Fungicide prochloraz and environmental pollutant dioxin induce the ABCG2 transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway.
The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter ABCG2 (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and prochloraz, we have systematically investigated the effect of both contaminants on functional ABCG2 transport activity in primary bovine mammary epithelial cells. TCDD or prochloraz doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific ABCG2 inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the ABCG2 5'-UTR. Receptor binding was significantly reduced by specific AhR antagonist salicyl amide. Induction of AhR by TCDD and prochloraz resulted in a time- and dose-dependent increase of ABCG2 gene expression and transporter protein levels. As ABCG2 represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary ABCG2 as a novel target gene of pesticide prochloraz and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products.
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dioxin TCDD prochloraz 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD prochloraz Hoechst H33342 Ko143 prochloraz arylhydrocarbon TCDD dioxin DRE ABCG2 AhR AhR ABCG2 ABCG2 AhR ABCG2 aryl hydrocarbon receptor salicyl amide AhR dioxin response elements DREs efflux transporter ABCG2 EU570105 AhR ABCG2 ABCG2 ABCG2 TCDD AhR arylhydrocarbon receptor ABCG2 prochloraz imidazole prochloraz prochloraz dioxin aryl hydrocarbon