Abstract
Bisphenol A (BPA) exposure results in numerous developmental and functional abnormalities in reproductive organs in rodent models, but limited data are available regarding BPA effects in the primate uterus. To determine if maternal oral BPA exposure affects fetal uterine development in a non-human primate model, pregnant rhesus macaques carrying female fetuses were exposed orally to 400 µg/kg BPA or vehicle control daily from gestation day (GD) 50–100 or GD100–165. Fetal uteri were collected at the completion of treatment (GD100 or GD165); tissue histology, cell proliferation, and expression of estrogen receptor alpha (ERα) and progesterone receptor (PR) were compared to that of controls. Gene expression analysis was conducted using rhesus macaque microarrays. There were no significant differences in histology or in the percentage of cells expressing the proliferation marker Ki-67, ERα, or PR in BPA-exposed uteri compared to controls at GD100 or GD165. Minimal differences in gene expression were observed between BPA-exposed and control GD100 uteri. However, at GD165, BPA-exposed uteri had significant differences in gene expression compared to controls. Several of the altered genes, including HOXA13, WNT4, and WNT5A, are critical for reproductive organ development and/or adult function. We conclude that second or third trimester BPA exposure does not significantly affect fetal uterus development based on morphological, proliferation, and steroid hormone receptor assessments. However, differences in expression of key developmental genes after third trimester exposure suggest that BPA could alter transcriptional signals influencing uterine function later in life.
Highlights
The disruptive effects of inappropriate estrogenic chemical exposure on human female reproductive tract development are well established
The dams included in this study were given an oral dose of Bisphenol A (BPA) that resulted in average serum concentrations of unconjugated biologically active BPA of,0.3–0.5 ng/ml [12], which is similar to levels found in human adults and fetuses [2,3]
In control animals at GD165 there was increased evidence of uterine glandulogenesis on histology and extensive changes in the gene expression profiles compared to GD100
Summary
The disruptive effects of inappropriate estrogenic chemical exposure on human female reproductive tract development are well established. Diethylstilbestrol is no longer used in pregnant women, there are concerns that environmental exposures to other estrogenic endocrine disrupting compounds could affect fetal reproductive tract development. Bisphenol A (BPA) is a widely used industrial chemical with estrogenic activity. As a component of polycarbonate plastics and epoxy resins, BPA is incorporated into food containers, cans, dental sealants, and thermal receipts. It leaches out of these parent compounds with heating and degradation and exposure is nearly ubiquitous in industrialized countries [2,3,4]
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