Influence of diet and maternal dioxin on endocrine disruption: puberty, metabolic syndrome, and breast cancer

Total lifetime estrogen (E2) exposure increases mammary cancer risk. TCDD indirectly affects E2 signaling and early life TCDD exposures are also implicated in breast cancer. E2 produced by adipose tissue is an underlying mechanism by which obesity contributes to early puberty, and if obesity and weight gain extend into adulthood, increased postmenopausal breast cancer risk. These observations are further complicated by greater TCDD stores in the adipose of obese- compared to lean- individuals. How several environmental exposures, maternal exposure to TCDD, lifelong exposure to high fat diet (HFD), and pubertal exposure to DMBA, modify the mammary gland was examined. It was expected that HFD and maternal exposure to TCDD would increase mammary cancer risk, through both structural remodeling of the pubertal gland and through molecular changes. Interactions of these exposures and phenotypes were examined using several mouse strains and mouse models of breast cancer, but objectives were primarily pursued using the DMBA mouse model of breast carcinogenesis. Growth trajectories, adiposity, blood glucose levels, and mammary gland development effects of HFD and maternal TCDD were examined as potential causal players in DMBA carcinogenesis. The growth trajectory, adiposity, and fasting blood glucose were increased in DMBA on HFD relative to low-fat diet (LFD). Maternal TCDD exposure increased blood glucose levels and depressed mammary gland growth at PND in DBA/2J mice fed HFD. Maternal TCDD exposure also increased blood glucose levels in DMBA transiently. Mammary lesion incidence was increased by HFD and maternal TCDD exposure. TCDD exposure increased the number of terminal end buds in DMBA on LFD, but decreased them at PND 35 in DMBA on HFD. Among DMBA on HFD, maternal TCDD increased epithelial Cyp1b1 and decreased Comt mRNA in PND 50 mammary glands. Maternal TCDD exposure also increased Cyp1b1 in mammary tumors of offspring. Thus increased steady state levels of E2 and its metabolites were likely associated with increased mammary tumor incidence in DMBA. The interactions of HFD and maternal TCDD exposure on type II diabetes risk, pubertal mammary morphology, mammary tumor incidence and estrogen pathway regulation should be further explored

A State-of-the-Science Review of Arsenic's Effects on Glucose Homeostasis in Experimental Models.

BackgroundThe prevalence of type 2 diabetes (T2D) has more than doubled since 1980. Poor nutrition, sedentary lifestyle, and obesity are among the primary risk factors. While an estimated 70% of cases are attributed to excess adiposity, there is an increased interest in understanding the contribution of environmental agents to diabetes causation and severity. Arsenic is one of these environmental chemicals, with multiple epidemiology studies supporting its association with T2D. Despite extensive research, the molecular mechanism by which arsenic exerts its diabetogenic effects remains unclear.ObjectivesWe conducted a literature search focused on arsenite exposure in vivo and in vitro, using relevant end points to elucidate potential mechanisms of oral arsenic exposure and diabetes development.MethodsWe explored experimental results for potential mechanisms and elucidated the distinct effects that occur at high vs. low exposure. We also performed network analyses relying on publicly available data, which supported our key findings.ResultsWhile several mechanisms may be involved, our findings support that arsenite has effects on whole-body glucose homeostasis, insulin-stimulated glucose uptake, glucose-stimulated insulin secretion, hepatic glucose metabolism, and both adipose and pancreatic β-cell dysfunction.DiscussionThis review applies state-of-the-science approaches to identify the current knowledge gaps in our understanding of arsenite on diabetes development. https://doi.org/10.1289/EHP4517

Oxidative Phosphorylation Impairment by DDT and DDE

There is increasing evidence supporting the characterization of the pesticide DDT and its metabolite, DDE, as obesogens and metabolic disruptors. Elucidating the mechanism is critical to understanding whether the association of DDT and DDE with obesity and diabetes is in fact causal. One area of research investigating the etiology of metabolic diseases is mitochondrial toxicity. Several studies have found associations between mitochondrial defects and insulin resistance, cellular respiration, substrate utilization, and energy expenditure. Although the mitotoxicity of DDT and DDE was established 20–40 years ago, it was not viewed in the light of the diseases faced today; therefore, it is prudent to reexamine the mitotoxicity literature for mechanistic support of DDT and DDE as causal contributors to obesity and diabetes, as well as associated diseases, such as cancer and Alzheimer's disease. This review aims to focus on studies investigating the effect of DDT or DDE on mammalian mitochondrial oxidative phosphorylation. We illustrate that both DDT and DDE impair the electron transport chain (ETC) and oxidative phosphorylation. We conclude that there is reasonable data to suggest that DDT and DDE target specific complexes and processes within the mitochondria, and that these insults could in turn contribute to the role of DDT and DDE in mitochondria-associated diseases

