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

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 (E-2)-stimulated uterine responses can be divided into early and late phases. Comparison of E-2 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 E-2, estriol (E-3), bisphenol A (BPA), and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). METHODS: Uterine RNA from ovariectomized wild-type mice, estrogen receptor alpha (ER alpha) knockout (alpha ERKO) mice, and mice expressing a DNA-binding-deficient ER alpha (KIKO) treated with E-2, E-3, 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 E-2 in the early response phase (2 hr), but the correlation diminished in the later response phase (24 hr), similar to the known weak estrogen E-3. Both xenoestrogens also mimicked E-2 in samples from KIKO mice, indicating that they are able to utilize the indirect tethering mode of ER alpha signaling. No response was detected in ER alpha-null uteri, indicating that ER alpha mediates the responses. CONCLUSION: Our study forms a basis on which patterns of response and molecular mechanisms of potentially estrogenic chemicals can be assessed.