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Endocrine-disrupting chemicals (EDCs) might contribute to the increase in female-specific cancers in Western countries. 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) is considered the “prototypical toxicant” to study EDCs’ effects on reproductive health. Epigenetic regulation by small noncoding RNAs (sncRNAs), such as microRNAs (miRNA), is crucial for controlling cancer development. The aim of this study was to analyze transcriptional activity and sncRNA expression changes in the KGN cell line after acute (3 h) and chronic (72 h) exposure to 10 nM TCDD in order to determine whether sncRNAs’ deregulation may contribute to transmitting TCDD effects to the subsequent cell generations (day 9 and day 14 after chronic exposure). Using Affymetrix GeneChip miRNA 4.0 arrays, 109 sncRNAs were found to be differentially expressed (fold change < −2 or >2; p-value < 0.05) between cells exposed or not (control) to TCDD for 3 h and 72 h and on day 9 and day 14 after chronic exposure. Ingenuity Pathway Analysis predicted that following the acute and chronic exposure of KGN cells, sncRNAs linked to cellular development, growth and proliferation were downregulated, and those linked to cancer promotion were upregulated on day 9 and day 14. These results indicated that TCDD-induced sncRNA dysregulation may have transgenerational cancer-promoting effects.

Aryl hydrocarbon receptor (AhR) is a member of the basic helix–loop–helix–(bHLH) superfamily of transcription factors, which are associated with cellular responses to environmental stimuli, such as xenobiotics and oxygen levels. Unlike other members of bHLH, AhR is the only bHLH transcription factor that is known to be ligand activated. Early AhR studies focused on understanding the role of AhR in mediating the toxicity and carcinogenesis properties of the prototypic ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In recent years, however, it has become apparent that, in addition to its toxicological involvement, AhR is highly receptive to a wide array of endogenous and exogenous ligands, and that its activation leads to a myriad of key host physiological functions. In this study, we review the current understanding of the functions of AhR in the mucosal immune system with a focus on its role in intestinal barrier function and intestinal immune cells, as well as in intestinal homeostasis.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function. SLC46A3 was localized to the lysosome where it modulated intracellular copper levels. Forced expression of hepatic SLC46A3 resulted in decreased mitochondrial membrane potential and abnormal mitochondria morphology consistent with lower copper levels. SLC46A3 expression increased hepatic lipid accumulation similar to the known effects of TCDD exposure in mice and humans. The TCDD-induced hepatic triglyceride accumulation was significantly decreased in Slc46a3 −/− mice and was more pronounced when these mice were fed a high-fat diet, as compared to wild-type mice. These data are consistent with a model where lysosomal SLC46A3 induction by TCDD leads to cytosolic copper deficiency resulting in mitochondrial dysfunction leading to lower lipid catabolism, thus linking copper status to mitochondrial function, lipid metabolism and TCDD-induced liver toxicity. The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function.

Endocrine-disrupting chemicals (EDCs) are environmental and industrial agents that interfere with hormonal functions. EDC exposure is linked to various endocrine diseases, especially in reproduction, although the mechanisms remain unclear and effects vary among individuals. Neuroinflammation, particularly hypothalamic inflammation, is an emerging research area with implications for endocrine-related diseases like obesity. The hypothalamus plays a crucial role in regulating reproduction, and its inflammation can adversely affect reproductive health. EDCs can cross the blood–brain barrier, potentially causing hypothalamic inflammation and disrupting the reproductive axis. This review examines the existing literature on EDC-mediated hypothalamic inflammation. Our findings suggest that exposure to 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), polychlorinated biphenyl (PCB), tributyltin (TBT), phthalates, bisphenol A (BPA), and chlorpyrifos (CPF) in animals is linked to hypothalamic inflammation, specifically affecting the hypothalamic centers of the gonadotropic axis. To our knowledge, this is the first comprehensive review on this topic, indicating hypothalamic inflammation as a possible mediator between EDC exposure and reproductive dysfunction. Further human studies are needed to develop effective prevention and treatment strategies against EDC exposure.

Understanding the transfer of polychlorinated dibenzo- p -dioxins (PCDDs) and dibenzofurans (PCDFs) as well as polychlorinated biphenyls (PCBs) from oral exposure into cow’s milk is not purely an experimental endeavour, as it has produced a large corpus of theoretical work. This work consists of a variety of predictive toxicokinetic models in the realms of health and environmental risk assessment and risk management. Their purpose is to provide mathematical predictive tools to organise and integrate knowledge on the absorption, distribution, metabolism and excretion processes. Toxicokinetic models are based on more than 50 years of transfer studies summarised in part I of this review series. Here in part II, several of these models are described and systematically classified with a focus on their applicability to risk analysis as well as their limitations. This part of the review highlights the opportunities and challenges along the way towards accurate, congener-specific predictive models applicable to changing animal breeds and husbandry conditions.

The aryl hydrocarbon receptor (AhR) was initially identified as the receptor that binds and mediates the toxic effects induced by 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) and structurally related halogenated aromatics. Other toxic compounds including some polynuclear aromatic hydrocarbons act through the AhR; however, during the last 25 years, it has become apparent that the AhR plays an essential role in maintaining cellular homeostasis. Moreover, the scope of ligands that bind the AhR includes endogenous compounds such as multiple tryptophan metabolites, other endogenous biochemicals, pharmaceuticals and health-promoting phytochemicals including flavonoids, indole-3-carbinol and its metabolites. It has also been shown that like other receptors, the AhR is a drug target for multiple diseases including cancer, where both AhR agonists and antagonists effectively block many of the critical hallmarks of cancer in multiple tumor types. This review describes the anti-cancer activities of AhR ligands and demonstrates that it is time to separate the AhR from TCDD and exploit the potential of the AhR as a novel target for cancer chemotherapy.

