Developmental exposure to diethylstilbestrol at low doses alters femur length and tensile strength

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 ?g/kg/day, BPA, 10 ?g/kg/day, EE(2), 0.01, 0.1, or 1.0 ?g/kg/day, or vehicle from Gestation Day 11 to Postnatal Day 12 via a mini-osmotic pump in the dam.

Developmental exposure to xenoestrogens at low doses alters femur length and tensile strength in adult mice, Biology of reproduction, NCBI PubMed PMID: 22088916, 2012 Mar.

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.

Comparison of Effects of Developmental Exposure to EE2, DES, and BPA

Developmental exposure to low-dose (0.01 and 0.1 ?g/kg) EE2 and DES resulted in similar bone profiles. Both chemicals increased femur length and decreased tensile strength, which was reflected as a trend toward decreased torsional ultimate strength. The chemicals differed, however, in that developmental DES exposure but not low-dose developmental EE2 exposure tended to decrease the overall energy the bones could absorb prior to breaking.

Compared to developmental exposure to EE2 and DES, developmental exposure to BPA caused few significant alterations in bone strength. In male animals, developmental exposure to BPA increased femur length but had no effect on femur strength. The effects of developmental exposure of BPA on females were more similar to those observed in females exposed to EE2 or DES with trends toward decreased torsional ultimate strength and energy to failure in BPA-exposed females. These are likely related to a change in shape of the bone and not due to differences in the material comprising the bone, because the shear modulus of elasticity and torsional stiffness were found not to be different in these animals.

US National Library of Medicine National Institutes of Health, Biology of reproduction, PMC3316267, 2012 Mar.

Developmental programming of the femur by BPA differed from that by DES and EE2. This is possibly because BPA is mechanistically distinct from DES and EE2. Compared to DES and EE2, BPA is a weak estrogen that preferentially binds to ESR2 rather than ESR1. Additionally, BPA binds the estrogen-related receptor with much higher affinity than either of the classical ESRs. It is also possible that these mechanistic differences are enhanced by differential expression of the ESRs and ESRRs in fetal bone.

In conclusion, this study demonstrates for the first time that low-dose developmental exposure to xenoestrogens at levels relevant to current human exposure negatively impacts adult femoral geometry and strength in mice. These studies suggest that bones from developmentally exposed animals are more susceptible to fracture. Although pregnant women are no longer prescribed DES, they are in fact, chronically exposed to myriad chemicals in the environment that are capable of disrupting estrogen signaling, including BPA, EE2, and other pharmaceuticals, pesticides, detergents, and naturally occurring phytoestrogens and mycoestrogens. Importantly, most humans are not likely to be exposed to estrogen-disrupting chemicals in isolation and are more likely exposed to many at any given time, and there is potential for additive effects. Taken together, the results from the current study and the potential for mixtures of chemicals to cause additive effects suggest that humans exposed to xenoestrogens while in the womb may have an increased risk of fracture due to alterations in bone geometry and material strength. Currently, this association has not been examined epidemiologically.

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