Differential DNA methylation and metabolite profiling of Atlantic killifish (Fundulus heteroclitus) from the New Bedford Harbor Superfund site.

Atlantic killifish (Fundulus heteroclitus) is a valuable model in evolutionary toxicology to study how the interactions between genetic and environmental factors serve the adaptive ability of organisms to resist chemical pollution. Killifish populations inhabiting environmental toxicant-contaminated New Bedford Harbor (NBH) show phenotypes tolerant to polychlorinated biphenyls (PCBs) and differences at the transcriptional and genomic levels. However, limited research has explored epigenetic alterations and metabolic effects in NBH killifish. To identify the involvement of epigenetic and metabolic regulation in the adaptive response of killifish, we investigated tissue- and sex-specific differences in global DNA methylation and metabolomic profiles of NBH killifish populations, compared to sensitive populations from a non-polluted site, Scorton Creek (SC). The results revealed that liver-specific global DNA hypomethylation and differential metabolites were evident in fish from NBH compared with those from SC. The sex-specific differences were not greater than the tissue-specific differences. We demonstrated liver-specific enriched metabolic pathways (e.g., amino acid metabolic pathways converged into the urea cycle and glutathione metabolism), suggesting possible crosstalk between differential metabolites and DNA hypomethylation in the livers of NBH killifish. Additional investigation of methylated gene regions is necessary to understand the functional role of DNA hypomethylation in the regulation of enzyme-encoding genes associated with metabolic processes and physiological changes in NBH populations.

In Vitro Cell Transformation Assays: A Valuable Approach for Carcinogenic Potentiality Assessment of Nanomaterials.

This review explores the application of in vitro cell transformation assays (CTAs) as a screening platform to assess the carcinogenic potential of nanomaterials (NMs) resulting from continuously growing industrial production and use. The widespread application of NMs in various fields has raised concerns about their potential adverse effects, necessitating safety evaluations, particularly in long-term continuous exposure scenarios. CTAs present a realistic screening platform for known and emerging NMs by examining their resemblance to the hallmark of malignancy, including high proliferation rates, loss of contact inhibition, the gain of anchorage-independent growth, cellular invasion, dysregulation of the cell cycle, apoptosis resistance, and ability to form tumors in experimental animals. Through the deliberate transformation of cells via chronic NM exposure, researchers can investigate the tumorigenic properties of NMs and the underlying mechanisms of cancer development. This article examines NM-induced cell transformation studies, focusing on identifying existing knowledge gaps. Specifically, it explores the physicochemical properties of NMs, experimental models, assays, dose and time requirements for cell transformation, and the underlying mechanisms of malignancy. Our review aims to advance understanding in this field and identify areas for further investigation.

Developmental trajectory of Caenorhabditis elegans nervous system governs its structural organization.

A central problem of neuroscience involves uncovering the principles governing the organization of nervous systems which ensure robustness in brain development. The nematode Caenorhabditis elegans provides us with a model organism for studying this question. In this paper, we focus on the invariant connection structure and spatial arrangement of the neurons comprising the somatic neuronal network of this organism to understand the key developmental constraints underlying its design. We observe that neurons with certain shared characteristics-such as, neural process lengths, birth time cohort, lineage and bilateral symmetry-exhibit a preference for connecting to each other. Recognizing the existence of such homophily and their relative degree of importance in determining connection probability within neurons (for example, in synapses, symmetric pairing is the most dominant factor followed by birth time cohort, process length and lineage) helps in connecting specific neuronal attributes to the topological organization of the network. Further, the functional identities of neurons appear to dictate the temporal hierarchy of their appearance during the course of development. Providing crucial insights into principles that may be common across many organisms, our study shows how the trajectory in the developmental landscape constrains the structural organization of a nervous system.

Integrated approach of eco-epigenetics and eco-metabolomics on the stress response of bisphenol-A exposure in the aquatic midge Chironomus riparius.

