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Effects of PCB70 and PCB75 on HeLa cell proliferation, membrane integrity and cell signaling pathway
⁎Corresponding authors. hshamari@kisr.edu.kw (Hassan Alshemmari), hashmi_qau@yhoo.com (Muhammad Zaffar Hashmi) zaffar.hashmi@comsats.edu.pk (Muhammad Zaffar Hashmi)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Polychlorinated biphenyls (PCBs) are persistent pollutants and pose toxic effects to humans and environment. In the current study, we focused to assess the effects of PCBs congeners (PCB70 and PCB75) upon HeLa cells using different concentrations (10-3, 10-2, 1, 10 and 15 µg/mL) and time (12, 24 and 48 h). The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay revealed that PCB70 and PCB75 induces cell proliferation at low doses (10-3, 10-2 and 1 µg/g) and inhibit the proliferation at high doses (10 and 15 µg/g) with different time suggesting cytotoxicity. The HeLa cells were analyzed for quantification of membrane integrity and it is found that PCB70 did not cause deformity in membrane integrity. However, PCB75 showed to cause deformity in membrane integrity in dose and time dependent manners. The results from western blot assay demonstrated that PCB70 and PCB75 exposure induced the expression of extracellular signal regulated-kinases (ERK1/2) and Jun N-terminal kinases (JNK) in dose- and time-dependent manners in the HeLa cells. The findings might provide mechanistic insight of PCB congeners induced cytotoxicity to HeLa cells.
Keywords
PCBs
Coplanar
Noncoplanar
Hormesis
Oxidative stress
HeLa cells
MAPK
1 Introduction
Polychlorinated biphenyls (PCBs) and variegated group of their congeners have widely been known as widespread environmental toxicants (McKinney and Waller, 1994; Wolff et al., 1997). Extensive use of PCBs were extensively employed in 1920 s in industrial processes (Ross, 2004; Safe, 1994) until their production was terminated in late 1980 s. As a result, large quantities of PCBs were released into the environment worldwide and unintentional industrial by-products such as electronic products, fossil fuel burning and other combustion processes have largely contribute to PCB contamination (Grimm et al., 2015). With the wide recognition of their diverse physical properties such as these chlorinated hydrocarbons are persistent and non-biodegradable in nature (Tanabe et al., 1987). Furthermore, they are persistent and their tendency to accumulate in wide range of media including biotic (human milk, adipose tissue, fish and wildlife) and abiotic (air, water, soil and sediment) components (Awad et al., 2016; Marek et al., 2013; Ueno et al., 2007), exponentially bio magnify in the food chain and made them undergo transboundary movement, reaching far destinations or in polar regions and the deep ocean (Gutleb et al., 2010). Thus, due to their specific characteristics, they are identified worldwide for international actions which are attributable to raise concerns over their potential toxicity.
In toxicological perspective, polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are agonists of the cytoplasmic aryl hydrocarbon receptor (AhR). PCBs are classified into two major structural classes named as co-planar or non-ortho substituted PCBs which are dependent-AhR agonism (Howard et al., 2003) and non-coplanar or ortho‐substituted PCBs which are independent-AhR agonism (Kietz and Fischer, 2003). However, these responses may alter depending upon the degree of chlorination and the position of chlorine substituents (Safe, 1994; Van den Berg et al., 2006). Epidemiologic studies suggest that the adverse effects mediated by PCBs are of particular concern as they are known to have detrimental effects by causing perturbations of the immune, reproductive, nervous and endocrine systems as well as oncogenic effects (Grandjean et al., 2001; Harper et al., 1995; Heilmann et al., 2010; International Agency for Research on et al., 1987; Winneke et al., 1998). It has also been revealed that structure-dependent toxicities and their mechanism of action includes the induction of changes in gene expression, formation of reactive oxygen species, the induction of oxidative damage, DNA-damage signaling pathways and effects on intercellular communication to various extents and through different pathways (Al-Anati et al., 2009). In this regard, the toxicity of PCB congeners may clearly occur through multiple mechanisms which can be used to determine their relative effective potency values.
