Antiestrogenic effects of the polyaromatic hydrocarbon 3-methylcholanthrene in the rat uterus and mammary gland

Polyaromatic hydrocarbons (PAHs) are products of incomplete combustion of organic compounds and are abundant in exhaust fumes and cigarette smoke among others. Many of these substances are toxic. They act by binding to the aryl hydrocarbon receptor (AHR) which causes the induction of expression of phase 1 and phase 2 enzymes in the liver. In addition PAHs induce AHR signaling in many organs where alternative AHR pathways are predominant. One of these pathways is the interaction with estrogen receptors (ER) in female reproductive organs.

Here we have investigated the effects of the PAH 3-methylcholanthrene (3-MC) on 17β-estradiol (E2) dependent signaling in mammary gland and the uterus of ovariectomized rats in a three day uterotrophic assay. Methods included histology and immunohistochemistry, microarray analysis and gene expression analysis by qPCR. Results show that 3-MC has a broad E2 antagonistic effect on several proliferation associated physiological parameters and on mRNA transcription of almost all E2 regulated genes in both organs including those associated with proliferation in the mammary gland and with prostaglandin signaling and biosynthesis in the uterus. E2 dependent regulation of prostaglandin signaling and biosynthesis is important for regulating inflammation like events during pregnancy including the initiation of labor. Adverse effects of PAHs on these events may therefore be caused by the interaction with E2 signaling, especially by disturbing the inhibition of E2 mediated downregulation of PGF2α. Furthermore we identified the regulation of ER expression by 3-MC, but not the regulation of E2 metabolism in the liver, as a potentially important factor in mediating this general antiestrogenic effect.