The stress response mechanisms of Bisphenol A (BPA), an endocrine disrupting compound, remain to be elucidated. In this study, we explored the effects of BPA on the non-biting midge Chironomus riparius through basic ecotoxicity assays, DNA damage (comet assay), eco-epigenetics (global DNA and histone methylations) and non-targeted global metabolomics (NMR based) approaches. The reproduction failure, increase in DNA damage, global DNA hyper-methylation, and increased global histone modification (H3K36) status were evident due to BPA exposure at 10% lethal concentration (LC10: 1 mg/L, based on 48 h acute toxicity). Moreover, non-targeted global metabolomics followed by pathway analysis identified alterations of energy metabolism, amino acids, and methionine metabolisms etc. Most importantly, we found a potential cross-talk between altered epigenetics and metabolites, such as, increase in methionine and o-phosphocholine metabolites corresponds with the phenomena of global hyper-methylation in DNA and H3K36 mark. Overall, our results suggests that the crosstalk of global metabolomics and epigenetic modification was fundamental of the underlying mechanisms in BPA-induced stress response in C. riparius.

In vitro transdifferentiation of human skin keratinocytes to corneal epithelial cells.

BACKGROUND AIMS: Skin keratinocytes (SKs) share the same surface ectodermal origin as that of corneal epithelium. In this study, the plasticity of epidermal keratinocytes was exploited to generate corneal epithelial-like cells, which might serve as an alternative source of autologous tissue for the treatment of bilateral limbal stem cell deficiency. METHODS: Skin samples were subjected to collagenase digestion to isolate SKs and transdifferentiated to corneal epithelial-like cells using limbal fibroblast conditioned medium (LFCM). SKs and transdifferentiated corneal epithelial cells (TDCECs) were characterized using immunofluorescence and fluorescence-activated cell sorting. The propensity for expression of angiogenic genes in TDCECs was compared with cultured oral mucosal epithelial cells (COMEC) in vitro. RT(2) quantitative polymerase chain reaction profiler array was performed to study the signaling pathways involved in the transdifferentiation process. RESULTS: The TDCECs obtained from SKs showed corneal epithelial-like morphology and expressed corneal epithelial markers, CK3 and CK12. Hematoxylin-eosin and immunohistochemistry showed stratified layers of TDCECs expressing CK 3/12, confirming the corneal epithelial phenotype. We found that the expression of several angiogenic and epithelial mesenchymal transition factors were down-regulated in TDCECs compared with COMEC, suggesting a lower capacity to induce angiogenesis in TDCECs. There was considerable difference in the signaling mechanisms between TDCECs and SKs on testing by RT(2) profiler array, signifying differences at the global gene profile. The comparison of TDCECs and limbal derived corneal epithelial cells showed similar gene expression. DISCUSSION: Our study shows that SKs have the potential to transdifferentiate into corneal epithelial-like cells using LFCM.

Endocannabinoids affect innate immunity of Muller glia during HIV-1 Tat cytotoxicity.

In the retina, increased inflammatory response can cause visual impairment during HIV infection in spite of successful anti-retroviral therapy (HAART). The HIV-1 Tat protein is implicated in neurodegeneration by eliciting a cytokine response in cells of the CNS, including glia. The current study investigated whether innate immune response in human retinal Muller glia could be immune-modulated to combat inflammation. Endocannabinoids, N-arachidonoylethanolamide and 2-arachidonoylglycerol are used to alleviate Tat-induced cytotoxicity and rescue retinal cells. The neuroprotective mechanism involved suppression in production of pro-inflammatory and increase of anti-inflammatory cytokines, mainly through the MAPK pathway. The MAPK regulation was primarily by MKP-1. Both endocannabinoids regulated cytokine production by affecting at the transcriptional level the NF-κB complex, including IRAK1BP1 and TAB2. Stability of cytokine mRNA is likely to have been influenced through tristetraprolin. These findings have direct relevance in conditions like immune-recovery uveitis where anti-retroviral therapy has helped immune reconstitution. In such conditions drugs to combat overwhelming inflammatory response would need to supplement HAART. Endocannabinoids and their agonists may be thought of as neurotherapeutic during certain conditions of HIV-1 induced inflammation.

Potential toxicity of differential functionalized multiwalled carbon nanotubes (MWCNT) in human cell line (BEAS2B) and Caenorhabditis elegans.

The aim of this study was to evaluate in vitro (human bronchial epithelial cells, BEAS2B cells) and in vivo (the nematode Caenorhabditis elegans, C. elegans) toxicity outcomes following exposure to pristine as well as surface-functionalized multiwalled carbon nanotubes (MWCNT) following hydroxylation-oxygenation (O(+)), amination (NH2), or carboxylation (COOH) of the carbon nanotubes (CNT). Cell viability and proliferation were measured by Ez-Cytox, trypan blue exclusion, and colony formation assays. The genotoxic potential of the MWCNT was determined by using the alkaline comet assay. In addition, survival and reproduction were used as endpoints for detection of toxicity of MWCNT in C. elegans. The carboxylated (COOH)-MWCNT was found most toxic as evidenced by cytotoxic and genotoxic among all tested compounds. The order of sensitivity was COOH > O(+) > NH2 > pristine. There were almost no marked changes in survival following exposure of C. elegans to MWCNT. It is of interest that only pristine MWCNT exerted significant reduction in reproductive capacity of C. elegans. Surface functionalization significantly influenced the bioactivity of MWCNT, which displayed species as well as target-organ specificity. The mechanisms underlying these specific modes of nano-biological interactions need to be elucidated.

Toxic potentiality of bio-oils, from biomass pyrolysis, in cultured cells and Caenorhabditis elegans.

Bio-oils, which are multicomponent mixtures, were produced from two different biomass (rice straw (rice oil) and sawdust of oak tree (oak oil)) by using the slow pyrolysis process, and chemical compositional screening with GC-MS detected several hazardous compounds in both bio-oil samples. The two bio-oils vary in their chemical compositional nature and concentrations. To know the actual hazard potentialities of these bio-oils, toxicological assessments were carried out in a comparative approach by using in vitro (Jurkat T and HepG2 cell) as well as in vivo (Caenorhabditis elegans) systems. A dose-dependent increase in cytotoxicity, cell death (apoptosis), and genotoxicity were observed in cultured cell systems. Similarly, the in vivo system, C. elegans also displayed a dose-dependent decrease in survival. It was found that in comparison with rice oil, oak oil displayed higher toxicity to all models systems, and the susceptibility order of the model systems were Jurkat T > HepG2 > C. elegans. Pursuing the study further toward the underlying mechanism by exploiting the C. elegans mutants screening assay, the bio-oils seem to mediate toxicity through oxidative stress and impairment of immunity. Taken together, bio-oils compositions mainly depend on the feedstock used and the pyrolysis conditions which in turn modulate their toxic potentiality.

HIV-1 Tat-Mediated Human Müller Glial Cell Senescence Involves Endoplasmic Reticulum Stress and Dysregulated Autophagy.

Antiretroviral treatments have notably extended the lives of individuals with HIV and reduced the occurrence of comorbidities, including ocular manifestations. The involvement of endoplasmic reticulum (ER) stress in HIV-1 pathogenesis raises questions about its correlation with cellular senescence or its role in initiating senescent traits. This study investigated how ER stress and dysregulated autophagy impact cellular senescence triggered by HIV-1 Tat in the MIO-M1 cell line (human Müller glial cells). Cells exposed to HIV-1 Tat exhibited increased vimentin expression combined with markers of ER stress (BiP, p-eIF2α), autophagy (LC3, Beclin-1, p62), and the senescence marker p21 compared to control cells. Western blotting and staining techniques like SA-ß-gal were employed to examine these markers. Additionally, treatments with ER stress inhibitor 4-PBA before HIV-1 Tat exposure led to a decreased expression of ER stress, senescence, and autophagy markers. Conversely, pre-treatment with the autophagy inhibitor 3-MA resulted in reduced autophagy and senescence markers but did not alter ER stress markers compared to control cells. The findings suggest a link between ER stress, dysregulated autophagy, and the initiation of a senescence phenotype in MIO-M1 cells induced by HIV-1 Tat exposure.

