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 (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.