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As a consequence of ubiquitous use of brominated organic chemicals, there is a concern for persistent or increasing environmental levels of polybrominated dibenzo‐p‐dioxins/furans (PBDD/Fs) and mixed polychlorinated and polybrominated di‐benzo‐p‐dioxins/furans (PXDD/Fs). Hence, there is a need to broaden the toxicological and environmental knowledge about these compounds, as a basis for risk assessment. In the study presented here, the relative potencies (REPs) for 18 PBDD/F and PXDD/F congeners were determined in four dioxin‐specific bioassays from different species: dioxin receptor chemically activated luciferase expression assay (DR‐CALUX, rat hepatoma cells), TV101L (human hepatoma cells), and GPC.2D (guinea pig adenoma cells), as well as ethoxyresorufin‐O‐deethylase induction in the fish cell line RTL‐W1 (rainbow trout liver cells). The bioassay specific REP factors presented here enable the assessment of the contribution from PBDD/Fs and PXDD/Fs to total 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) equivalents (TEQs: toxic equivalents), using bioassay analysis. The PBDD/Fs were found to be equally potent as their chlorinated analogues in the three mammalian assays, whereas the PXDD/Fs showed relatively higher potencies. Of special concern were the 2,3,7,8‐substituted penta‐ and tetrahalogenated congeners, for which mean REPs were >1. The 2‐B‐1,3,7,8‐CDD (2‐bromo‐1,3,7,8‐tetrachlorodibenzo‐p‐dioxin) was up to three times more potent than TCDD in individual experiments (on weight basis). The RTL‐W1 was less sensitive to the tested compounds with overall 10‐fold lower REPs than the mammalian cell lines. Although the REP factors exhibited species‐specific differences, overall resembling rank orders of dioxin‐like potency were obtained.

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.

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. We investigated the effects of subchronic exposure to low doses of the POP 2,3,7,8-tetrachlorodibenzo- -dioxin (TCDD), an aryl hydrocarbon receptor ligand, on NAFLD progression in diet-induced obese C57BL/6J mice. Male C57BL/6J mice were fed either a 10% low-fat (LFD) or a 45% high-fat (HFD) purified diet for 14 weeks and TCDD-exposed groups were injected once a week with 5 μg/kg TCDD or the vehicle for the last 6 weeks of the diet. Liver histology and triglyceride levels showed that exposure of HFD fed mice to TCDD worsened hepatic steatosis, as compared to either HFD alone or LFD plus TCDD and the mRNA levels of key genes of hepatic lipid metabolism were strongly altered in co-treated mice. Further, increased liver collagen staining and serum transaminase levels showed that TCDD induced liver fibrosis in the HFD fed mice. TCDD in LFD fed mice increased the expression of several inflammation and fibrosis marker genes with no additional effect from a HFD. Exposure to TCDD amplifies the impairment of liver functions observed in mice fed an enriched fat diet as compared to a low fat diet. The results provide new evidence that environmental pollutants promote the development of liver fibrosis in obesity-related NAFLD in C57BL/6J mice. Citation: Duval C, Teixeira-Clerc F, Leblanc AF, Touch S, Emond C, Guerre-Millo M, Lotersztajn S, Barouki R, Aggerbeck M, Coumoul X. 2017. Chronic exposure to low doses of dioxin promotes liver fibrosis development in the C57BL/6J diet-induced obesity mouse model. Environ Health Perspect 125:428-436; http://dx.doi.org/10.1289/EHP316.

Dioxin-like chemicals are a group of ubiquitous environmental toxicants that received intense attention in the last two decades of the 20th century. Through extensive mechanistic research and validation, the global community has agreed upon a regulatory strategy for these chemicals that centers on their common additive activation of a single receptor. Applying these regulations has led to decreased exposure in most populations studied. As dioxin-like chemicals moved out of the limelight, research and media attention has turned to other concerning contaminants, including per- and polyfluoroalkyl substances (PFAS). During the 20th century, PFAS were also being quietly emitted into the environment, but only in the last 20 years have we realized the serious threat they pose to health. There is active debate about how to appropriately classify and regulate the thousands of known PFAS and finding a solution for these \"forever chemicals\" is of the utmost urgency. Here, we compare important features of dioxin-like chemicals and PFAS, including the history, mechanism of action, and effective upstream regulatory strategies, with the objective of gleaning insight from the past to improve strategies for addressing PFAS. The differences between these two chemical classes means that regulatory strategies for dioxin-like chemicals will not be appropriate for PFAS. PFAS exert toxicity by both receptor-based and nonreceptor-based mechanisms, which complicates mixtures evaluation and stymies efforts to develop inexpensive assays that accurately capture toxicity. Furthermore, dioxin-like chemicals were unwanted byproducts, but PFAS are useful and valuable, which has led to intense resistance against efforts to restrict their production. Nonetheless, useful lessons can be drawn from dioxin-like chemicals and applied to PFAS, including eliminating nonessential production of new PFAS and proactive investment in environmental remediation to address their extraordinarily long environmental persistence. https://doi.org/10.1289/EHP14449.

