An evaluation of estrogenic activity of parabens using uterine calbindin-d9k gene in an immature rat model

Toxicol Sci. 2009 Nov;112(1):68-77. doi: 10.1093/toxsci/kfp176. Epub 2009 Aug 4.

Abstract

In the present study, calbindin-D9k (CaBP-9k), a potent biomarker for screening estrogen-like environmental chemicals in vivo and in vitro, was adopted to examine the potential estrogen-like property of the following parabens: propyl-, isopropyl-, butyl-, and isobutylparaben. Immature female rats were administered for 3 days from postnatal day 14 to 16 with 17alpha-ethinylestradiol (EE, 1 mg/kg body weight [BW]/day) or parabens (62.5, 250, and 1000 mg/kg BW/day). In uterotrophic assays, significantly increased uterus weights were detected in the EE-treated group and in the groups treated with the highest dose of isopropyl-, butyl-, and isobutylparaben. In addition, these parabens induced uterine CaBP-9k messenger RNA (mRNA) and protein levels, whereas cotreatment of parabens and fulvestrant, a pure estrogen receptor (ER) antagonist, completely reversed the paraben-induced gene expression and increased uterine weights. To investigate the ER-mediated mechanism(s) by which parabens exert their effects, the expression level of ER-alpha and progesterone receptor (PR) was analyzed. Exposure to EE or parabens caused a dramatic decrease in expression of both ER-alpha mRNA and protein levels, whereas cotreatment with fulvestrant reversed these effects. These data showed the difference of CaBP-9k and ER-alpha expression, suggesting that CaBP-9k may not express via ER-alpha pathway. In the effect of parabens on CaBP-9k expression through PR mediation, a significantly increased expression of uterine PR gene, a well-known ER-regulating gene, at both transcriptional and translational levels was indicated in the highest dose of isopropyl- and butylparaben. These parabens-induced PR gene expression was completely blocked by fulvestrant. This result indicates that CaBP-9k expression may involve with PR mediates in the estrogenic effect of paraben in immature rat uteri. Taken together, parabens exhibited an estrogen-like property in vivo, which may be mediated by a PR and/or ER-alpha signaling pathway. In addition, our results expanded the current understanding of the potential adverse effects of parabens associated with their estrogen-like activities. Further investigation is needed to elucidate in greater detail the adverse effects of parabens in humans and wildlife.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Blotting, Western
  • Calbindins
  • DNA Primers
  • Estrogens / pharmacology*
  • Female
  • Models, Biological*
  • Parabens / pharmacology*
  • RNA, Messenger / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / genetics
  • Receptors, Progesterone / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • S100 Calcium Binding Protein G / genetics*
  • Uterus / drug effects*
  • Uterus / metabolism

Substances

  • Calbindins
  • DNA Primers
  • Estrogens
  • Parabens
  • RNA, Messenger
  • Receptors, Estrogen
  • Receptors, Progesterone
  • S100 Calcium Binding Protein G
  • S100G protein, human
  • S100g protein, rat