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Sci Rep. 2016 Nov 9;6:36805. doi: 10.1038/srep36805.

Maternal High Estradiol Exposure is Associated with Elevated Thyroxine and Pax8 in Mouse Offspring.

Lv PP1,2, Tian S2,3, Feng C2,3, Li JY1,2, Yu DQ2,3, Jin L4, Shen Y2, Yu TT4, Meng Y2, Ding GL4, Jin M2,3, Chen XJ1,2, Sheng JZ2, Zhang D1,2, Huang HF1,2,4,5.

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Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, Zhejiang 310058, China.
The Center of Reproductive Medicine, the 2nd affiliated Hospital of Medical School, Zhejiang University, Hangzhou, Zhejiang 310006, China.
International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
Institute of Embryo-Fetal Original Adult Diseases and Shanghai Key laboratory of Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.


Our previous studies have shown that maternal high estradiol (E2) environment increased the risk of thyroid dysfunction in offspring. However, the mechanism involved remains unexplored. To evaluate the thyroid function of offspring after high E2 exposure and to explore the underlying mechanism, we established a high E2 mouse model of early pregnancy, and detected thyroid hormones of their offspring. In thyroids of offspring, the expressions of Tg, Nis, Tpo, Pax8, and Titf1 and CpG island methylation status of Pax8 and genes involved in methylation were analyzed. We found that thyroxine (T4) and FT4 levels of offspring were obviously increased in the high-E2 group, especially in females. In both 3- and 8-week-old offspring of the high-E2 group, Pax8 was significantly up-regulated in thyroid glands, accompanied by the abnormal CpG island methylation status in the promoter region. Furthermore, Dnmt3a and Mbd1 were obviously down-regulated in thyroids of the high E2 group. Besides, the disturbance of thyroid function in females was more severe than that in males, implying that the effects were related to gender. In summary, our study indicated that maternal high E2 exposure disturbed the thyroid function of offspring through the dysregulation and abnormal DNA methylation of Pax8.

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