Epigenetic pattern changes in prenatal female Sprague-Dawley rats following exposure to androgen
Yanjie Xia A , Shanmei Shen B , Xinlin Zhang A , Zhantao Deng A , Zou Xiang A , Hongwei Wang A , Long Yi A , Qian Gao A and Yong Wang A C
+ Author Affiliations
- Author Affiliations
A State Key Laboratory of Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Hankou Road 22, Nanjing 210093, China.
B Divisions of Endocrinology, The Affiliated Drum Tower Hospital, Medical School, Nanjing University, Zhongshan Road 321, Nanjing 210008, China.
C Corresponding author. Email: yongwang@nju.edu.cn
Reproduction, Fertility and Development 28(9) 1414-1423 https://doi.org/10.1071/RD14292
Submitted: 8 August 2014 Accepted: 28 January 2015 Published: 31 March 2015
Abstract
Androgen excess is generally considered to be one of the major characteristics of polycystic ovary syndrome (PCOS). Evidence from both clinical research and animal studies has revealed that this syndrome may have fetal origins, with epigenetics being proposed as the underlying mechanism. Our PCOS rat model induced by prenatal administration of 3 mg testosterone from Embryonic Day (E) 16 to E19 showed polycystic ovaries, irregular oestrous cycles and endocrine disorders in adulthood. The methylation status of 16, 8 and 4 cytosine–phosphate–guanine (CpG) sites in the promoter regions of the androgen receptor (Ar), cytochrome P450 family 11, subfamily A, polypeptide 1 (Cyp11a1) and cytochrome P450, family 17, subfamily A, polypeptide 1 (Cyp17a1) genes, respectively, were measured by pyrosequencing. We identified three hypomethylated sites (CpG +58, +65 and +150) in Ar and one hypomethylated site (CpG +1016) in Cyp11a1 in peripheral blood cells of prenatally androgenised (PNA) rats. In ovarian tissue, five CpG sites of Ar (CpG +87, +91, +93, +98, +150) and one single CpG site in Cyp11a1 (CpG +953) were significantly hypomethylated in PNA rats, but the modified methylation of these two genes may not be sufficient to significantly alter levels of gene expression. Furthermore, tissue-specific methylation analysis revealed that both Ar and Cyp11a1 exhibited significant hypomethylation in testis in contrast with ovary and blood. PNA may lead to methylation pattern changes and the development of PCOS, but further studies are required to reveal causal relationships.
Additional keywords: infertility, methylation, ovary.
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