Integrative analysis of endocrine-disrupting chemical effects in the developing hypothalamus : adult behaviors and neural networks




Topper, Viktoria Yuryevna

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Endocrine-disrupting chemicals (EDCs) are environmental pollutants known to perturb hormone systems and interfere with normal endocrine function. Exposure to EDCs during hormone-sensitive developmental periods can result in profound dysfunction in reproductive physiology and behavior. In this dissertation, effects of gestational exposure to a class of EDCs called polychlorinated biphenyls (PCBs) were examined in the developing hypothalamus, which is known to control reproductive physiology and behavior in vertebrates. The specific hypothesis was that PCBs caused changes in sexually dimorphic hypothalamic nuclei, resulting in perturbation of adult sociosexual behaviors and alteration of neural networks with changes in expression of microRNAs and genes during development and in adulthood.

This research focused on two brain areas relevant to understanding the PCB effects on the developing hypothalamus: 1) microRNA and related target gene expression during postnatal development, 2) adult sociosexual behaviors and gene expression. In both sections, molecular changes were examined in two sexually dimorphic hypothalamic nuclei, medial preoptic nucleus (MPN) and ventromedial nucleus (VMN), known for their role in regulation of sociosexual behavior. In the first section of the dissertation, the effects of PCBs were examined on the expression of microRNAs and target genes at four ages during postnatal [P] development (P15, P30, P45, and P90). Age and sex specific effects were observed in both MPN and VMN, with greater effects in the MPN. The second research section of the dissertation explored whether sociosexual behaviors, namely ultrasonic vocalizations and sociosexual preference behaviors, were altered by gestational PCBs. Expression of forty-eight neuroendocrine candidate genes was also examined in the MPN and VMN of the same animals. Several sociosexual behaviors were affected, including number and acoustic properties of ultrasonic vocalizations, and nose-touching with opposite-sex animals. Gene expression was altered in sex and region-specific manner in the brains of behaviorally affected rats. Taken together, these findings suggest that gestational PCBs have lasting effects on molecular mechanisms during postnatal development and in adulthood, and could result in altered sociosexual behavior. These results have implications for human health and disease, as early life exposures to EDCs have been linked to reproductive decline in humans.



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