the goal in a short time. For children and expecting mothers, special strategies must be designed and implemented through a joint effort of health workers and policymakers. UNICEF and WHO are already recommending Zn supplements for vulnerable groups. Economically poor sections in countries like India, China, Pakistan, and African countries need special attention and should be included in the global programs. Zn fortification programs can provide some immediate relief to such an economically weaker population. Some countries like Indonesia have made it mandatory to fortify flour for noodles with Zn. Some Latin American countries are also encouraging the fortification of cereal flour. Food processing and enrichment techniques may also improve the Zn content of the diet. Phytate is a well-known inhibitory substance contributing to Zn malabsorption in the duodenum. Phytate in a cereal-based diet can be reduced by modifying milling practices, soaking, and germination of grains. Scientists through molecular biology approaches have also reduced the phytate content in the grains. Therefore, varieties of cereal crops with high Zn efficiency and reduced phytate content grown with Zn biofertilizers can improve the situation significantly and should be studied immediately.
5 Conclusions
Zn undeniably is a metal of life as it plays crucial roles in plant and human physiology. Its roles in processes basic for life are becoming increasingly clear, ranging from photosynthesis in plants to the brain's functioning in humans. Inadequate Zn supply in soil is causing decreased crop productivity and nutritional quality of the crops resulting in Zn depletion in food chain, consequently, affecting human health and reproductivity, claiming millions of lives, especially children, every year. The global socio-economic cost of Zn deficiency is expected to be in billions of dollars annually. This is due to the losses in crop productivity, increased medical cost, and DAILYs caused by the Zn deficiency. The cost can be so high that it accounts for 2–11% of the country’s GDP for some countries. To minimize these economic losses and loss of life, it is imperative to understand the problem's scale and convince stakeholders about the seriousness of the problem. Zn deficiency is caused by various reasons starting from the prevalence of Zn-deficient soil (30% of world soils) to the Zn malabsorption in humans. It is suggested that these problems should be grouped into three stages or categories, namely problems leading to Zn deficiency in soil (1), Zn deficiency in plants (2), and problems leading to Zn deficiency in humans (3). The main reasons for soil Zn deficiency include the unavailability of Zn in soil, insoluble forms of Zn in soil, and edaphic factors. Zn deficiency in soil can be corrected by adding Zn fertilizers to the soil, correcting edaphic factors, and using Zn biofertilizers. The Zn status of plants can be improved using the following approaches. (i) Designing easy methods/kits for the timely detection of Zn deficiency in plant tissues. (ii) Development of Zn efficient genotypes or varieties. (iii) Understanding the mechanism of Zn transport to the edible parts of the plants. (iv) Development of methods for minimizing components like phytate that interferes with Zn absorption in humans. The issues that need attention to improve Zn status in the human population are as follows. (i) Low dietary intake is one of the primary reasons for Zn deficiency in humans due to socioeconomic reasons, widespread poverty where a significant section of the world population cannot afford a Zn-rich diet. Much of the population is dependent on a cereal-based diet which is becoming increasingly Zn deficient. Infants, children, and expecting mothers constitute high-risk groups due to higher Zn demand. Short-term supplementation programs and long-term dietary diversification with economic approaches like dry fish flour can help correct the deficiency. (ii) Although serum Zn is a widely accepted method to detect Zn deficiency, the development of still easy and economical methods is a bottleneck for broader analysis and prevention. (iii) Investigations are required to understand how the absorption of Zn from the diet can be improved. The joint effort of policy-makers, scientists, agricultural scientists, farmers, dieticians, physicians, and others is required to deal with Zn deficiency. Various regulatory agencies and scientists also need to develop consensus on various aspects like defining a critical lower limit in soil with internationally approved easy-to-use methods. Correcting Zn deficiency will save millions of lives and add billions of dollars to the world economy through increased crop productivity and reduced medical costs.
Acknowledgement
Authors acknowledge the generous financial help provided by the MHRD, Govt. of India, under the Scheme for Promotion of Academic and Research Collaboration (SPARC; P594).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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