Molecular mechanisms of endocrine disruption in the hypothalamus throughout the life cycle



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Endocrine disrupting chemicals (EDCs) are compounds in the environment that interfere with hormone systems in the body. I investigated if gestational exposure to a known class of EDCs, polychlorinated biphenyls (PCBs), resulted in life long alterations in neuroendocrine function. My overall hypothesis was that prenatal PCB exposure would cause molecular and cellular changes to the developing hypothalamus that would manifest across development through differences in hypothalamic gene expression, molecular epigenetic modifications, and corresponding effects on sexual development. To perform this work, I characterized changes in gene expression in two regions of the hypothalamus required for reproductive function throughout the life cycle and measured changes in somatic markers associated with reproductive physiology and development. This approach allowed me to relate specific neuroendocrine changes back to altered reproductive function. First, I present normative data showing gene and hormone changes throughout development in male and female rats to use as a basis of comparison for my further studies on EDCs. Second, I investigated how gestational exposure to PCBs on embryonic day 16 and 18 affected development of the hypothalamus through adulthood and caused corresponding changes in physiological functions. PCBs altered estrous cyclicity in females and delayed the timing of puberty in males. Developmental changes in gene expression were associated with sex, age and region of the hypothalamus. As a whole, the data suggested that gestational exposure to PCBs altered a network of hypothalamic genes and was associated with altered reproductive physiology. Finally, I extended my study farther along the life cycle to investigate if gestational exposure to PCBs altered the timing of reproductive aging in male and female rats. Few effects in males were observed. However, females exposed to PCBs had lower serum concentrations of LH on proestrus, and altered expression of numerous genes in the hypothalamus. These changes in gene expression were specific to the females’ cycle status and the results provided novel insight into the molecular mechanisms underlying reproductive aging. Taken together, my dissertation resulted in a comprehensive profile of both normal hypothalamic developmental changes, as well as providing insight into endocrine disruption of hypothalamic gene networks from birth through aging.