Effects of the putative xenoestrogens Benzophenone-2 (BP2) and Octyl-methoxycinnamate (OMC) on gene expression in the rat pituitary

Based on the rat uterotrophic assay, Benzophenone-2 (BP2) and Octyl-methoxycinnamate (OMC), two frequently used UV-filters in cosmetics, have been recently accused as estrogenic endocrine disrupters. An estrogenic action requires induction of the estrogen receptor (ER) signalling pathway comprising ERα and ß and their splice variants like the truncated estrogen receptor protein 1 (TERP1). Other known modulators of the ER signalling pathway are the aryl hydrocarbon receptor (AhR) and the estrogen receptor-related receptor 1 (ERR1). To further characterise the suggested estrogenic activity of OMC and BP2, the expression pattern of these nuclear receptors were measured in the pituitary of ovariectomized (ovx) rats. As reference compounds Estradiol-valerate (E2, ER ligand), Diethylstilbestrol (DES, ERR1 ligand) and 3-Methylcholanthrene (3MC, AhR ligand) were used. Adult ovx rats were treated orally once per day for 5 days with either E2, DES (0.6mg/kg each), 3MC (40mg/kg), or BP2 or OMC (10, 33, 100, 333mg/kg dissolved in olive oil). The control group received olive oil only. Gene expression was determined with real-time RT-PCR. A strong uterotrophic effect, cornification of the vaginal epithelium and a significant reduction of LHß-expression was observed in E2, DES and BP2 but not in OMC and 3-MC treated rats. Pituitary mRNA levels of ERα and ERR1 remained unaffected in all treatment groups, while levels of ERß and AhR were reduced to about 50% of the control group by E2 and DES (p<0.01). A profound increase in TERP1 expression occurred in the E2, DES and BP2 groups (about 200 fold, p<0.01).

Conclusions: The UV filter BP2 is a strong but selective estrogenic compound (uterus weight, vaginal cytology, changes of LHß- and TERP1 expression but no effect on AhR-, ERR1- and ER mRNA levels), while OMC, even at the highest dose of 333mg/kg did not exert any detectable estrogenic activity. We suggest that selective effects of estrogenic compounds like BP2 on pituitary gene expression might represent a possible molecular basis of endocrine disrupting activity