Hormonal regulation of bone health: novel understandings of xenoestrogens and estrogen receptor-[alpha]

Estrogen is one of the most influential hormones on bone growth and maintenance throughout the life cycle in both men and women, but there are still unknown roles of estrogen and the estrogen receptors in males. In addition, exposure to xenoestrogens, or environmental compounds that have anti-estrogenic qualities, is increasing in industrial countries, but the impact of these compounds on skeletal health in males and females remains unknown. In this dissertation, we used animal models to explore a, the importance of estrogen receptor-[alpha] (ER[alpha]) in male mice at different points in the life cycle and b, the long-term impact of gestational exposure to xenoestrogens, specifically bisphenol-A (BPA) and bisphenol-S (BPS), on male and female offspring. We found that both young and aged male ER[alpha] knockout (ERKO) animals had impaired measures of cortical geometry, but improved measures of trabecular microarchitecture, implying differential roles for ER[alpha] in different bone compartments. We also found that ERKO could lead to increased expression of sclerostin, a bone growth inhibitor, in aged, male mice. In younger, male ERKO mice we found that ERa is not required for an osteogenic response to exercise, which is in direct contrast with females. Finally, we found that gestational and lactational exposure to BPA, but not BPS, had significant negative impacts on the skeleton of adult male, but not female, mice. Male offspring exposed to BPA had significantly lower measures of both cortical geometry and trabecular microarchitecture, indicating long-term effects of interrupted estrogen signaling during uterine and early childhood on skeletal development. These findings further our understandings of the importance of estrogen on skeletal health across the lifespan and could have significant public health impacts if they are translatable to humans.