ToxSci Advance Access originally published online on August 4, 2009
Toxicological Sciences 2009 112(1):68-77; doi:10.1093/toxsci/kfp176
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
An Evaluation of Estrogenic Activity of Parabens Using Uterine Calbindin-D9k Gene in an Immature Rat Model
Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea
1 To whom correspondence should be addressed. Fax: +82-43-267-3150. E-mail: ebjeung{at}chungbuk.ac.kr.
Received May 15, 2009; accepted July 23, 2009
 |
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 17
-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- and progesterone receptor (PR) was analyzed. Exposure to EE or parabens caused a dramatic decrease in expression of both ER- mRNA and protein levels, whereas cotreatment with fulvestrant reversed these effects. These data showed the difference of CaBP-9k and ER- expression, suggesting that CaBP-9k may not express via ER- 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- 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.
Key Words: parabens; endocrine disruptors; CaBP-9k; uterus; rat.