More recently, oxidative stress is recognized as a well-accepted paradigm and through this mechanism, PCBs may alter cell growth, proliferation (Hassoun et al., 2002; Hennig et al., 2002; Twaroski et al., 2001; Venkatesha et al., 2008), membrane fluidity (Tan et al., 2004), cell death (De et al., 2010) and stress responsive signal transduction cascades such as mitogen-activated protein kinases (MAPKs) pathways. The MAPK plays a key role in various cellular events including cell survival and cell death (Cagnol and Chambard, 2010). Recent literatures have reported the activation of ERK1/2 and JNK pathways by some environmental toxicants including the PCBs are generally associated with cell proliferation and growth as well as growth arrest and apoptosis, respectively (Cagnol and Chambard, 2010; Xia et al., 1995). However, detailed knowledge of the mechanism induced by xenobiotic compounds including PCBs is still not elucidated fully. Thus, in order to identify possible mechanism with focus on oxidative stress, HeLa cells are used to investigate dose- and time-dependent toxicological effects of PCBs congeners. Nevertheless, HeLa cell lines are widely used, readily accessible and easily studied resource for research into cellular processed linked to normal and diseased cells (Frattini et al., 2015).
Based on the hormesis, a well-suited model to investigate cytotoxic effects that could be extensively used to elucidate a metabolically integrated and coherent cellular actions in response to biological stress (Calabrese et al., 2007), the present study aims to identify the hormetic role of PCB70 (2,3′,4′,5-Tetrachlorobiphenyl), mono-ortho chlorinated, coplanar congener and PCB75 (2,4,4′,6-Tetrachlorobiphenyl), ortho-chlorinated, non-coplanar congener disruption as potential prelude on HeLa cells disturbance in the respect of cell viability, membrane fluidity and the underlying intracellular MAPKs signaling cascade through induction of extracellular signal regulated kinases (ERK1/2) as well as the c-Jun N-terminal kinase (JNK) pathway which are urgently needed to set a benchmark for guideline thresholds for human health and safety and is the very important first step in environmental risk evaluations.
2 Methods
2.1 Chemicals
The PCBs (PCB70 and PCB75) were purchased from Accustandard (New Haven, CT) and PI/RNase staining buffer from BD Pharmingen (San Diego, CM). The HeLa cells were obtained from Shanghai Institute of Cell Biology, Chinese Academy of Sciences (Shanghai, China). The chemicals were dissolved in dimethyl sulfoxide (DMSO) to prepare stock solutions for later use. The final concentration of DMSO was ≤ 0.2% (vol/vol).
2.2 Cell line
Human carcinoma (HeLa) cell line was cultured in petri dish containing Dulbecco’s Modified Eagle Medium (DMEM), containing 10% (vol/vol) fetal calf serum (FCS), penicillin (100 units/mL) and streptomycin (100 µg/mL). The cells were kept in a humidified incubator at 37 °C and 5% CO2 atmosphere conditions.
2.3 Cell viability assay
For cell viability determination, the 3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay was followed. Briefly, 96-well flat-bottomed microtiter plates were plated with HeLa cells at a strength of 1 × 104 cells overnight before treatment with PCBs (50, 100, 200 and 400 μM) for 12, 48 and 72 h, respectively. Afterwards, to each well about 20 μL of the MTT solution (5 mg/mL) was poured and plates were then incubated at 37 °C for 4 h. After which the supernatant was collected and mixed in 100 mL of DMSO to dissolve the insoluble formazan product. Finally, the absorbance of each sample was noted at a wavelength of 570 nm using a SpectraMax Plus 384 Microplate Reader.
2.4 Flow Cytometry/Fluorometric assay
The disruption of plasma membrane integrity was determined by propidium iodide (PI) fluorometry, this assay depicted low and high fluorescence for healthy cells and disrupted cells (Tan et al., 2003). Briefly, the HeLa cells were firstly washed with phosphate buffer solution (PBS) twice and then incubated with 0.5 mL of PI/RNase staining buffer for 5 min. Afterwards the fluorescence was determined via flow cytometer. Fluorescence output of single cells was determined with a FACSCalibur flow cytometer. For each condition, fifteen thousand events were observed to ensure monitoring of live cells using the CELLQuest software.