Dietary Fat Alters Body Composition, Mammary Development, and Cytochrome P450 Induction after Maternal TCDD Exposure in DBA/2J Mice with Low-Responsive Aryl Hydrocarbon Receptors

BackgroundIncreased fat intake is associated with obesity and may make obese individuals uniquely susceptible to the effects of lipophilic aryl hydrocarbon receptor (AHR) ligands.ObjectivesWe investigated the consequences of high-fat diet (HFD) and AHR ligands on body composition, mammary development, and hepatic P450 expression.MethodsPregnant C57BL/6J (B6) and DBA/2J (D2) dams, respectively expressing high- or low-responsive AHR, were dosed at mid-gestation with TCDD. At parturition, mice were placed on an HFD or a low-fat diet (LFD). Body fat of progeny was measured before dosing with 7,12-dimethylbenz[a]anthracene (DMBA). Fasting blood glucose was measured, and liver and mammary glands were analyzed.ResultsMaternal TCDD exposure resulted in reduced litter size in D2 mice and, on HFD, reduced postpartum survival in B6 mice. In D2 mice, HFD increased body mass and fat in off-spring, induced precocious mammary gland development, and increased AHR expression compared with mice given an LFD. Maternal TCDD exposure increased hepatic Cyp1a1 and Cyp1b1 expression in offspring on both diets, but DMBA depressed Cyp1b1 expression only in mice fed an HFD. In D2 progeny, TCDD exposure decreased mammary terminal end bud size, and DMBA exposure decreased the number of terminal end buds. Only in D2 progeny fed HFD did perinatal TCDD increase blood glucose and the size of mammary fat pads, while decreasing both branch elongation and the number of terminal end buds.ConclusionsWe conclude that despite having a low-responsive AHR, D2 progeny fed a diet similar to that consumed by most people are susceptible to TCDD and DMBA exposure effects blood glucose levels, mammary differentiation, and hepatic Cyp1 expression

Dietary fat-dependent transcriptional architecture and copy number alterations associated with modifiers of mammary cancer metastasis

Breast cancer is a complex disease resulting from a combination of genetic and environmental factors. Among environmental factors, body composition and intake of specific dietary components like total fat are associated with increased incidence of breast cancer and metastasis. We previously showed that mice fed a high-fat diet have shorter mammary cancer latency, increased tumor growth and more pulmonary metastases than mice fed a standard diet. Subsequent genetic analysis identified several modifiers of metastatic mammary cancer along with widespread interactions between cancer modifiers and dietary fat. To elucidate diet-dependent genetic modifiers of mammary cancer and metastasis risk, global gene expression profiles and copy number alterations from mammary cancers were measured and expression quantitative trait loci (eQTL) identified. Functional candidate genes that colocalized with previously detected metastasis modifiers were identified. Additional analyses, such as eQTL by dietary fat interaction analysis, causality and database evaluations, helped to further refine the candidate loci to produce an enriched list of genes potentially involved in the pathogenesis of metastatic mammary cancer

Maternal Dioxin Exposure Combined with a Diet High in Fat Increases Mammary Cancer Incidence in Mice

BackgroundRESULTS from previous studies have suggested that breast cancer risk correlates with total lifetime exposure to estrogens and that early-life 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or diets high in fat can also increase cancer risk.ObjectivesBecause both TCDD and diet affect the estrogen pathway, we examined how TCDD and a high-fat diet (HFD) interact to alter breast cancer susceptibility.MethodsWe exposed pregnant female FVB/NJ mice (12.5 days postcoitus) to 1 microg/kg TCDD or vehicle; at parturition, the dams were randomly assigned to a low-fat diet (LFD) or a high-fat diet (HFD). Female offspring were maintained on the same diets after weaning and were exposed to 7,12-dimethylbenz[a]anthracene on postnatal days (PNDs) 35, 49, and 63 to initiate mammary tumors. A second cohort of females was treated identically until PND35 or PND49, when mammary gland morphology was examined, or PND50, when mammary gland mRNA was analyzed.ResultsWe found that maternal TCDD exposure doubled mammary tumor incidence only in mice fed the HFD. Among HFD-fed mice, maternal TCDD exposure caused rapid mammary development with increased Cyp1b1 (cytochrome P450 1B1) expression and decreased Comt (catechol-O-methyltransferase) expression in mammary tissue. Maternal TCDD exposure also increased mammary tumor Cyp1b1 expression.ConclusionsOur data suggest that the HFD increases sensitivity to maternal TCDD exposure, resulting in increased breast cancer incidence, by changing metabolism capability. These results provide a mechanism to explain epidemiological data linking early-life TCDD exposure and diets high in fat to increased risk for breast cancer in humans

Parma consensus statement on metabolic disruptors

A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16–18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as “metabolic disruptors”, in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome