Dataset Information

Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures.

ABSTRACT: Endocrine and metabolism disrupting chemicals (EDCs/MDCs) have been associated with environmental liver diseases including toxicant-associated steatohepatitis (TASH). TASH has previously been characterized by hepatocellular necrosis, disrupted intermediary metabolism, and liver inflammation. Polychlorinated biphenyls (PCBs) are environmental EDCs/MDCs associated with the genesis and progression of steatohepatitis in animal models and human liver injury in epidemiology studies. The cross-sectional Anniston Community Health Survey (ACHS) investigates ortho-substituted PCB exposures and health effects near a former PCB manufacturing complex. The rates of obesity, diabetes, and dyslipidemia were previously determined to be high in ACHS. In this study, 738 ACHS participants were categorized by liver disease status using the serum cytokeratin 18 biomarker. Associations between PCB exposures and mechanistic biomarkers of intermediary metabolism, inflammation, and hepatocyte death were determined. The liver disease prevalence was high (60.2%), and 80.7% of these individuals were categorized as having TASH. Sex and race/ethnicity differences were noted. TASH was associated with increased exposures to specific PCB congeners, insulin resistance, dyslipidemia, proinflammatory cytokines, and liver necrosis. These findings are consistent with PCB-related steatohepatitis. ?PCBs was inversely associated with insulin resistance/production, leptin, and hepatocyte apoptosis, while other adipocytokines were increased. This is possibly the largest environmental liver disease study applying mechanistic biomarkers ever performed and the most comprehensive analysis of PCBs and adipocytokines. It provides insight into the mechanisms of PCB-related endocrine and metabolic disruption in liver disease and diabetes. In the future, associations between additional exposures and liver disease biomarkers will be evaluated in the ACHS and follow-up ACHS-II studies.

SUBMITTER: Clair HB

PROVIDER: S-EPMC6016643 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures.

Clair Heather B HB Pinkston Christina M CM Rai Shesh N SN Pavuk Marian M Dutton Nina D ND Brock Guy N GN Prough Russell A RA Falkner Keith Cameron KC McClain Craig J CJ Cave Matthew C MC

Toxicological sciences : an official journal of the Society of Toxicology 20180701 1

Endocrine and metabolism disrupting chemicals (EDCs/MDCs) have been associated with environmental liver diseases including toxicant-associated steatohepatitis (TASH). TASH has previously been characterized by hepatocellular necrosis, disrupted intermediary metabolism, and liver inflammation. Polychlorinated biphenyls (PCBs) are environmental EDCs/MDCs associated with the genesis and progression of steatohepatitis in animal models and human liver injury in epidemiology studies. The cross-sectiona ...[more]

PMID: 29684222

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Project description:BackgroundThe prevalence of alcohol-associated liver disease (ALD), a subtype of fatty liver disease (FLD), continues to rise. ALD is a major cause of preventable death. Polychlorinated biphenyl (PCB) 126 is an environmentally relevant, dioxin-like pollutant whose negative metabolic effects have been well documented. In human and animal studies, PCB has been associated with the severity of nonalcoholic fatty liver disease (NAFLD). However, few studies have investigated whether exposures to environmental toxicants can worsen ALD. Thus, the objective of the current study was to develop an alcohol-plus-toxicant model to study how an environmental pollutant, PCB 126, impacts rodent ALD pathology.MethodsBriefly, male C57BL/6J mice were exposed to 0.2 mg/kg PCB 126 or corn oil vehicle four days prior to ethanol feeding using the chronic-binge (10-plus-one) model.ResultsConcentrations of macromolecules, including hepatic lipids, carbohydrates, and protein (albumin) were impacted. Exposure to PCB 126 exacerbated hepatic steatosis and hepatomegaly in mice exposed to the chemical and fed an ethanol diet. Gene expression and the analysis of blood chemistry showed a potential net increase and retention of hepatic lipids and reductions in lipid oxidation and clearance capabilities. Depletion of glycogen and glucose was evident, which contributes to disease progression by generating systemic malnutrition. Granulocytic immune infiltrates were present but driven solely by ethanol feeding. Hepatic albumin gene expression and plasma levels were decreased by ~50% indicating a potential compromise of liver function. Finally, gene expression analyses indicated that the aryl hydrocarbon receptor and constitutive androstane receptor were activated by PCB 126 and ethanol, respectively.ConclusionsVarious environmental toxicants are known to modify or enhance FLD in high-fat diet models. Findings from the present study suggest that they interact with other lifestyle factors such as alcohol consumption to reprogram intermediary metabolism resulting in exacerbated ethanol-associated systemic malnutrition in ALD.

Project description:In 1973, accidental contamination of Michigan livestock with polybrominated biphenyls (PBBs) led to the establishment of a registry of exposed individuals that have been followed for > 40 years. Besides being exposed to PBBs, this cohort has also been exposed to polychlorinated biphenyls (PCBs), a structurally similar class of environmental pollutants, at levels similar to average US exposure. In this study, we examined the association between current serum PCB and PBB levels and various female reproductive health outcomes to build upon previous work and inconsistencies. Participation in this cross-sectional study required a blood draw and completion of a detailed health questionnaire. Analysis included only female participants who had participated between 2012 and 2015 (N = 254). Multivariate linear and logistic regression models were used to identify associations between serum PCB and PBB levels with each gynecological and infertility outcome. Additionally, a generalized estimating equation (GEE) model was used to evaluate each pregnancy and birth outcome in order to account for multiple pregnancies per woman. We controlled for age, body mass index, and total lipid levels in all analyses. A p-value of <0.05 was used for statistical significance. Among the women who reported ever being pregnant, there was a significant negative association with higher total PCB levels associating with fewer lifetime pregnancies ( β = -0.11, 95% CI = -0.21 to -0.005, p = 0.04). There were no correlations between serum PCB levels and the self-reported gynecological outcomes (pelvic inflammatory disease, endometriosis, polycystic ovarian syndrome, or uterine fibroids). No associations were identified between serum PCB levels and the prevalence of female infertility in women reporting ever having sexual intercourse with a male partner. There were no associations identified between serum PCB levels and pregnancy outcomes (singleton live births or miscarriages) or birth outcomes (preterm birth, birth weight, birth defects, hypertensive disorders of pregnancy, or gestational diabetes). PBB was not associated with any outcome. Further research is needed to determine if and how PCB may reduce pregnancy number.

Dataset Information

Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures.

Publications

Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures.

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