2.5 Protein expression
The protein expression was determined through western blot analysis. Initially, the cells were treated with PCB70 and PCB75 with range of concentrations overnight, then cell lysing was performed in ice cold buffer containing 300 mL of 50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 50 mM NaF, 1 mM Na3 VO, 5 mM NaF EDTA, 50 mM NaPPi, 1 mM PMSF, 1 mM DTT, 5 mg/mL leupeptin, 2 mg/mL aprotinin and 1% NP-40. The lysates were then centrifuged at 12,000 g for 30 min at 48 °C. After which the supernatants were collected and the protein content was determined following Bradford assay (Bio-Rad Laboratories, Hercules, CA). The extracts were subjected to electrophoresis in 10% SDS-polyacrylamide gel, followed by transfer to a nitrocellulose membrane (Hy-bond-ECL; Amersham Pharmacia Biotech, Buckinghamshire, UK). After blocking with 5% nonfat dry milk for 1 h at room temperature, the membrane was exposed overnight at 4 °C with a specific primary antibody (1:000 dilution, vol/vol) and then exposed for 2 h with the secondary antibody (1:5000 dilution, vol/vol). The immune reactive bands were visualized with densitometry and the β-actin (Cell Signaling Technology, Beverly, MA) expression was used as an internal loading control for protein expression normalization. For the densitometric analysis, the protein bands were measured by Quantity One software. Each experiment is representative of three replicates.
2.6 Statistical analysis
The data is expressed as mean ± standard deviation. For comparison among treatment groups, one-way analysis of variance (ANOVA) was applied. Whereas the significant difference among two groups was then checked through Dunnett’s test. All experiments were repeated at least in triplicate and a value of p < 0.05 was considered significant.
3 Results
3.1 Cell proliferation
Upon examining the dose response for PCB70 and PCB75 effects in the HeLa cells model, we used a MTT test for cell proliferation evaluation (Fig. 1A, B). The cells were exposed to PCB congeners at dose concentrations 10-3, 10-2, 1, 10 and 15 µg/mL for 12, 24 and 48, hours. In the initial phase, the results of the cell proliferation test for both congeners indicated that the most obvious increase in proliferation at concentration dose 10-3, 10-2 and 1 µg/g for 12, 24 and 48 hrs in comparison to the DMSO-treated control cells. However, during the late phase, applying 10 and 15 µg/g in time dependent manner robustly suppressed the proliferation which may be attributed to cytotoxicity induced by PCBs congeners. Furthermore, biphasic dose–response phenomenon indicated that PCB75 was a more efficient inducer of reduced proliferation in HeLa cell over the exposure as compared to PCB70. Collectively, these data confirm an intrinsic and profound role of PCBs effects in HeLa cell proliferation via hormetic approach.
Schematic representation depicting cell viability (A), PCB70 induces cell proliferation (B), PCB75 induces cell proliferation under different concentration doses (Control (DSMO), t1 (0.001), t2 (0.01), t3 (1), t4 (10), t5 (15) µmg/mL) for (12, 24 and 48 h). Data are expressed as means ± SD of three experiments.
3.2 Fluorescence intensity promotes membrane alteration
Next, to confirm the changes in membrane integrity, we determined the fluorescence signals by exposing HeLa cells to two PCB congeners and observed significant differences in membrane fluidity (Fig. 2A, B). The cytoplasmic membrane owing to its location is highly vulnerable to injury caused by external environment. Its integrity is critical in maintaining the cell viability and physiological functions under stressed environment, particularly under stress (Denich et al., 2003). Xenobiotics such as PCBs are lipophilic and have negative effects on cell membranes and alter the membrane structure and functions (Donato et al., 2000). To better study the membrane physiology in response to stress, fluorescence polarization method for quantitative relative measurement in fluidity of the cytoplasmic membrane has been used to study different environmental conditions (Hazel, 1990). The sensitivity, specificity, ease and role in bio membrane structure and functions of fluorescence polarization methods make it suitable for studying different aspects of cell responses. Subsequently, the results of this study showed the PI fluorescence accumulation were significantly dose-time dependently increased at 12, 24 and 48 hrs at comparable concentrations to PCB70 and PCB75. After incubation with different dose concentrations and time duration to PCB70, the fluorescence polarization had no fluctuations in the membrane fluidity compared to the DMSO control indicating that membrane alteration did not happened against coplanar congeners including PCB70 stress. However, a very rapid effect, being most prominent at dose concentration at 1, 10 and 15 at any time period after treatment with PCB75 reflecting PI fluorescence accumulation has been shown to damage membrane, disrupt intracellular containment and consequently decrease cell viability; thereby suggesting that ortho-substituted PCBs may disrupt membrane structure and function in a relatively nonspecific mode.
Schematic representation depicting membrane potential (A), PCB70 induces membrane potential (B), PCB75 induces membrane potential under different concentration doses (Control (DSMO), t1 (0.001), t2 (0.01), t3 (1), t4 (10), t5 (15) µmg/mL) for (12, 24 and 48 h).
3.3 The role of ERK1/2 and JNK
Finally, to confirm the involvement of PCB congeners in the apoptotic cascade, we investigated the expression of signal transduction proteins such as such as ERK1/2 and JNK which reported to have a crucial role in the regulation of cell cycle, migration, cell survival, differentiation, metabolism, proliferation, and transcription as well as apoptosis and stress (Fei et al., 2015; Lu et al., 2016; Wei et al., 2014). The western blotting was performed to determine the effects of PCB70 and PCB75 on MAPK signaling pathways in HeLa cells by following different dose concentrations for 12 and 24 h and data presented in (Fig. 3A, B). It is noteworthy to mention that after short exposures, various chemicals including phenolics, antioxidants and some PCBs may activate MAPKs (Canesi et al., 2003; Frigo et al., 2004; Slim et al., 2000). In the similar context, our results indicated that PCB70 and PCB75 exposure at dose concentration 10-3, 10-2 µg/mL for 12 and 24 h did not cause a significant change in the level of JNK, p-JNK, ERK1/2, p-ERK1/2. However, the apoptotic proteins signal was significantly upregulated at concentration 1, 10 and 15 µg/mL in time dependent manner for both congeners indicating the cytotoxic effects of PCB congeners by activating MAPK in response to apoptosis in HeLa cells.
Schematic representation depicting protein expression (A), PCB70 induces expression of JNK and ERK1/2 proteins (B), PCB75 induces expression of JNK and ERK1/2 proteins under different concentration doses (Control, 0.001, 0.01, 1, 10, 15) µmg/mL) for (12 and 48 h). Data (n = 3 for each group) were analyzed by one-way ANOVA followed by Student’s t-test. β-actin protein was used as the control.
4 Discussion
PCB caused heterogeneous effects on humans depending upon involved congeners, types of cells affected, the extent of exposure and genetic predisposition (Grimm et al., 2015). Generally, PCBs exposure-induced toxicity may be mediated through oxidative stress and has been linked to range of adverse effects from immunotoxicity and carcinogenesis to apoptosis (Safe, 1993). Cell death and proliferation are considered as therapeutically tractable mechanism which control the homeostatic balance (Chan et al., 2015). Various studies have demonstrated that PCBs though different mechanisms are capable of inducing apoptosis in different types of cells (Ghosh et al., 2010; Sánchez-Alonso et al., 2003). It is well reported that cells that experience apoptosis undergo different structural and functional changes which do not always occur simultaneously. Therefore, to understand independent and dependent cell death, different methods were employed with special care. Concomitantly, our results indicated dose–response linkage between the effects of two tetra-substituted congener (PCB70 and PCB75) in HeLa cells. Using MTT assay, we established that the lowest doses at which cell proliferation were linked to stimulatory effects and the highest doses in time dependent manners linked to inhibitory effects in response to PCB70 and PCB75 suggesting the cytotoxic effects on HeLa cells viability. Overall, this result provided a hormetic means of oxidative stress-induced cell proliferation which are aligned with previous results indicating altered cell growth and proliferation due to oxidative stress induced by PCBs (Glauert et al., 2008; Hassoun et al., 2002; Hennig et al., 2002; Köhle et al., 1999; Twaroski et al., 2001; Venkatesha et al., 2008).
