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Identification of a unique gene expression signature in mercury and 2,3,7,8-tetrachlorodibenzo-p-dioxin co-exposed cells.

ABSTRACT: Mercury (Hg) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are major environmental contaminants that commonly co-occur in the environment. Both Hg and TCDD are associated with a number of human diseases including cancers. While the individual toxicological effects of Hg and TCDD have been extensively investigated, studies on co-exposure are limited to a few genes and pathways. Therefore, a significant knowledge gap exists in the understanding of the deleterious effects of co-exposure to Hg and TCDD. Due to the prevalence of Hg and TCDD co-contamination in the environment and the major human health hazards they pose, it is important to obtain a fuller understanding of genome-wide effects of Hg and TCDD co-exposure. In this study, by performing a comprehensive transcriptomic analysis of human bronchial epithelial cells (BEAS-2B) exposed to Hg and TCDD individually and in combination, we have uncovered a subset of genes with altered expression only in the co-exposed cells. We also identified the additive as well as antagonistic effects of Hg and TCDD on gene expression. Moreover, we found that co-exposure impacted several biological and disease processes not affected by Hg or TCDD individually. Our studies show that the consequences of Hg and TCDD co-exposure on the transcriptional program and biological processes could be substantially different from single exposures, thus providing new insights into the co-exposure-specific pathogenic processes.

SUBMITTER: Jagannathan L

PROVIDER: S-EPMC5648359 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Identification of a unique gene expression signature in mercury and 2,3,7,8-tetrachlorodibenzo-p-dioxin co-exposed cells

Project description:Mercury (Hg) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are major environmental contaminants that commonly co-occur in the environment. Both Hg and TCDD are associated with a number of human diseases including cancers. While the individual toxicological effects of Hg and TCDD have been extensively investigated, studies on co-exposure are limited to a few genes and pathways. Therefore, a significant knowledge gap exists in the understanding of the deleterious effects of co-exposure to Hg and TCDD. Due to the prevalence of Hg and TCDD co-contamination in the environment and the major human health hazards they pose, it is important to obtain a fuller understanding of genome-wide effects of Hg and TCDD co-exposure. In this study, by performing a comprehensive transcriptomic analysis of human bronchial epithelial cells (BEAS-2B) exposed to Hg and TCDD individually and in combination, we have uncovered a subset of genes with altered expression only in the co-exposed cells. We also identified the additive as well as antagonistic effects of Hg and TCDD on gene expression. Moreover, we found that co-exposure impacted several biological and disease processes not affected by Hg or TCDD individually. Our studies show that the consequences of Hg and TCDD co-exposure on the transcriptional program and biological processes could be substantially different from single exposures, thus providing new insights into the co-exposure-specific pathogenic processes.

2017-02-27 | GSE83886 | GEO

Identification and characterization of long non-coding RNAs in porcine granulosa cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Project description:Background:Long non-coding RNAs (lncRNAs) may regulate gene expression in numerous biological processes including cellular response to xenobiotics. The exposure of living organisms to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, results in reproductive defects in many species including pigs. The aims of the study were to identify and characterize lncRNAs in porcine granulosa cells as well as to examine the effects of TCDD on the lncRNA expression profile in the cells. Results:One thousand six hundred sixty-six lncRNAs were identified and characterized in porcine granulosa cells. The identified lncRNAs were found to be shorter than mRNAs. In addition, the number of exons was lower in lncRNAs than in mRNAs and their exons were longer. TCDD affected the expression of 22 lncRNAs (differentially expressed lncRNAs [DELs]; log2 fold change ???1, P-adjusted <?0.05) in the examined cells. Potential functions of DELs were indirectly predicted via searching their target cis- and trans-regulated protein-coding genes. The co-expression analysis revealed that DELs may influence the expression of numerous genes, including those involved in cellular response to xenobiotics, dioxin metabolism, endoplasmic reticulum stress and cell proliferation. Aryl hydrocarbon receptor (AhR) and cytochrome P450 1A1 (CYP1A1) were found among the trans-regulated genes. Conclusions:These findings indicate that the identified lncRNAs may constitute a part of the regulatory mechanism of TCDD action in granulosa cells. To our knowledge, this is the first study describing lncRNAs in porcine granulosa cells as well as TCDD effects on the lncRNA expression profile. These results may trigger new research directions leading to better understanding of molecular processes induced by xenobiotics in the ovary.

