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BACKGROUND: Exposure to persistent organic pollutants (POPs) has been associated with the progression of chronic liver diseases, yet the contribution of POPs to the development of fibrosis in non-alcoholic fatty liver disease (NAFLD), a condition closely linked to obesity, remains poorly documented. [ABSTRACT FROM AUTHOR]

Chlordane compounds (CHLs) are components of technical chlordane listed in the Stockholm convention on persistent organic pollutants identified as endocrine disrupting chemicals (EDCs) and may interfere with hormone biosynthesis, metabolism or action resulting in an unbalanced hormonal function. There is increasing scientific evidence showing EDCs as risk factors in the pathogenesis and development of obesity and obesity-related metabolic syndromes such as type 2 diabetes, but there is no systematized information on the effect of CHLs in humans. Our aim is to identify the epidemiological data on the association between CHLs with adiposity and diabetes using a systematic approach to identify the available data and summarizing the results through meta-analysis. We searched PubMed and Web of Science from inception up to 15 February 2021, to retrieve original data on the association between chlordanes, and adiposity or diabetes. For adiposity, regression coefficients and Pearson or Spearman correlation coefficients were extracted and converted into standardized regression coefficients. Data were combined using fixed effects meta-analyses to compute summary regression coefficients and corresponding 95% confidence intervals (95% CI). For the association between chlordanes and diabetes, Odds ratios (ORs) were extracted and the DerSimonian and Laird method was used to compute summary estimates and respective 95% CI. For both, adjusted estimates were preferred, whenever available. Among 31 eligible studies, mostly using a cross-sectional approach, the meta-analysis for adiposity was possible only for oxychlordane and transchlordane, none of them were significantly associated with adiposity [(β = 0.04, 95% CI 0.00; 0.07, I2 = 89.7%)] and (β = 0.02, 95% CI − 0.01; 0.06), respectively. For diabetes, the estimates were positive for all compounds but statistically significant for oxychlordane [OR = 1.96 (95% CI 1.19; 3.23)]; for trans-nonachlor [OR = 2.43 (95% CI 1.64; 3.62)] and for heptachlor epoxide [OR = 1.88 (95% CI 1.42; 2.49)]. Our results support that among adults, the odds of having diabetes significantly increase with increasing levels of chlordanes. The data did not allow to reach a clear conclusion regarding the association with adiposity. [ABSTRACT FROM AUTHOR]

The mechanisms by which pollutants participate in the development of diverse pathologies are not completely understood. The pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) activates the AhR (aryl hydrocarbon receptor) signaling pathway. We previously showed that TCDD (25 nM, 30 h) decreased the expression of several alcohol metabolism enzymes (cytochrome P450 2E1, alcohol dehydrogenases ADH1, 4 and 6) in differentiated human hepatic cells (HepaRG). Here, we show that, as rapidly as 8 h after treatment (25 nM TCDD) ADH expression decreased 40 % ( p < 0.05). ADH1 and 4 protein levels decreased 40 and 27 %, respectively ( p < 0.05), after 72 h (25 nM TCDD). The protein half-lives were not modified by TCDD which suggests transcriptional regulation of expression. The AhR antagonist CH-223191 or AhR siRNA reduced the inhibitory effect of 25 nM TCDD on ADH1A, 4 and 6 expression 50-100 % ( p < 0.05). The genomic pathway (via the AhR/ARNT complex) and not the non-genomic pathway involving c-SRC mediated these effects. Other AhR ligands (3-methylcholanthrene and PCB 126) decreased ADH1B, 4 and 6 mRNAs by more than 78 and 55 %, respectively ( p < 0.01). TCDD also regulated the expression of ADH4 in the HepG2 human hepatic cell line, in primary human hepatocytes and in C57BL/6J mouse liver. In conclusion, activation of the AhR/ARNT signaling pathway by AhR ligands represents a novel mechanism for regulating the expression of ADHs. These effects may be implicated in the toxicity of AhR ligands as well as in the alteration of ethanol or retinol metabolism and may be associated further with higher risk of liver diseases or/and alcohol abuse disorders. [ABSTRACT FROM AUTHOR]

It is well known that several metals, such as lead, mercury, cadmium, and vanadium, can mimic the effects of estrogens (metallo-estrogens). Nevertheless, there are only a few studies that have assessed the effects of toxic metals on the female genital tract and, in particular, endometrial tissue. In this context, we measured the concentrations of several trace elements in human endometrial tissue samples from individuals with hyperplasia or adenocarcinoma and in normal tissues. Hyperplasic endometrial tissue has a 4-fold higher concentration of mercury than normal tissue. Mercury can affect both the AhR and ROS signaling pathways. Thus, we investigated the possible toxic effects of mercury by in vitro studies. We found that mercury increases oxidative stress (increased HO1 and NQO1 mRNA levels) and alters the cytoskeleton in the human endometrial Ishikawa cell line and to a lesser extent, in the “less-differentiated” human endometrial Hec-1b cells. The results might help to explain a potential link between this metal and the occurrence of endometrial hyperplasia. [ABSTRACT FROM AUTHOR]

