Estrogenic Activity of Bisphenol A and 2,2-bis(p-Hydroxyphenyl)-1,1,1-trichloroethane (HPTE) Demonstrated in Mouse Uterine Gene Profiles

摘要

Background Interest and concern regarding potentially estrogenic substances have resulted in development of model systems to evaluate mechanisms of such chemicals. Microarray studies have indicated that estradiol (E₂)-stimulated uterine responses can be divided into early and late phases. Comparison of E₂ uterine transcript profiles and those of other estrogenic chemicals of interest in vivo indicates mechanisms and activities of test compounds. Objectives We compared transcript responses and mechanisms of response using mouse reproductive tracts after treatment with E₂, estriol (E₃), bisphenol A (BPA), and 2,2-bis( p -hydroxyphenyl)-1,1,1-trichloroethane (HPTE). Methods Uterine RNA from ovariectomized wild-type mice, estrogen receptor α (ERα) knockout (αERKO) mice, and mice expressing a DNA-binding–deficient ERα (KIKO) treated with E₂, E₃, BPA, or HPTE for 2 or 24 hr was analyzed by microarray. Resulting regulated transcripts were compared by hierarchical clustering and correlation analysis, and response patterns were verified by reverse-transcription real-time polymerase chain reaction (RT-PCR). Results Both xenoestrogens, BPA and HPTE, showed profiles highly correlated to that of E₂ in the early response phase (2 hr), but the correlation diminished in the later response phase (24 hr), similar to the known weak estrogen E₃. Both xenoestrogens also mimicked E₂ in samples from KIKO mice, indicating that they are able to utilize the indirect tethering mode of ERα signaling. No response was detected in ERα-null uteri, indicating that ERα mediates the responses. Conclusion Our study forms a basis on which patterns of response and molecular mechanisms of potentially estrogenic chemicals can be assessed.