| Estrogen Sensitivity of Target Genes and
Expression of Nuclear Receptor
Co-Regulators in Rat
Prostate after Pre- and Postnatal Exposure to the Ultraviolet
Filter 4-Methylbenzylidene Camphor Stefan Durrer, Colin Ehnes, Michaela
Fuetsch, Kirsten Maerkel, Margret Schlumpf, and Walter
Lichtensteiger Institute of Pharmacology and Toxicology
and GREEN Tox, University of Zurich, Zurich, Switzerland Abstract
Background and objectives: In previous studies, we found that the ultraviolet filter 4-methylbenzylidene camphor (4-MBC) exhibits estrogenic activity, is a preferential estrogen receptor (ER) -β ligand, and interferes with development of female reproductive organs and brain of both sexes in rats. Here, we report effects on male development. Methods: 4-MBC (0.7, 7, 24, 47 mg/kg/day) was administered in chow to the parent generation before mating, during gestation and lactation, and to offspring until adulthood. mRNA was determined in prostate lobes by real-time reverse transcription–polymerase chain reaction and protein was determined by Western blot analysis. Results: 4-MBC delayed male puberty, decreased adult prostate weight, and slightly increased testis weight. Androgen receptor (AR) , insulin-like growth factor-1 (IGF-1) , ER-α, and ER-β expression in prostate were altered at mRNA and protein levels, with stronger effects in dorsolateral than ventral prostate. To assess sensitivity of target genes to estrogens, offspring were castrated on postnatal day 70, injected with 17β-estradiol (E2 ; 10 or 50 µg/kg, sc) or vehicle on postnatal day 84, and sacrificed 6 hr later. Acute repression of AR and IGF-1 mRNAs by E2, studied in ventral prostate, was reduced by 4-MBC exposure. This was accompanied by reduced co-repressor N-CoR (nuclear receptor co-repressor) protein in ventral and dorsolateral prostate, whereas steroid receptor coactivator-1 (SRC-1) protein levels were unaffected. Conclusions: Our data indicate that 4-MBC affects development of male reproductive functions and organs, with a lowest observed adverse effect level of 0.7 mg/kg. Nuclear receptor coregulators were revealed as targets for endocrine disruptors, as shown for N-CoR in prostate and SRC-1 in uterus. This may have widespread effects on gene regulation. Key words: androgen receptor, development, estrogen receptors, gene expression, insulin-like growth factor-1, 4-methylbenzylidene camphor (4-MBC) , N-CoR, prostate, puberty, SRC-1, UV filter. Environ Health Perspect 115(suppl 1) :42–50 (2007) . doi:10.1289/ehp.9134 available via http://dx.doi.org/ [Online 8 June 2007]
This article is part of the monograph "Endocrine Disruptors—Exposure Assessment, Novel End Points, and Low-Dose and Mixture Effects." Address correspondence to M. Schlumpf, GREEN Tox, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Telephone: 41 43 233 9517. Fax: 41 43 268 9573. E-mail: margret.schlumpf@access.uzh.ch Supplemental material is available at http://www.ehponline.org/members/2007/9134/suppl.pdf We thank M. Conscience for support in the conduct of animal experiments and H. Tinwell and J. Ashby (Syngenta Central Toxicology Laboratory, Alderley Park, UK) for advice in prostate dissection. The study was supported by Swiss NRP50, EU 5th Framework Programme (EURISKED) , Swiss Federal Office for the Environment, Hartmann-Müller Stiftung, and Olga Mayenfisch Stiftung. The authors declare they have no competing financial interests. Received 1 March 2006 ; accepted 8 February 2006.
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