| S-EPMC6180664 | biostudies-literature

Age at menarche in Seveso daughters exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Project description:In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with delayed pubertal development in animal studies. No epidemiologic study has investigated this association. We examined the relationship of in utero exposure to TCDD with reported age at onset of menarche in female children born to a unique cohort of TCDD-exposed women resulting from an explosion in Seveso, Italy, on 10 July 1976.MethodsIn 2014, nearly 40 years after the explosion, we enrolled postexplosion offspring, 2 to 39 years of age, in the Seveso Second Generation Study. Age at onset of menarche (years) was collected for 316 daughters by maternal report or self-report at interview. In utero TCDD exposure was defined by maternal TCDD serum concentrations extrapolated to the pregnancy.ResultsAt interview, 287 daughters were postmenarche and reported age at menarche averaged 12.1 years (±1.3 years). Overall, we found no change in risk of menarche onset with a 10-fold increase in in utero TCDD exposure (hazard ratio [HR] = 0.86; 95% confidence interval [CI] = 0.71, 1.04). When we considered maternal menarche status in 1976 as a potentially sensitive developmental exposure window, in utero TCDD (log10) was associated with later age at menarche among daughters whose mothers were premenarche (HR = 0.71; 95% CI = 0.52, 0.97) but not postmenarche (HR = 0.89; 95% CI = 0.71, 1.12) at the time of the explosion (P int = 0.24).ConclusionsThese results suggest that in utero TCDD exposure may alter pubertal timing among daughters of women who were prepubescent at the time of the Seveso accident.

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Identification of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible genes in human amniotic epithelial cells.

Project description:Exposure to dioxins results in a broad range of pathophysiological disorders in human fetuses. In order to evaluate the effects of dioxins on the feto-placental tissues, we analyzed the gene expression in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated primary cultures of human amniotic epithelial cells.Human amniotic epithelial cells were dispersed by trypsin from amniotic membranes and cultured in DME/Ham's F12 medium supplemented with 10% FBS. Two weeks after plating, cells were treated with 50 nM TCDD or DMSO (control), further incubated for 48 hrs, and the gene expression was analyzed by DNA microarray technology and quantitative real-time PCR.Thirty eight TCDD-inducible genes, including cytochromeP4501A1 and cytochromeP4501B1, were identified. One of the remarkable profiles of the gene expression was the prominent up-regulation of interferon-inducible genes. The genes involved in the interferon gene expression and interferon signaling pathways were also up-regulated. Furthermore, the expression of genes related to collagen synthesis or degradation was enhanced by TCDD.Using DNA microarray and quantitative real-time PCR analyses, we identified TCDD-inducible genes, including interferon-inducible genes and genes related to collagen synthesis or degradation, in human amniotic epithelial cells.

| S-EPMC1557667 | biostudies-literature

2,3,7,8-Tetrachlorodibenzo-p-dioxin modifies alternative splicing in mouse liver.

Project description:Alternative splicing is a co-transcriptional mechanism that generates protein diversity by including or excluding exons in different combinations, thereby expanding the diversity of protein isoforms of a single gene. Abnormalities in this process can result in deleterious effects to human health, and several xenobiotics are known to interfere with splicing regulation through multiple mechanisms. These changes could lead to human diseases such as cancer, neurological disorders, autoimmune diseases, and developmental disorders. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant generated as a byproduct of various industrial activities. Exposure to this dioxin has been linked to a wide range of pathologies through the alteration of multiple cellular processes. However, the effects of TCDD exposure on alternative splicing have not yet been studied. Here, we investigated whether a single po. dose of 5 μg/kg or 500 μg/kg TCDD influence hepatic alternative splicing in adult male C57BL/6Kou mouse. We identified several genes whose alternative splicing of precursor messenger RNAs was modified following TCDD exposure. In particular, we demonstrated that alternative splicing of Cyp1a1, Ahrr, and Actn1 was significantly altered after TCDD treatment. These findings show that the exposure to TCDD has an impact on alternative-splicing, and suggest a new avenue for understanding TCDD-mediated toxicity and pathogenesis.

| S-EPMC6684058 | biostudies-literature

2,3,7,8-Tetrachlorodibenzo-p-dioxin upregulates FoxQ1b in zebrafish jaw primordium.

