Hepatic steatosis is recognized as an independent risk factor for the development of cardiovascular disease. While obesity and type 2 diabetes are well-established risk factors in the development of hepatic steatosis, recent studies have revealed exposure to mixtures of persistent organic pollutants (POPs), which are environmental contaminants in various fatty foods, can promote steatosis. Thus, the present study was designed to determine if exposure to a defined mixture of prevalent polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides or their metabolites promote hepatic steatosis in a genetically induced model of type 2 diabetes, the leptin-deficient ob/ob mouse. Male C57BL/6J wild type (WT) or ob/ob mice were administered an environmentally relevant mixture of PCBs and OCs for 7 weeks via oral gavage. Exposure to POPs did not significantly alter fasting serum glucose or insulin levels. However, POPs exposure significantly increased hepatic triglyceride content in ob/ob animals, while decreasing serum triglyceride levels. This POPs-mediated increase in hepatic triglyceride content did not appear to be associated with significantly increased inflammation in either the liver or adipose. Exposure to POPs significantly induced the expression of cytochrome P450 3a11 in WT animals, yet the expression of this cytochrome was significantly downregulated in ob/ob animals regardless of POPs exposure. Taken together, the present data indicate exposure to an environmentally relevant mixture of both PCBs and OC pesticides in ob/ob mice promotes hepatic steatosis while decreasing hypertriglyceridemia, which demonstrates exposure to a defined mixture of POPs alters systemic lipid metabolism in a genetically induced model of obesity and type 2 diabetes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1399-1411, 2017.

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The effects of obesity on organophosphate pesticide-mediated toxicities, including both cholinergic and non-cholinergic targets, have not been fully elucidated. Therefore, the present study was designed to determine if high fat diet intake alters the effects of repeated exposure to chlorpyrifos (CPS) on the activities of both cholinergic and noncholinergic serine hydrolase targets. Male C57BL/6J mice were placed on either standard rodent chow or high fat diet for four weeks with CPS exposure (2.0 mg/kg) for the last 10 days of diet intake. Exposure to CPS did not alter acetylcholinesterase in the central nervous system, but it did significantly inhibit circulating cholinesterase activities in both diet groups. CPS significantly inhibited hepatic carboxylesterase and fatty acid amide hydrolase and this inhibition was significantly greater in high fat fed animals. Additionally, CPS exposure and high fat diet intake downregulated genes involved in hepatic de novo lipogenesis as well as cytochrome P450 enzymes involved in hepatic xenobiotic metabolism. In summary, the present study demonstrates that high fat diet intake potentiates CPS mediated inhibition of both carboxylesterase and fatty acid amide hydrolase in the liver of obese animals following subacute exposure and suggests obesity may be a risk factor for increased non-cholinergic hepatic CPS toxicity.