Differential impact of diesel exhaust particles on glutamatergic and dopaminergic neurons in Caenorhabditis elegans: A neurodegenerative perspective.

The growing body of evidence links exposure to particulate matter pollutants with an increased risk of neurodegenerative diseases. In the present study, we investigated whether diesel exhaust particles can induce neurobehavioral alterations associated with neurodegenerative effects on glutamatergic and dopaminergic neurons in Caenorhabditis elegans (C. elegans). Exposure to DEP at concentrations of 0.167 µg/cm2 and 1.67 µg/cm2 resulted in significant developmental delays and altered locomotion behaviour. These effects were accompanied by discernible alterations in the expressions of antioxidant genes sod-3 and gst-4 observed in transgenic strains. Behaviour analysis demonstrated a significant reduction in average speed (p < 0.001), altered paths, and decreased swimming activities (p < 0.01), particularly at mid and high doses. Subsequent assessment of neurodegeneration markers in glutamatergic (DA1240) and dopaminergic (BZ555) transgenic worms revealed notable glutamatergic neuron degeneration at 0.167 µg/cm2 (∼30 % moderate, ∼20 % advanced) and 1.67 µg/cm2 (∼28 % moderate, ∼24 % advanced, p < 0.0001), while dopaminergic neurons exhibited structural deformities (∼16 %) without significant degeneration in terms of blebs and breaks. Furthermore, in silico docking simulations suggest the presence of an antagonistic competitive inhibition induced by DEP in the evaluated neuro-targets, stronger for the glutamatergic transporter than for the dopaminergic receptor from the comparative binding affinity point of view. The results underscore DEP's distinctive neurodegenerative effects and suggest a link between locomotion defects and glutamatergic neurodegeneration in C. elegans, providing insights into environmental health risks assessment.

Mixture and individual effects of benzene, toluene, and formaldehyde in zebrafish (Danio rerio) development: Metabolomics, epigenetics, and behavioral approaches.

In this study, we aimed to investigate the potential hazards of volatile organic compounds (VOCs) on the development of zebrafish. To this end, zebrafish embryos were exposed in two different windows, either alone or in a mixture with VOCs (benzene, toluene, and formaldehyde) [EW1: 4 ± 2 h post-fertilization (hpf) to 24 hpf and EW2: 24 ± 2 hpf to 48 hpf]. Alterations in global DNA methylation and related gene expression, behavioral responses, and stress-related gene expression were observed. In addition to these endpoints, non-targeted NMR-based global metabolomics followed by pathway analysis showed significant changes in the metabolism of various amino acids during VOC exposure. Regardless of the analyzed endpoints, toluene was the most toxic chemical when exposed individually and possibly played the most pivotal role in the mixture treatment conditions. In conclusion, our data show that exposure to VOCs at embryonic developmental stages causes physiological perturbations and adverse outcomes at later life stages.

A Comparative Analysis of Heavy Metal Effects on Medicinal Plants.