Project description:Vertebrate jaw development can be disrupted by exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-a potent activator of the aryl hydrocarbon receptor (AHR) transcription factor required for transducing the toxic effects of TCDD. We used zebrafish (Danio rerio) embryos to investigate transcriptional responses to TCDD with the goal of discovering novel, jaw-specific genes affected by TCDD exposure. Our results uncovered a novel target of TCDD-activated Ahr belonging to the evolutionarily conserved family of forkhead box transcription factors. Quantitative real-time polymerase chain reaction analysis demonstrated that FoxQ1b was upregulated by TCDD 7- and 10-fold at 24 and 48 h postfertilization (hpf), respectively. The rate of TCDD-induced FoxQ1b expression was more rapid than that of Cyp1a, a known direct target of TCDD-activated Ahr. TCDD-mediated induction of FoxQ1b was suppressed in the presence of an Ahr antagonist, alpha-naphthoflavone, as well as following knockdown of Ahr2 expression using an Ahr2-specific morpholino antisense oligonucleotide. In situ hybridization analysis of FoxQ1b expression at 48 hpf demonstrated that FoxQ1b is specifically expressed in the jaw primordium where it discretely outlines a developing jaw structure known as Meckel's cartilage--a conserved structure in all jawed vertebrates that develops abnormally in the presence of TCDD. These results identify a novel target of TCDD-activated Ahr and suggest that FoxQ1b may play a role in craniofacial abnormalities induced by developmental exposure to TCDD.

| S-EPMC2839046 | biostudies-literature

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Application of pharmacokinetic modelling for 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure assessment.

Project description:Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and mono- and non-ortho polychlorinated biphenyls (dioxin-like PCBs) are identified as a family or group of organic compounds known as 'dioxins' or dioxin-like chemicals (DLCs). The most toxic member of this group is 2,3,7,8-tetrachlorodibenzo-(p)-dioxin (TCDD). Historically, DLCs have caused a variety of negative human health effects, but a disfiguring skin condition known as chloracne is the only health effect reported consistently. As part of translational research to make computerized models accessible to health risk assessors, the Concentration- and Age-Dependent Model (CADM) for TCDD was recoded in the Berkeley Madonna simulation language. The US Agency for Toxic Substances and Disease Registry's computational toxicology laboratory used the recoded model to predict TCDD tissue concentrations at different exposure levels. The model simulations successfully reproduced the National Health and Nutrition Examination Survey (NHANES) 2001-2002 TCDD data in age groups from 6 to 60 years and older, as well as in other human datasets. The model also enabled the estimation of lipid-normalized serum TCDD concentrations in breastfed infants. The model performed best for low background exposures over time compared with a high acute poisoning case that could due to the large dose and associated liver toxicity. Hence, this model may be useful for interpreting human biomonitoring data as a part of an overall DLC risk assessment.

| S-EPMC8204318 | biostudies-literature

Hepatic transcriptional networks induced by exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

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| S-EPMC2515491 | biostudies-literature

Isolation and identification of a 2,3,7,8-Tetrachlorodibenzo-P-dioxin degrading strain and its biochemical degradation pathway.

Project description:This study aims to find a high-efficiency degradation strain which can biodegrade the 2,3,7,8-Tetrachlorodibenzo-P-dioxin (2,3,7,8-TCDD). In this paper, a new fungus strain was isolated from activated sludge of Dagu Drainage River in Tianjin which was able to degrade 2,3,7,8-TCDD in the medium. Based on its morphology and phylogenetic analysis of its 18S rDNA sequence, the strain was identified as Penicillium sp. QI-1. Response surface methodology using central composite rotatable design of cultural conditions was successfully employed for optimization resulting in 87.9 % degradation of 2,3,7,8-TCDD (1 µg/mL) within 6 days. The optimum condition for degrading 2,3,7,8-TCDD was at 31℃ and pH 7.4. The biodegradation process was fitted to a first-order kinetic model. The kinetic equation was Ct=0.939e- 0.133t and its half-life was 5.21d. The fungus strain degraded 2,3,7,8-TCDD to form intermediates, they were 4,5-Dichloro-1,2-benzoquinone, 4,5-Dichlorocatechol, 2-Hydrooxy-1,4-benzoquinone, 1,2,4-Trihydroxybenzene and β-ketoadipic acid. A novel degradation pathway for 2,3,7,8-TCDD was proposed based on analysis of these metabolites. The results suggest that Penicillium sp. QI-1 may be an ideal microorganism for biodegradation of the 2,3,7,8-TCDD-contaminated environments.

| S-EPMC8172717 | biostudies-literature

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