Assessing long-term health effects from a potentially harmful environment is challenging. Endocrine-disrupting compounds (EDCs) have become omnipresent in our environment. Individuals may or may not experience clinical health issues from being exposed to the increasing environmental pollution in daily life, but an issue of high concern is that also the non-exposed progeny may encounter consequences of these ancestral exposures. Progress in understanding epigenetic mechanisms opens new perspectives to estimate the risk of man-made EDCs. However, the field of epigenetic toxicology is new and its application in public health or in the understanding of disease etiology is almost non-existent, especially if it concerns future generations. In this review, we investigate the literature on transgenerational inheritance of diseases, published in the past 10 years. We question whether persistent epigenetic changes occur in the male germ line after exposure to synthesized EDCs. Our systematic search led to an inclusion of 43 articles, exploring the effects of commonly used synthetic EDCs, such as plasticizers (phthalates and bisphenol A), pesticides (dichlorodiphenyltrichloroethane, atrazine, vinclozin, methoxychlor), dioxins, and polycyclic aromatic hydrocarbons (PAHs, such as benzo(a)pyrene). Most studies found transgenerational epigenetic effects, often linked to puberty- or adult-onset diseases, such as testicular or prostate abnormalities, metabolic disorders, behavioral anomalies, and tumor development. The affected epigenetic mechanisms included changes in DNA methylation patterns, transcriptome, and expression of DNA methyltransferases. Studies involved experiments in animal models and none were based on human data. In the future, human studies are needed to confirm animal findings. If not transgenerational, at least intergenerational human studies and studies on EDC-induced epigenetic effects on germ cells could help to understand early processes of inheritance. Next, toxicity tests of new chemicals need a more comprehensive approach before they are introduced on the market. We further point to the relevance of epigenetic toxicity tests in regard to public health of the current population but also of future generations. Finally, this review sheds a light on how the interplay of genetics and epigenetics may explain the current knowledge gap on transgenerational inheritance.

Chemical contamination and pollution are an ongoing threat to human health and the environment. The concern over the consequences of chemical exposures at the global level continues to grow. Because resources are constrained, there is a need to prioritize interventions focused on the greatest health impact. Data, especially related to chemical exposures, are rarely available for most substances of concern, and alternate methods to evaluate their impact are needed. A Structured Expert Judgment (Research Outreach, 2021) process was performed to provide plausible estimates of health impacts for 16 commonly found pollutants: asbestos, arsenic, benzene, chromium, cadmium, dioxins, fluoride, highly hazardous pesticides (HHPs), lead, mercury, polycyclic-aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), Per- and Polyfluorinated Substances (PFAs), phthalates, endocrine disrupting chemicals (EDCs), and brominated flame retardants (BRFs). This process, undertaken by sector experts, weighed individual estimations of the probable global health scale health impacts of each pollutant using objective estimates of the expert opinions' statistical accuracy and informativeness. The foremost substances, in terms of mean projected annual total deaths, were lead, asbestos, arsenic, and HHPs. Lead surpasses the others by a large margin, with an estimated median value of 1.7 million deaths annually. The three other substances averaged between 136,000 and 274,000 deaths per year. Of the 12 other chemicals evaluated, none reached an estimated annual death count exceeding 100,000. These findings underscore the importance of prioritizing available resources on reducing and remediating the impacts of these key pollutants. Based on the evidence available, experts concluded some of the more notorious chemical pollutants, such as PCBs and dioxin, do not result in high levels of human health impact from a global scale perspective. However, the chemical toxicity of some compounds released in recent decades, such as Endocrine Disrupters and PFAs, cannot be ignored, even if current impacts are limited. Moreover, the impact of some chemicals may be disproportionately large in some geographic areas. Continued research and monitoring are essential; and a preventative approach is needed for chemicals. These results, and potential similar analyses of other chemicals, are provided as inputs to ongoing discussions about priority setting for global chemicals and pollution management. Furthermore, we suggest that this SEJ process be repeated periodically as new information becomes available.