Popularity of herbal drugs has always been in high demand, but recently it has been increasing all over the world, especially in India, because of the lower range of adverse health effects as compared to synthetic or man-made drugs. Not only this but their cost-effectiveness and easy availability to the poor people and the masses, particularly in developing countries, are major causes for their demand. But there lies a huge problem during the process of plant collection that affects their medicinal properties to certain degrees. This is caused by heavy metal toxicity in soil in different locations of the Indian subcontinent. This was correlated with their potential to cause health damage. Exposure of humans to heavy metals includes diverse pathways from food to water to consumption and inhalation of polluted air to permanent damage to exposed skin and even by occupational exposure at workplaces. As we can understand, the main mechanisms of heavy metal toxicity include the production of free radicals to affect the host by oxidative stress, damaging biological molecules such as enzymes, proteins, lipids, and even nucleic acids and finally damaging DNA which is the fastest way to carcinogenesis and in addition, neurotoxicity. Therefore, in this paper, we have researched how the plants/herbs are affected due to heavy metal deposition in their habitat and how it can lead to serious clinical complications.

Differential Expression of miRNA-192 is a Potential Biomarker for HIV Associated Immune Recovery Uveitis.

PURPOSE: Notwithstanding well-established clinical features of Immune Recovery Uveitis (IRU), specific diagnostic tools to identify at-risk patients are lacking. Identification of biomarkers for IRU prediction can allow high-risk patients to benefit from specific preventive strategies, development of therapies, and elucidate immune reconstitution associated pathogenesis. METHODS: HIV+ patients were classified into four groups (A, B, C and D) with and without ocular manifestations, with follow-up over a year. Patients' ocular parameters were examined and manifestations like uveitis and IRU noted. Selected miRNAs were investigated in PBMCs by using miRNA PCR assay. Bioinformatic analysis used miRNet to predict the targets of miRNA-192-5p and miRNA-543 and KOBAS for pathways. RESULTS: Hsa-miR-192-5p and hsa-miR-543 levels were measured by qPCR using RNA isolated from PBMCs of HIVinfected patients. Hsa-miR-192-5p and hsa-miR-543 were down regulated in patients exhibiting ocular manifestations. Our results showed hsa-miR-192-5p (Group B vs D p 0.007) and hsa-miR-543 levels in PBMCs reliably distinguish between HIV patients diagnosed with IRU. Both miRNAs target multiple genes involved in inflammatory pathways as predicted by bioinformatic analysis. CONCLUSION: Decreased expression levels of miRNA-192 in patients with ocular manifestations and IRU, could facilitate identification of the status of the disease in HIV patients.

Prediction of zebrafish embryonic developmental toxicity by integrating omics with adverse outcome pathway.

New approach methodologies (NAMs), especially omics-based high-throughput bioassays have been developed rapidly, providing rich mechanistic information such as molecular initiation events (MIEs) and (sub)cellular key events (KEs) in adverse outcome pathways (AOPs). However, how to apply the knowledge of MIEs/KEs to predict adverse outcomes (AOs) induced by chemicals represents a new challenge for computational toxicology. Here, an integrated method named ScoreAOP was developed and evaluated to predict chemicals' developmental toxicity for zebrafish embryos by integrating four related AOPs and dose-dependent reduced zebrafish transcriptome (RZT). The rules of ScoreAOP included 1) sensitivity of responsive KEs demonstrated by point of departure of KEs (PODKE), 2) evidence reliability and 3) distance between KEs and AOs. Moreover, eleven chemicals with different modes of action (MoAs) were tested to evaluate ScoreAOP. Results showed that eight of the eleven chemicals caused developmental toxicity at tested concentration in apical tests. All the tested chemicals' developmental defects were predicted using ScoreAOP, whereas eight out of the eleven chemicals predicted by ScoreMIE which was developed to score MIEs disturbed by chemicals based on in vitro bioassays data. Finally, in terms of mechanism explanation, ScoreAOP clustered chemicals with different MoAs while ScoreMIE failed, and ScoreAOP revealed the activation of aryl hydrocarbon receptor (AhR) plays a significant role in dysfunction of cardiovascular system, resulting in zebrafish developmental defects and mortality. In conclusion, ScoreAOP represents a promising approach to apply mechanism information obtained from omics to predict AOs induced by chemicals.

