Xenoestrogen exposure imprints expression of genes (Hoxa10) required for normal uterine development

  • Smith C
  • Taylor H
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Abstract

The developing reproductive tract is sensitive to endocrine perturbation. Bisphenol A {(BPA),} a xenoestrogen, is a common component of food storage plastics and dental composites. We tested the ability of {BPA} to alter expression of {HOXA10,} a gene necessary for uterine development. A dose-response increase in {HOXA10} {mRNA} expression was demonstrated in Ishikawa cells treated with 0.1 {nM} to 25 {microM} {BPA.} To determine whether in utero {BPA} exposure resulted in a lasting alteration of uterine {HOXA10} expression, mice were treated with 0.5-5.0 mg/kg {BPA} on gestational days 9-16. A dose-responsive increase was seen in stromal cell {HOXA10} expression in 2- and 6-week-old mice exposed in utero. To discern the mechanism of {BPA} action, the {HOXA10} estrogen response element {(ERE)} and autoregulatory element {(ARE)} were tested for {BPA} responsiveness. {BPA} drove luciferase expression from {HOXA10-ERE} and {ARE} reporter constructs. {HOXA10} {ERE} mediated induction was blocked by {ER} antagonist {ICI,} while {HOXA10} {ARE} induction was blocked by either {ICI} or {HOXA10} antisense. {BPA} affects {HOXA10} expression through the {HOXA10} {ERE} and indirectly through the {ARE.} {BPA} initially alters {HOXA10} expression through the {ERE,} however, the response is imprinted and uncoupled from estrogen stimulation in the adult. Several xenoestrogens alter {HOX} gene expression, indicating that {HOX} genes are a common target of endocrine disruption. In utero exposure to a xenoestrogen produces reproductive tract alterations by imprinting essential developmental regulatory genes.

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Smith, C. C., & Taylor, H. S. (2006). Xenoestrogen exposure imprints expression of genes (Hoxa10) required for normal uterine development. The FASEB Journal, 21(1), 239–246. https://doi.org/10.1096/fj.06-6635com

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