Perinatal exposure to organophosphate flame retardants: effects on gene expression, metabolism, feeding and exploratory behavior
Creators: name: Walley, Sabrina Nicole
Publisher: name: No Publisher Supplied
Year: 2019

description: Following the phase out of polybrominated diphenyl ethers (PBDEs) due to their persistence in the environment and endocrine disrupting properties, organophosphate flame retardants (OPFR) massively increased in production. Because of this persistence, flame retardants (FR) are ubiquitous in the environment and can interact with multiple nuclear receptors, including the estrogen receptors (ERs) and peroxisome proliferating activated receptors (PPARs). While many studies have assessed the effects of developmental exposure to EDCs on energy homeostasis, little is known about FR like OPFRs, individual food intake, metabolic parameters and their effects on metabolic syndrome. Therefore, we investigated maternal OPFR exposure followed by adult high-fat diet (HFD) or low-fat diet (LFD) challenge results in sexually dimorphic differences in behavior, activity and neuropeptides through interactions with steroids and nuclear receptors (experiment 1) and if maternal OPFR exposure with a HFD or LFD challenge results in sexually dimorphic changes in gene expression and higher susceptibility to symptoms of metabolic syndrome (experiment 2). In experiment 1, WT C57Bl/6J dams were orally dosed with vehicle (oil) or an OPFR mixture {1mg/kg combination each of tris(1,3-dichloro-2-propyl)phosphate, triphenyl phosphate, and tricresyl phosphate} from gestation day 7 to postnatal day 14. During maternal exposure, anogenital distance (AGD) was measured in pups as an early sign of maternal influences on progeny. Males had a reduced AGD, exhibiting estrogenic or anti-androgenic effects. After weaning, pups were challenged with a high fat (HFD) or low fat diet (LFD). In order to evaluate anxiety- like behavior, we used the elevated plus maze (EPM) and open field test (OFT) and the comprehensive lab animal monitoring system (CLAMS) for general locomotor activity. EPM results found males exhibited more anxiogenic behavior, while females had the same effect in OFT. CLAMS showed a reduction in activity for males. Individual food intake, and meal patterns were quantified with the Biological Data Acquisition System (BioDAQ), which found that OPFR and HFD males ate more during acrophase. Increased energy intake was observed in OPFR HFD female mice. Arcuate (ARC) neuropeptide and hormone receptor expression were measured to assess changes in gene expression, which showed only females had an increase in ARC expression genes. Showing that OPFR, or an interaction of OPFR and diet had a sexually dimorphic effect.In experiment 2, WT C57Bl/6J dams were orally dosed with vehicle (oil) or an OPFR mixture {1mg/kg combination each of tris(1,3-dichloro-2-propyl)phosphate, triphenyl phosphate, and tricresyl phosphate} from gestation day 7 to postnatal day 14. After weaning, pups were challenged with a high-fat (HFD) or low-fat diet (LFD). As symptoms of metabolic syndrome are not exclusive to obese individuals, we not only analyzed bodyweight and body composition, but other metabolic activity parameters. OPFR altered substrate utilization in both sexes, altered carbon dioxide and oxygen consumption in females following CLAMS use. OPFR altered fasting glucose in females, and glucose and hepatic glucose homeostasis in males. Plasma leptin was reduced in males while liver enzymes and receptors were reduced in both sexes. These data suggest that OPFRs alter ARC and liver homeostatic gene expression and energy balance in a sex-dependent manner.