Investigating the effects of peripubertal Bisphenol-A exposure on puberty onset, depression-related behaviors, and hypothalamic orexin system function in rats

The regulation of pubertal timing and reproductive development is a highly coordinated endocrine process, critically governed by hypothalamic-pituitary-gonadal (HPG) axis signaling. Disruption of these hormone pathways by environmental exposure to endocrine- disrupting chemicals (EDCs) such as bisphenol A (BPA) has profound public health implications. BPA is widely prevalent and is biologically active at low exposures, exhibiting estrogenic and anti-androgenic activity. Increasing evidence links BPA exposure to altered pubertal outcomes, which in turn are associated with the emergence of mental health conditions in adolescence and early adulthood. This dissertation investigates the neuroendocrine, behavioral, and mechanistic consequences of BPA exposure, focusing on puberty as a sensitive exposure window for hormonal reprogramming. We were particularly interested in determining how BPA-induced changes in pubertal outcomes may predispose to depression- and anxiety-related outcomes, and if this was associated with persistent disruption of brain reward systems. First, the sex- and dose-dependent effects of BPA exposure during puberty are characterized using both male and female rat models. Parameters evaluated include timing of pubertal onset, estrous cyclicity, circulating reproductive hormone levels, and hypothalamic gene expression relevant to HPG function. Results demonstrate that peripubertal BPA exposure accelerates puberty onset and disrupts estrous cycling in females with an increase in pre-puberty luteinizing-hormone (LH) levels, while causing dose-dependent reductions in testosterone in males, but not overtly altering male pubertal initiation. Second, because of clinical evidence linking altered pubertal outcomes with the emergence of depression and anxiety disorders in early adulthood, behavioral phenotypes relevant to these conditions were assessed in BPA-exposed rats. In female rats, peripubertal exposure was associated with diminished reward sensitivity and motivational drive; opposite effects were observed in BPA-exposed males. Both sexes exhibited increased anxiety-related behaviors following BPA. Thus, BPA exposure during puberty may heighten vulnerability to depression- and anxiety-like behaviors in females, but increase propensity towards reward-directed behaviors in males. Finally, mechanistic studies revealed that BPA exposure reprograms the hypothalamic orexin system in a sexually dimorphic manner; female BPA rats exhibit overall reduced orexin function, whereas orexin function is overall enhanced in BPA males. Potential regulators of these changes in orexin function, including disrupted estrogen receptor signaling and engagement of inflammatory pathways are explored. Altogether, this work establishes puberty as an overlooked critical period of endocrine vulnerability to EDCs, identifies molecular and circuit-level pathways susceptible to BPA, and highlights the sex- differentiated health consequences of environmental hormone disruption. These findings underscore the urgency for stricter chemical regulation and provide an expanded framework for understanding how endocrine disruptors shape neurobehavioral development and psychiatric risk across the lifespan.