Developmental Exposure to Xenoestrogens at Low Doses Alters Femur Length and Tensile Strength in Adult Mice1

Abstract

Developmental exposure to high doses of the synthetic xenoestrogen diethylstilbestrol (DES) has been reported to alter femur length and strength in adult mice. However, it is not known if developmental exposure to low, environmentally relevant doses of xenoestrogens alters adult bone geometry and strength. In this study we investigated the effects of developmental exposure to low doses of DES, bisphenol A (BPA), or ethinyl estradiol (EE(2)) on bone geometry and torsional strength. C57BL/6 mice were exposed to DES, 0.1 μg/kg/day, BPA, 10 μg/kg/day, EE(2), 0.01, 0.1, or 1.0 μg/kg/day, or vehicle from Gestation Day 11 to Postnatal Day 12 via a mini-osmotic pump in the dam. Developmental Xenoestrogen exposure altered femoral geometry and strength, assessed in adulthood by micro-computed tomography and torsional strength analysis, respectively. Low-dose EE(2), DES, or BPA increased adult femur length. Exposure to the highest dose of EE(2) did not alter femur length, resulting in a nonmonotonic dose response. Exposure to EE(2) and DES but not BPA decreased tensile strength. The combined effect of increased femur length and decreased tensile strength resulted in a trend toward decreased torsional ultimate strength and energy to failure. Taken together, these results suggest that exposure to developmental exposure to environmentally relevant levels of xenoestrogens may negatively impact bone length and strength in adulthood.

The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity

“…As mentioned above and discussed further below, exposure to low versus high doses of estrogenic EDCs during development can have qualitatively different effects. This was recently observed for developmental programming of bone where exposure to low doses of DES (0.1 µg/kg), ethinylestradiol or BPA (10 µg/kg) increased femur length in adulthood [65], which was the opposite effect of that seen at higher pharmacologic doses. For example, developmental exposure to ethinylestradiol showed an inverted U dose response on femur length in mice, that is, low doses of 0.01 and 0.1 µg/kg increased femur length, while 1.0 µg/kg did not alter femur length relative to controls [65].…”

“…This was recently observed for developmental programming of bone where exposure to low doses of DES (0.1 µg/kg), ethinylestradiol or BPA (10 µg/kg) increased femur length in adulthood [65], which was the opposite effect of that seen at higher pharmacologic doses. For example, developmental exposure to ethinylestradiol showed an inverted U dose response on femur length in mice, that is, low doses of 0.01 and 0.1 µg/kg increased femur length, while 1.0 µg/kg did not alter femur length relative to controls [65]. Since developmental exposure to BPA resulted in fewer (but larger) fat cells and increased bone length in adult mice, exposure to xenoestrogens like BPA may favor differentiation of mesenchymal stem cells into bone versus adipocytes during development as well as in adulthood, although a more detailed analysis is required to examine this hypothesis.…”

Establishing Biomechanical Mechanisms in Mouse Models: Practical Guidelines for Systematically Evaluating Phenotypic Changes in the Diaphyses of Long Bones

“…The mouse is a remarkable model for identifying the molecular mechanisms underlying common and rare musculoskeletal diseases. Musculoskeletal biology research using mouse models has involved the analysis of inbred, outbred, and hybrid mouse strains to identify quantitative trait loci and genes of interest; the analysis of mutated mice to assess gene function; and the analysis of adaptive responses to perturbations such as pharmacological treatments, mechanical loading, and environmental toxins …”

Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta

“…Suggestive evidence comes from epidemiologic cohort studies, which report correlations between weight at birth and 1 y of age with bone integrity later in life (7,8). In animal models, gestational nutrition and hormone concentrations affect skeletal microarchitecture, bone mineral content, strength, growth plate morphology, and osteoblast differentiation capability (9)(10)(11)(12)(13)(14). However, the mechanisms remain unknown.…”