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theses

ETD doctoral

The maintenance of energy homeostasis is an integral endocrine-mediated function and is centrally coordinated through hypothalamic melanocortin circuitry. Two nuclear receptors that regulate energy homeostasis are estrogen receptor (ER) α and peroxisome proliferator-activated receptor (PPAR) γ. Disruption of these pathways can cause metabolic disturbances that may lead to serious disorders such as diabetes and metabolic syndrome. This gives cause for concern regarding chemicals that can interfere with endogenous endocrine signaling such as ERα and PPARγ. One such chemical class are organophosphate flame retardants (OPFRs). OPFRs demonstrate widespread human exposure and have been implicated in disruption of energy homeostasis. In this dissertation, I will be examining the toxicological impact of adult exposure to OPFRs on neuroendocrine and physiological endpoints of metabolic disruption. First, I characterize the diet- and sex-dependent physiological effects of adult exposure to OPFRs in wildtype (WT) mice, examining parameters such as weight gain, adiposity, metabolism, activity, ingestive behaviors, glucose tolerance and insulin sensitivity, and plasma peptide hormone levels. I found that OPFR exposure alters circulating peptide hormone levels, feeding behavior, disrupts diurnal fluid intake patterns, and decreases female activity and energy expenditure while promotes weight gain and adiposity in male mice fed a high-fat diet (HFD). Next, I characterized similar parameters within global ERα knockout (ERαKO) and brain-specific PPARγ knockout (PPARγKO) mice to assess the responsibility of the respective receptors in OPFR-induced disruption of energy homeostasis. I found that the weight gain and adiposity associated with OPFR exposure in WT males can, in part, be attributed to both ERα and PPARγ action. Additionally, I observed numerous novel effects of OPFR in KO genotypes, which may be a result of the absence of ERα and PPARγ targets making alternative OPFR targets more vulnerable to disruption. Lastly, I characterize the neuroendocrine impact of OPFR exposure on hypothalamic neurons governing energy homeostasis. Overall, OPFR exposure augmented neuronal excitability, concluding in a net increase of neuronal output from arcuate neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons. Collectively, these data represent significant disruptions to energy homeostasis and demonstrate that the capacity for OPFRs to cause adverse health effects extends to adult exposures.

ETD_11043

Ph.D.

Includes bibliographical references

doi:10.7282/t3-yjr3-1h35

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