Explores the latest science on dioxins and other POPs, and their impact on human health Now in its third edition, Dioxins and Health is the most respected reference of its kind, presenting the latest scientific findings on dioxins, dibenzofurans, polychlorinated biphenyls and related compounds, and their impact on human health. The book fully examines the many toxicological effects-including immunological, neurological, developmental, dermatological, and cardiological-these chemicals have on health. This Third Edition has been greatly expanded with the latest research findings on dioxins and related compounds. Moreover, it now includes coverage of other persistent organic pollutants (POPs) and endocrine disruptors, including: Brominated flame retardants, such as polybrominated diphenyl ethers and hexabromocyclododecane Perfluorinated chemicals such as perfluorooctanoic acid and perfluorooctanesulfonic acid Other endocrine disrupting chemicals similar to POPs such as bisphenol A Readers will also learn about the latest findings on the long-term impacts caused by the use of Agent Orange in Vietnam. Other chapters review the Seveso disaster in Italy and the Yusho and Yucheng rice oil poisoning incidents in Japan and Taiwan. In addition, there is a full chapter dedicated to the dioxin poisoning of former Ukraine President Victor Yushchenko. All the chapters in the book have been written by leading international experts. References at the end of each chapter guide readers to the primary literature in the field. Expertly organized in one volume, Dioxins and Health offers readers quick access to essential information about dioxins and related compounds written in clear, simple language that is accessible to not only scientists, clinicians and public health professionals, but also general readers.

BACKGROUND: In humans, persistent organic pollutants (POPs) are stored primarily in adipose tissue. Their total body burden and their contribution to obesity-associated diseases remain unclear. OBJECTIVES: We characterized POP total body burden and their redistribution in obese individuals before and after drastic weight loss and compared these values with a variety of molecular, biological, and clinical parameters. METHODS: Seventy-one obese subjects were enrolled and underwent bariatric surgery. Blood and adipose tissue samples were obtained at different times from these individuals as well as from 18 lean women. RESULTS: POP content (17 dioxins/furans and 18 polychlorinated biphenyl congeners) in different adipose tissue territories was similar, allowing us to assess total POP body burden from a single biopsy. Total POP body burden was 2 to 3 times higher in obese than in lean individuals. We also found increased expression of some POP target genes in obese adipose tissue. Drastic weight loss led to increased serum POPs and, within 6-12 months, to a significant 15% decrease in total polychlorinated biphenyl body burden. Importantly, serum POP levels were positively correlated with liver toxicity markers and lipid parameters, independently of age and body mass index. CONCLUSIONS: POP content in adipose tissue and serum correlate with biological markers of obesity-related dysfunctions. Drastic weight loss leads to a redistribution of POPs and to a moderate decrease of their total body burden.

Globally, endometriosis affects almost 10% of reproductive-aged women, leading to chronic pain and discomfort. Endocrine-disrupting compounds (EDCs) seem to play a pivotal role as a causal factor. The current manuscript aims to explain potential molecular pathways, synthesize current evidence regarding EDCs as causative agents of endometriosis, and highlight implications in the general population and clinical work. A thorough review of experimental, epidemiologic, and mechanistic research studies was conducted to explain the association between EDCs and endometriosis. Among the primary EDCs under investigation are polychlorinated biphenyls, dioxins, phthalates, and bisphenol A (BPA). Despite methodological heterogeneity and some discrepancies, epidemiologic evidence supports a positive association between some increased levels of BPA, phthalates, and dioxins in urine or in blood, and endometriosis. Experiments support some effect of EDCs on endometrial cells and causing endometriosis. EDCs function as xenoestrogens, alter immune function, induce oxidative stress, and disrupt progesterone signaling. Epigenetic reprogramming may play a role in mediating EDC-induced endometriosis. Endocrine, immunological, and epigenetic pathways link EDCs and endometriosis. Prevention techniques require deeper comprehension of those factors. Causal linkages and possible treatment targets should be based on longitudinal studies and multi-omics techniques. Restriction of EDCs could be beneficial for endometriosis prevalence limitation.

Dioxin-like pollutants, especially 2,3,7,8-Tetrachlorodibenzo-p-dioxin, are recognized human carcinogens. Retrospective studies suggest a link between dioxins and soft tissue sarcomas, including liposarcoma, but mechanisms remain unclear. This study explores the toxicological effects of dioxins on liposarcoma, identifies key proteins, and proposes potential solutions. We identified dioxin- and liposarcoma-related targets via databases, analyzed overlaps through enrichment and network toxicology, and validated them with phenotypic and clinical data. We built a prediction model using 117 combinations of machine learning algorithms, confirmed the results with molecular docking and simulations, and proposed therapies through drug experiments. TCDD modulates adipocytic malignancy through activation of xenobiotic response pathways, disruption of cellular metabolism, and interactions with cancer-related receptors. AhR partially mediates this toxicological effect, and five key proteins, including CDH3, ADORA2B, MMP14, IP6K2, and HTR2A, are used to predict the development of dioxin-related liposarcoma. The selective HTR2A receptor antagonist ketanserin has the potential to alleviate this toxicological impact. Our study presents an efficient, cost-effective toxicological analysis using network toxicology, offering new insights into dioxin-associated liposarcoma.