Exposure to an environmentally relevant mixture of organochlorine compounds and polychlorinated biphenyls Promotes hepatic steatosis in male Ob/Ob mice

Abstract

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.

Persistent organic pollutants (POPs) increase rage signaling to promote downstream cardiovascular remodeling

“…Given the critical role of activation of the AGE‐RAGE axis in the pathogenesis of T2DM and cardiac remodeling, these findings demonstrate that exposure to POPs promotes cardiometabolic risk and cardiac remodeling, due as least in part to POPs‐induced activation of the AGE‐RAGE axis. In states of metabolic dysfunction such as obesity and diabetes, ROS levels become exceedingly high, and when compounded with POPs exposure, innate antioxidant defense mechanisms become overwhelmed with increased levels of ROS from the activation of RAGE/NF‐κB signaling . The following results demonstrate a potential role for AGE‐RAGE signaling in the POPs‐mediated remodeling.…”

“…In a previous a study by Mulligan et al, the experimental design and POPs mixture were reported to successfully promote NAFLD hepatic steatosis in ob / ob mice . Briefly, four‐week old male WT and ob / ob mice were randomly divided into treatment groups with 10 animals per group.…”

“…RAGEs are transmembrane cell surface receptors whose cytoplasmic domain is key for downstream signaling . The AGE‐RAGE signaling pathway can trigger multiple cellular signaling pathways in which various downstream signaling pathways, such as Ras‐extracellular signal regulated protein kinase (ERK1/2), Jak/Stat, and the transcription regulator nuclear factor‐κB (NF‐κB) are involved in the generation of reactive oxygen species (ROS) …”

Effect of Naringenin, Quercetin, and Sesamin on Xenobiotica-Metabolizing CYP1A and CYP3A in Mice Offspring after Maternal Exposure to Persistent Organic Pollutants

“…In the present study we investigated the ability of quercetin, naringenin, and sesamin to affect two major drug-metabolizing enzymes CYP1A and CYP3A after exposure to a mixture of POPs relevant to human exposure scenarios. Activity of both enzymes was previously shown to be induced by the presence of POPs [22]. It is well known that CYP1A-dependent EROD activity is induced by various toxicants including polycyclic aromatic hydrocarbons (PAH), polychlorated biphenyl (PCB), or polychlorodibenzo-p-dioxine (PCDD) [23–25].…”

The Role of Reactive Oxygen Species in β-Adrenergic Signaling in Cardiomyocytes from Mice with the Metabolic Syndrome

“…In some experiments 8–10 weeks old 6N leptin-deficient, genetically obese male mice ( ob / ob , Taconic, Denmark) and their wild-type (WT) littermates were used [18]. Varying fasting glucose levels have been reported (~4.5–8.5 mM) in control, HFD and ob/ob mice [18, 20–24]. The specific focus of the present study was on the effects of β-adrenergic stimulation on mitochondrial ROS production, cellular Ca 2+ handling and contractile function and we therefore decided to keep glucose concentration of the superfusing Tyrode solution standardized at 5.5 mM (see detailed composition below).…”