Toxicokinetics and Metabolic Disrupting Actions of the Flame Retardant Mixture FM

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Obesity rates in the US have reached epidemic proportions. Although lifestyle factors are clearly primary contributors, fetal metabolic reprogramming by environmental chemicals collectively called “obesogens” has been hypothesized to exacerbate obesity risk. Data collaboratively generated by the three co-PIs have identified the newly introduced fire retardant mixture Firemaster® 550 (FM 550) as an emerging contaminant in US homes and that (in rats) perinatal exposure to FM 550 results in obesity, and hallmarks of metabolic syndrome including altered exploratory behaviors, disrupted glucose sensitivity and cardiac hypertrophy. There is pressing need to assess the toxicity of FM 550 because it is at least the second most common fire retardant used in residential furniture and baby products with ubiquitous exposure in the US, yet its potential toxicological effects are not well characterized. Working as an interdisciplinary, multi- PI team, comprising an environmental chemist, a neuroendocrinologist and an endocrine pharmacologist, we submitted an R01 application to test the hypothesis that FM 550 is an obesogen, and perinatal exposure induces hallmarks of metabolic syndrome (e.g. hypertension, type-2 diabetes and cardiovascular disease) via metabolic reprograming. To strengthen the R01 application and generate additional data required to address reviewer concerns, work in this R56 application will (1) characterize the toxicokinetics of FM 550 in female rats (pregnant and non- pregnant) to specifically assess the potential for fetal transfer; and (2) characterize the hallmarks of metabolic disrupting and behavioral effects of FM550 (one dose) in exposed offspring of both sexes. Importantly, whether or not the increase in body weight (identified as sexually dimorphic in the parent R01) observed in our pilot study is accompanied by increased food intake and/or changes in overall activity will be determined. These are key markers of metabolic reprogramming and will thus help address the central hypothesis of the parent R01 that FM550 is an “obesogen” and can predispose exposed offspring to metabolic disease. Examining phenotypic sex differences is a fundamental feature of this application, and the data will ultimately be used to inform future work (and a specific aim of the R01 application) exploring the sex specific mechanisms underlying adipogenesis and the metabolic disrupting activity of FM 550, its components, and primary metabolites. Understanding the contributions of each FM 550 component to an obesogenic phenotype is critical because some have large volume applications as plasticizers in a wide variety of consumer products (e.g. polyvinyl chloride (PVC), circuit boards, hydraulic fluids, adhesives, nail polish). Collectively the proposed studies will contribute to our long term efforts to secure R01 funding for this work but also provide new knowledge required for evaluating potential human health effects of developmental FM 550 exposures including: fate and transport in tissues; obesogenic potential of the mixture and its individual components across a wide dose range; sex-specific mechanism of action; and the possible long term metabolic health consequences of early life exposure in both sexes.