Background: Environmental exposure to some persistent organic pollutants has been reported to be associated with metabolic syndrome in the U.S. population. Objectives: We evaluated the associations of body burden levels of dioxins and related compounds with the prevalence of metabolic syndrome among the general population in Japan. Methods: We conducted a cross-sectional study with 1,374 participants not occupationally exposed to these pollutants, living throughout Japan during 2002-2006. In fasting blood samples, we measured biochemical factors and determined lipid-adjusted concentrations of 10 polychlorinated dibenzo-p-dioxins (PCDDs), 7 polychlorinated dibenzofurans (PCDFs), and 12 dioxin-like polychlorinated biphenyls (DL-PCBs) all of which have toxic equivalency factors. We also performed a questionnaire survey. Results: The toxic equivalents (TEQs) of PCDDs, PCDFs, and DL-PCBs and total TEQs had significant adjusted associations with metabolic syndrome, whether or not we excluded diabetic subjects. By analyzing each component of metabolic syndrome separately, the DL-PCB TEQs and total TEQs were associated with all components, and the odds ratios (ORs) in the highest quartile of DL-PCB TEQs in four of the five components were higher than those for PCDDs or PCDFs. We also found congener-specific associations with metabolic syndrome; in particular, the highest quartiles of PCB-126 and PCB-105 had adjusted ORs of 9.1 and 7.3, respectively. Conclusions: These results suggest that body burden levels of dioxins and related compounds, particularly those of DL-PCBs, are associated with metabolic syndrome. Of the components, high blood pressure, elevated triglycerides, and glucose intolerance were most closely associated with these pollutants.

Sturgeon populations worldwide are threatened with extirpation but little is known about their tendency to bioaccumulate contaminants and their sensitivities to environmental burdens of these contaminants. Shortnose sturgeon and Atlantic sturgeon, two species that are federally endangered in the USA, co-occur in the Hudson River (HR) where high sediment levels of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzo-p-furans (PCDFs) occur. Previous controlled laboratory studies showed that young life-stages of both species are sensitive to toxicities at low levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and PCB126 exposure. The objective here was to measure congener-specific hepatic levels of PCBs and PCDD/Fs in HR specimens in order to determine if in situ bioaccumulation of these compounds is sufficiently high to have caused the early life-stage toxicities previously observed. Estimates of hepatic burdens of PCBs and PCDD/Fs were obtained from a small number of specimens of each species collected between 2014 and 2016 and specimens of shortnose sturgeon collected over 30 years earlier and archived in a museum collection. Several significant patterns emerged. Hepatic levels of legacy PCBs and PCDDs were low in specimens of both species but typically higher in shortnose than Atlantic sturgeon, a pattern consistent with their habitat use in the HR. Hepatic burdens in shortnose sturgeon tended to be higher in archived specimens than in more recently collected ones despite expected reduction in archived specimens due to preservation methods. Several inadvertent PCBs congeners were detected at high levels, including PCB11, but their toxicity to natural populations remains unknown. Levels of select PCDFs congeners, 2,3,7,8-TCDF and 2,3,4,7,8 PeCDF, were elevated in some shortnose sturgeon individuals from the HR. Using Relative Potency (ReP) factors derived from white sturgeon, the observed levels of some hepatic PCDFs in HR shortnose sturgeon may have been sufficiently high to impair recruitment of young life-stages in this ecosystem.

Environmental compounds can promote epigenetic transgenerational inheritance of adult-onset disease in subsequent generations following ancestral exposure during fetal gonadal sex determination. The current study examined the ability of dioxin (2,3,7,8-tetrachlorodibenzo[p]dioxin, TCDD) to promote epigenetic transgenerational inheritance of disease and DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to dioxin during fetal day 8 to 14 and adult-onset disease was evaluated in F1 and F3 generation rats. The incidences of total disease and multiple disease increased in F1 and F3 generations. Prostate disease, ovarian primordial follicle loss and polycystic ovary disease were increased in F1 generation dioxin lineage. Kidney disease in males, pubertal abnormalities in females, ovarian primordial follicle loss and polycystic ovary disease were increased in F3 generation dioxin lineage animals. Analysis of the F3 generation sperm epigenome identified 50 differentially DNA methylated regions (DMR) in gene promoters. These DMR provide potential epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Observations demonstrate dioxin exposure of a gestating female promotes epigenetic transgenerational inheritance of adult onset disease and sperm epimutations.

Fifty-five children aged 2 years from a birth cohort in the largest dioxin-contaminated area in Bien Hoa city, Vietnam participated in this survey to examine gaze behavior. Exposure levels were indicated by 2,3,7,8-tetrachlorodibenzo-p-dibenzodioxin (TCDD) and toxic equivalent of polychlorinated dibenzo-p-dioxin and polychlorinated dibenzofuran (TEQ-PCDD/Fs) levels in maternal breast milk. The percentage of the total fixation duration on the face (% Face), mouth (% Mouth), and eye areas (% Eyes) when viewing silent and conversation scenes was used as gaze behavior indices. When they reached 3-year-old, autistic behavior was assessed using the Autism Spectrum Rating Scale (ASRS). A general linear model adjusted for confounding factors was used to compare gaze indices and ASRS scores between high and low dioxin exposure groups. Effects of perinatal dioxin exposure on gaze behavior were found only when viewing conversation scenes indicated by lower % Face for boys in high TCDD exposure group and lower % Eyes for girls in high TEQ-PCDD/Fs group. Increased autistic traits showed by higher ASRS scores at 3-year-old were found in both gender in the high TCDD exposure group. These findings indicate that perinatal TCDD and TEQ-PCDD/Fs exposure may reduce gaze behavior in 2-year-old children, predicting increased autistic traits at 3-year-old.