Mechanisms for endocrine disrupting chemical action on sexual differentiation of the rat brain



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Endocrine disrupting chemicals (EDCs) are a class of environmental toxicants, of both natural and synthetic origin, that interfere with normal endocrine function. Exposure to EDCs during susceptible periods of development, particularly embryogenesis, can result in profound neurological and reproductive deficits. While the impact of developmental exposure to EDCs on reproductive function and behavior has been much studied, the underlying mechanisms responsible for these observed effects are not well understood. The goal of the research detailed in this dissertation is to elucidate the cellular and molecular targets by which a representative class of EDCs, polychlorinated biphenyls (PCBs), disrupts normal reproductive neuroendocrine function. My specific hypothesis is that PCBs cause changes in sexually dimorphic brain regions underlying sex-specific reproductive physiology and behavior through the perturbation of normal developmental apoptosis, with long-term consequences for reproductive success.

The studies detailed herein focus on three areas which contribute to an understanding of the effects of PCBs on neuroendocrine reproductive function: (1) the in vitro effects of PCBs on a neuroendocrine cell line, (2) developmental effects of PCBs on the gestationally exposed F1 generation, and (3) the physiological consequences of these developmental alterations for adult reproductive function. In the first section of this dissertation, the neurotoxic and endocrine disrupting effects of PCBs on a representative developing neuroendocrine cell model, the GT1-7 GnRH cell line, are investigated in time- and dose-response experiments. Treatment and dose-dependent effects are observed for GnRH peptide concentrations, cell viability, apoptotic and necrotic cell death, and caspase activation. In general, GnRH peptide levels are suppressed by high doses and longer durations of PCBs, and elevated at low doses and shorter time points. The suppression of GnRH peptide levels was partially reversed in cultures co-treated with the estrogen receptor antagonist ICI 182,780. All PCBs tested reduced viability and increased both apoptotic and necrotic cell death. The second section of this dissertation examines whether prenatal PCB exposure alters normal neuroendocrine development in the F1 generation, including sexual differentiation of the brain. Disruption of hypothalamic development is detectable as early as the day after birth (postnatal day (P) 1), as indicated by abnormal programmed cell death, and alterations in neuroendocrine gene and protein expression. The third section discusses the physiological impact of developmental PCB exposure on reproductive maturation and adult neuroendocrine function. Pubertal onset is advanced and estrous cyclicity irregular in PCB endocrine-disrupted females. Furthermore, sexual differentiation of female neuroendocrine systems is masculinized/defeminized. Collectively, these results suggest that the disrupted sexual differentiation of the POA can be detected as early as the day after birth, effects that may underlie the adult reproductive phenotype.