Endocrine-disrupting chemicals, epigenetics, and skeletal system dysfunction: exploration of links using bisphenol A as a model system

Abstract

Early life exposures to endocrine-disrupting chemicals (EDCs) have been associated with physiological changes of endocrine-sensitive tissues throughout postnatal life. Although hormones play a critical role in skeletal growth and maintenance, the effects of prenatal EDC exposure on adult bone health are not well understood. Moreover, studies assessing skeletal changes across multiple generations are limited. In this article, we present previously unpublished data demonstrating dose-, sex-, and generation-specific changes in bone morphology and function in adult mice developmentally exposed to the model estrogenic EDC bisphenol A (BPA) at doses of 10 μg (lower dose) or 10 mg per kg bw/d (upper dose) throughout gestation and lactation. We show that F1 generation adult males, but not females, developmentally exposed to bisphenol A exhibit dose-dependent reductions in outer bone size resulting in compromised bone stiffness and strength. These structural alterations and weaker bone phenotypes in the F1 generation did not persist in the F2 generation. Instead, F2 generation males exhibited greater bone strength. The underlying mechanisms driving the EDC-induced physiological changes remain to be determined. We discuss potential molecular changes that could contribute to the EDC-induced skeletal effects, with an emphasis on epigenetic dysregulation. Furthermore, we assess the necessity of intact sex steroid receptors to mediate these effects. Expanding future assessments of EDC-induced effects to the skeleton may provide much needed insight into one of the many health effects of these chemicals and aid in regulatory decision making regarding exposure of vulnerable populations to these chemicals.

Impact of prenatal exposure to bisphenol A on pregnant rats: Fetal bone development and immunohistochemistry implications

“…Xin et al (2018) demonstrated dose-, sex-, and generation-specific differences in skeletal morphology and mechanical function following gestational and lactational exposure to BPA. The lateral growth of the femur was affected depending on sex and dose, while there was no change in the longitudinal growth of the femur.…”

“…Therefore, this study may be the first reported research in this area. Apart from this, studies that examined the effects of BPA on bone development following prenatal exposure have shown a delay in ossification, skeletal disorders, and increased femur length (Agas et al, 2013; Kim et al, 2001; Xin et al, 2018). Hardin et al (1981) reported that 85- and 125-mg/kg doses of BPA reduced the number of live fetuses and suppressed fetal BW and head-to-shoulder length.…”

“…Total cross-sectional area, which depends on osteoblast function, was significantly reduced at the high dose. As a result, BPA exposure is associated with dose- and sex-specific alterations in femoral morphological parameters that could influence bone strength (Xin et al, 2018). Our results are consistent with those of the Xin study.…”

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

“…When given during gestation, BPA appears to have sex-and dose-dependent results. Almost no studies showed any differences in female offspring of BPA-exposed dams compared to control offspring [61][62][63][64]. In rats, male offspring had increased cortical thickness at the 25 µg dose compared to control, but decreased cortical thickness at the 250 µg dose [61].…”

“…In mice, male offspring had increased femur lengths, but no differences in biomechanical strength [63]. In another study in mice, male offspring showed decreased cortical thickness and biomechanical strength regardless of dose [64]. In addition to animal models, BPA exposure blocks osteoblastic and osteoclastic differentiation and increases markers of apoptosis in a dosedependent manner in progenitor cells [65] and human osteosarcoma cells [66].…”