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Submitted on September 27, 2004
Accepted on January 24, 2005
Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich
* To whom correspondence should be addressed. E-mail: lichtens{at}pharma.unizh.ch.
Since the estrogen receptor (ER) ligand type influences transactivation, it is important to obtain information on molecular actions of non-classical ER agonists. UV filters from cosmetics represent new classes of endocrine active chemicals, including the preferential ER
ligands 4-methylbenzylidene camphor (4-MBC) and 3-benzylidene camphor (3-BC). We studied estrogen target gene expression in uterus of Long Evans rats after developmental exposure to 4-MBC (0.7, 7, 24, 47 mg/kg/day) administered in feed to the parent generation before mating, during pregnancy and lactation, and to the offspring until adulthood. 4-MBC altered steady-state levels of mRNAs encoding for ER
, ER
, progesterone receptor (PR), insulin-like growth factor I (IGF-I), androgen receptor (AR), determined by real-time RT PCR in uterus of 12 week-old offspring. Western blot analyses of the same tissue homogenates indicated changes in ER
and PR but not ER
proteins. To assess sensitivity to estradiol (E2), offspring were ovariectomized on day 70, injected with E2 (10 or 50 µg/kg sc) on day 84, and killed 6 h later. Acute up-regulation of PR and IGF-I, and down-regulation of ER
and AR by E2 was dose-dependently reduced in 4-MBC-exposed rats. The reduced response to E2 was accompanied by reduced coactivator SRC-1 mRNA and protein levels. Our data indicate that developmental exposure to 4-MBC affects the regulation of estrogen target genes and the expression of nuclear receptor coregulators in uterus at mRNA and protein levels.
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