Individuals, typically, are exposed to mixtures of environmental xenobiotics affecting multiple organs and acting through different xenosensors and pathways in species and cell-type specific manners. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and α-endosulfan are Persistent Organic Pollutants (POPs) and endocrine disruptors which act through different xenosensors and accumulate in the liver. Our objective in this HEALS study was to investigate the effects of the mixture of these POPs on gene expression in a human-derived hepatocyte cell line, HepaRG. We found that, in spite of having largely uncorrelated effects, TCDD and α-endosulfan, when mixed, alter the expression of genes. The combined effects of the mixture of the POPs significantly altered the expression of 100 genes (42 up- and 58 down-regulated) whereas the same concentration of either POP alone did not alter significantly the expression of these genes. For 32 other genes, selective inhibitory crosstalk between TCDD and α-endosulfan was observed. One of the POPs inhibited the effect, on gene expression, of the other in the mixture although, when used alone, that POP did not affect expression. The expression of another 82 genes was significantly altered (up- or down-regulated) by a single POP. The addition of the second POP either increased, in the same direction, the effect on gene expression or had no further effect. At low concentrations (0.2 nM TCDD and 1 μM α-endosulfan), the POPs still had significant effects and the levels of expression of the corresponding proteins were found to be affected for some genes. Particularly striking was the 80–90% inhibition, by the mixture, of the expression of a number of genes of several hepatic intermediary metabolic pathways (glycerolipid metabolism, FXR/RXR activation, glycolysis/gluconeogenesis, retinoid and bile acid biosynthesis), whereas each pollutant alone had only a moderate effect. [ABSTRACT FROM AUTHOR]

Exposure to environmental chemicals has become one of the major concerns in the past decades. Phthalates are a family of synthetic organic chemicals used in the manufacture of plastics, solvents, and personal care products. These compounds are considered as endocrine-disrupting compounds (EDCs) since they may interfere with the endocrine system and disrupt its physiologic function. The purpose of this work is to synthesize results from published literature on the association between the exposure to phthalates and adiposity in adults and children. We searched PubMed from inception up to 01 August 2019, to retrieve original papers reporting data on the association between EDCs and adiposity, using the following search expression: (("Endocrine disruptor" OR Endocrine disruptor[mh] OR phthalate) AND (Obesity OR Overweight OR BMI OR "Body fat" OR Adipose tissue[mh] OR Body size[mh] OR "body size" OR "body weight" OR Anthropometry OR "anthropometric measures")) AND (humans[mh]). The study variables and characteristics were collected during data extraction, namely the study design, sample, exposure, outcome, descriptive and association measures. Study quality was assessed using the STROBE template for observational studies. Although studies examined several adiposity measures, Body Mass Index (BMI) and Waist Circumference (WC) were the most commonly used, therefore, we used the beta coefficients regarding BMI and WC, and odds ratios when BMI outcome was categorical to perform the meta-analysis. Data from the studies were combined using fixed effects meta-analyses to compute summary regression coefficients or odds ratios and corresponding 95% confidence intervals (95% CI). Heterogeneity between studies was assessed by the I2 statistic. In the systematic review we found 29 publications addressing the association between phthalate compounds and adiposity. The vast majority of the included studies reported associations that were not statistically significant. For most of the phthalate compounds there were few studies providing compatible measures and therefore it was not possible to combine the results in a meta-analysis. Both for BMI and WC, the meta-analysis for MiBP, MCPP and MbzP showed negative associations and null association for MBP in children, although none of them was significant. For MEP, positive but not significant associations were found both in children and adults. Conversely, for MEHP a negative association was found also in children and adults although it did not reach statistical significance. Only for MECPP a significant association was found for obesity in adults (OR = 1.67 (95% CI 1.30; 2.16). In general, a positive association between phthalates and adiposity measures was found, especially in adults. However, most of the results did not reach statistical significance and the inconsistencies found between studies did not allow to reach a definitive conclusion. Additionally, we cannot exclude a possible effect of publication bias. • The results tend to be consistent whatever the measure of adiposity used. • The associations were strong for adults than for children. • In general, MEP, MiBP, MMP, MEOHP and MEHHP showed a positive association. • Overall inconsistent results were found for MbP, MEHP and MbzP. • The scarcity of longitudinal studies hind the interpretation of causality. [ABSTRACT FROM AUTHOR]

Individuals as well as entire ecosystems are exposed to mixtures of Persistent Organic Pollutants (POPs). Previously, we showed, by a non-targeted approach, that the expression of several genes involved in carbohydrate metabolism was almost completely inhibited in the human hepatic cell line HepaRG following exposure to a mixture of the organochlorine insecticide alpha-endosulfan and 2,3,7,8 tetrachlorodibenzo-p-dioxin. In this European HEALS project, which studies the effects of the exposome on human health, we used a Physiologically Based BioKinetic model to compare the concentrations previously used in vitro with in vivo exposures for humans. We investigated the effects of these POPs on the levels of proteins, on glycogen content, glucose production and the oxidation of glucose into CO 2 and correlated them to the expression of genes involved in carbohydrate metabolism as measured by RT-qPCR. Exposure to individual POPs and the mixture decreased the expression of the proteins investigated as well as glucose output (up to 82%), glucose oxidation (up to 29%) and glycogen content (up to 48%). siRNAs that specifically inhibit the expression of several xenobiotic receptors were used to assess receptor involvement in the effects of the POPs. In the HepaRG model, we demonstrate that the effects are mediated by the aryl hydrocarbon receptor and the estrogen receptor alpha, but not the pregnane X receptor or the constitutive androstane receptor. These results provide evidence that exposure to combinations of POPs, acting through different signaling pathways, may affect, more profoundly than single pollutants alone, metabolic pathways such as carbohydrate/energy metabolism and play a potential role in pollutant associated metabolic disorders. • TCDD and α-endosulfan mixture decreases carbohydrate metabolism in liver cells. • PBBK model of TCDD and α-endosulfan in human liver. • α-endosulfan acts via estrogen α receptor in HepaRG cells. • Glucose oxidation and production and glycogen content are decreased by the mixture. [ABSTRACT FROM AUTHOR]