The plasma membrane act as interface between cell and its external environment by providing platform for transmembrane signaling and trafficking. However its performance greatly depends on membrane hardness and flexibility which ultimately is influenced by composition of membrane and linkages with external environment and the cytoskeleton (Escriba et al., 2008). More importantly, PCBs are highly lipophilic substances which are readily store in cell membranes as body fats in animals and humans (Steck, 1974). Consequently, changes in environmental conditions such as temperature (Li et al., 2011; Schoug et al., 2008) pH, pressure (Hua et al., 2009; Zhao et al., 2009) and chemical content including PCBs (Raff and De Petris, 1973; Woodson et al., 1976) causes morphological and biochemical changes in cell membrane leading to loss of membrane integrity and permeability (Marielle and Sarrah, 2017). Here, our data convincingly shows dose and time-dependent disruption of membrane integrity caused by PCB75, while PCB70 did not elicited membrane alteration. This study concluded that compared to non-ortho-substituted coplanar PCBS, ortho-substituted non-coplanar congeners seems to evoke detrimental effects on cell membrane integrity. These findings correlate well with previous finding which suggests the membrane fluidity was affected by PCB153, but not by PCB 77 in renal tubular cells in rat (Lopez-Aparicio et al., 1997), PCB40 showed a greater disruption than PCB77 in HELF cells (Hashmi et al., 2017), PCB52 showed potent actions than PCB54 in rat hepatocytes (Nishihara and Utsumi, 1986), PCB8, PCB28, PCB47 and PCB52 showed effects on membrane integrity as compared to PCB77, PCB80 and PCB81 in cerebellar granule cells (Tan et al., 2004).
It is well reported that MAPK cascades functions to regulate cell stability and multiple physiological processes under environmental stress. The general functions of ERK1/2 includes cell proliferation and growth as well as apoptosis (Cagnol and Chambard, 2010). The external stress conditions including genotoxic substances, cell growth suppressers, apoptosis and cytokines stimulates the JNK and p38 pathways (Xia et al., 1995). However, it has been seen that to control different cell processes under stress conditions, the MAPK cascade is activated in more complex manner (Chuang et al., 2000). The current study have demonstrated the activation ofERK1/2 and JNK phosphorylation in response to PCB70 and PCB75 in different time-course and dose–response profiles. Intriguingly, our results indicated that PCB-induced oxidative stress which is likely the means of upstream signal of MAPK cascades including JNK and ERK1/2. Taking into account the close relationship of PCB and associated oxidative stress, the current study provides new insight into molecular events involved in apoptosis induction in Hela cells by PCBs. These observations are aligned with previous results showing that PCB congeners are capable of activating MAPKs as prominent intracellular signaling event (Liu et al., 2012; Liu et al., 2015; Song, 2005).
5 Conclusion
In conclusion, the present study investigated hormetic dose response-induced intracellular oxidative stress and molecular mechanism for PCB70 and PCB75 on HeLa cells. Firstly, the variation of proliferation was seen in HeLa cells as it is found that cell proliferation stimulated /suppressed at low and high doses respectively indicating mechanistic link between PCB toxicity and cellular oxidative stress in HeLa cells. Conversely, based on toxic profile of PCB congeners, our data showed relative changes in membrane fluidity by PCB75 (noncoplanar) suggesting that ortho-substituted congeners have high potency for disruption of membrane integrity. Finally, PCB congeners induced oxidative stress that ultimately causes activation of ERK1/2 and JNK activity indicating stress signals into the HeLa cells which ultimately shown to be linked with apoptosis. In summary, these findings elicited novel compensatory mechanism at low doses and inhibitory mechanism at high doses which influencing the normal redox balance and ultimately leads to apoptosis, thereby contributing potential prelude for the risk assessment of PCBs toxic potency in HeLa Cells.
Acknowledgement
We extend special thanks to Higher Education Commission of Pakistan NRPU projects 7958 and 7964. The author also thanks to Pakistan Science Foundation project PSF/Res/CP/C-CUI/Envr (151).
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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