Epigenetic Changes in the Mature Uterus Following Neonatal Feeding of Tamoxifen in Female ICR Mice

PURPOSE: To evaluate changes in immunoexpression of proteins involved in epigenetic regulation in the uterus in female ICR mice following neonatal exposure to tamoxifen. METHODS: Thirty-two neonatal mice were randomly assigned to 2 groups: the control and the tamoxifen-treated group. At post-natal day 5 and 42, 8 mice each from the two groups were sacrificed and their uterine tissues were harvested and processed for histology and immunohistochemistry analyses. The immunostaining of Hdac1-3, Dnmt1, Dnmt3a, Kat2a, Ehmt2, Jmjd3, Setdb1, Ezh2, Suz12, Tet1-3, and Six1, an estrogen responsive protein known to regulate endometrial aberrations following developmental exposure to xenobiotic estrogens, was evaluated. RESULTS: At adulthood, tamoxifen-exposed mice exhibited elevated endometrial staining of Hdac1, Setdb1, Suz12, Dnmt1, Dnmt3a, and Six1, but reduced staining of Hdac3, Kat2a, Ezh2, Jmjd3, and Tet1 in the endometrium. In the myometrium, Dnmt1, Dnmt3a, and Six1 staining was elevated, whereas Hdac3, Kat2a, and Jmjd3 staining was decreased. CONCLUSIONS: Neonatal tamoxifen exposure induces possibly lasting remodeling of uterine epigenetic regulators as well as Six1 overexpression in female ICR/CD-1 mice, especially in the endometrium. Collectively, these findings indicate that neonatal tamoxifen exposure in female ICR/CD-1 mice not only induces adenomyosis but also might sear a lasting exposure imprint on the reproductive tract.