Endocannabinoids alleviate proinflammatory conditions by modulating innate immune response in muller glia during inflammation.

Muller cells play a prominent role in inflammatory conditions of the retina. They are part of the retinal innate immune response. The endocannabinoid system functions as an immune modulator in both the peripheral immune system as well as the central nervous system. We hypothesized that the neuroprotective ability of exogenous endocannabinoids in the retina is partially mediated through Muller glia. This study reports that exposure to endocannabinoids in activated but not resting primary human Muller glia inhibit production of several proinflammatory cytokines, while elevating anti-inflammatory mediators. Cytokine generation in activated Muller glia is regulated by endocannabinoids through the mitogen-activated protein kinase (MAPK) family at multiple signaling stages. Anandamide (AEA) acts to control MAPK phosphorylation through MKP-1. Both AEA and 2-arachidonoylglycerol (2-AG) inhibit the transcription factor NF-κB and increases the regulatory protein, IL1-R-associated kinase 1-binding protein 1. Endocannabinoids also increase expression of Tristetraprolin in activated Muller cells, which is implicated in affecting AU-rich proinflammatory cytokine mRNA. We demonstrate that exogenous application of AEA and 2-AG aid in retinal cell survival under inflammatory conditions by creating an anti-inflammatory milieu. Endocannabinoids or synthetic cannabinoid therapy may therefore orchestrate a molecular switch to bias the innate immune system suchthat the balance of pro- and anti-inflammatory cytokine generation creates a prosurvival milieu.

Nanosafety: An Evolving Concept to Bring the Safest Possible Nanomaterials to Society and Environment.

The use of nanomaterials has been increasing in recent times, and they are widely used in industries such as cosmetics, drugs, food, water treatment, and agriculture. The rapid development of new nanomaterials demands a set of approaches to evaluate the potential toxicity and risks related to them. In this regard, nanosafety has been using and adapting already existing methods (toxicological approach), but the unique characteristics of nanomaterials demand new approaches (nanotoxicology) to fully understand the potential toxicity, immunotoxicity, and (epi)genotoxicity. In addition, new technologies, such as organs-on-chips and sophisticated sensors, are under development and/or adaptation. All the information generated is used to develop new in silico approaches trying to predict the potential effects of newly developed materials. The overall evaluation of nanomaterials from their production to their final disposal chain is completed using the life cycle assessment (LCA), which is becoming an important element of nanosafety considering sustainability and environmental impact. In this review, we give an overview of all these elements of nanosafety.

CRISPR approach in environmental chemical screening focusing on population variability.

A significant barrier to include population variability in risk assessment is our incomplete understanding of inter-individual variability and the differential susceptibility to environmental exposures induced adverse outcomes. By combining genome editing tools with the population diversity model, this article intended to highlight a potential strategy to identify and characterize the inter-individual variability factors, the determinant gene anchoring to a particular phenotype. The goal could be achieved by integrating the perturbed CRISPR-based unbiased functional genomics screening, genome-wide or a focused subset of genes, in a population-based in vitro model system (such as the lymphoblastoid cell lines, LCL, available from HapMap and 1000 Genomes project). Then data can be translated to genetic variability and individual (or subpopulation) susceptibility by incorporating ethnicity and corresponding genome-wide association studies (GWAS) with functional genomics screening results. This approach can provide complementary data for next-generation risk assessment, in particular, for environmental stressors. The current paper outlined the previous work conducted with a population-based in vitro model system, perturbed CRISPR-based functional toxicogenomic screening of environmental chemicals, and finally, the potential strategies to combine these two platforms with their opportunities and challenges to achieve a mechanistic understanding of population variability.

Critical window of exposure of CMIT/MIT with respect to developmental effects on zebrafish embryos: Multi-level endpoint and proteomics analysis.

Systemic toxicity, particularly, developmental defects of humidifier disinfectant chemicals that have caused lung injuries in Korean children, remains to be elucidated. This study evaluated the mechanisms of the adverse effects of 5-chloro-2-methyl-4-isothiazoline-3-one/2methyl-4-isothiazolin-3-one (CMIT/MIT), one of the main biocides of the Korean tragedy, and identify the most susceptible developmental stage when exposed in early life. To this end, the study was designed to analyze several endpoints (morphology, heart rate, behavior, global DNA methylation, gene expressions of DNA methyl-transferases (dnmts) and protein profiling) in exposed zebrafish (Danio rerio) embryos at various developmental stages. The results showed that CMIT/MIT exposure causes bent tail, pericardial edema, altered heart rates, global DNA hypermethylation and significant alterations in the locomotion behavior. Consistent with the morphological and physiological endpoints, proteomics profiling with bioinformatics analysis suggested that the suppression of cardiac muscle contractions and energy metabolism (oxidative phosphorylation) were possible pivotal underlying mechanisms of the CMIT/MIT mediated adverse effects. Briefly, multi-level endpoint analysis indicated the most susceptible window of exposure to be ≤ 6 hpf followed by ≤ 48 hpf for CMIT/MIT. These results could potentially be translated to a risk assessment of the developmental exposure effects to the humidifier disinfectants.

Cr-(III)-organic compounds treatment causes genotoxicity and changes in DNA and protein level in Saccharomyces cerevisiae.

Natural Cr-(III)-organic species are being known as the part of natural biogeochemical cycle of chromium, but unfortunately, their mechanism of toxicity as well as genotoxic potentiality is still unknown. To evaluate the characteristic toxic effect exerted by natural Cr-(III)-organic species on the cellular macromolecules, changes in DNA and protein level was observed. Besides, Comet assay was applied to measure genotoxic potentiality of Cr-(III)-organic species in the target organism Saccharomyces cerevisiae exposed to Cr-(III)-citrate and Cr-(III)-histidine. It has been observed that both of the Cr-(III)-organic compounds are responsible for diminution in macromolecules concentration. Cr-(III)-citrate showed ladder pattern of DNA fragmentation in support of apoptosis. Two new protein bands appeared in protein profile of the Saccharomyces cerevisiae treated with Cr-(III)-organic compounds. Thus it supports the possibility of the synthesis of stress proteins. Comet assay proved positive correlation between Cr-(III)-organic compounds' concentration and DNA damage. The Cr-(III)-citrate causes DNA damage at the concentrations ranging from 50 to 150 mg L(-1), whereas the DNA damaging capacity of Cr-(III)-histidine was found insignificant, except at highest concentration (150 mg L(-1)). These results can throw light on the mechanism of the toxic effect as well as genotoxicity exerted by natural Cr-(III)-organic species.

Endoplasmic reticulum stress mediated apoptosis via JNK in MWCNT-exposed in vitro systems: size, surface functionalization and cell type specificity.

The aim of the present study was to evaluate the underlying mechanism of multi-walled carbon nanotubes (MWCNT) induced cellular response and their potential cross-talk, specifically, between endoplasmic reticulum (ER) stress, MAPK activation and apoptosis and how these nano-bio interactions depend on the physico-chemical properties of MWCNT. For this purpose, human bronchial epithelial (Beas2B) and human hepatoma (HepG2) cell lines, were exposed to five kinds of MWCNTs which differ in functionalization and aspect ratios. Tissue-specific sensitivity was evident for calcium homeostasis, ER-stress response, MAPK activation and apoptosis, which further depended on surface functionalization as well as aspect ratios of MWCNT. By applying specific pharmaceutical inhibitors, relevant biomarkers gene and proteins expressions, we found that possibly MWCNT induce activation of IRE1α-XPB1 pathway-mediated ER-stress response, which in turn trigger apoptosis through JNK activation in both type of cells but with variable intensity. The information presented here would have relevance in better understanding of MWCNT toxicity and their safer applications.