title: Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes.
abstract: Androgen excess is a central feature of polycystic ovary syndrome (PCOS), which affects 6% to 10% of young women. Mammals exposed to elevated androgens in utero develop PCOS-like phenotypes in adulthood, suggesting fetal origins of PCOS. We hypothesize that excess androgen exposure during early embryonic development may disturb the epigenome and disrupt metabolism in exposed and unexposed subsequent generations. Zebrafish were used to study the underlying mechanism of fetal origins. Embryos were exposed to androgens (testosterone and dihydrotestosterone) early at 26 to 56 hours post fertilization or late at 21 to 28 days post fertilization. Exposed zebrafish (F0) were grown to adults and crossed to generate unexposed offspring (F1). For both generations, global DNA methylation levels were examined in ovaries using a luminometric methylation assay, and fasting and postprandial blood glucose levels were measured. We found that early but not late androgen exposure induced changes in global methylation and glucose homeostasis in both generations. In general, F0 adult zebrafish exhibited altered global methylation levels in the ovary; F1 zebrafish had global hypomethylation. Fasting blood glucose levels were decreased in F0 but increased in F1; postprandial glucose levels were elevated in both F0 and F1. This androgenized zebrafish study suggests that transient excess androgen exposure during early development can result in transgenerational alterations in the ovarian epigenome and glucose homeostasis. Current data cannot establish a causal relationship between epigenetic changes and altered glucose homeostasis. Whether transgenerational epigenetic alteration induced by prenatal androgen exposure plays a role in the development of PCOS in humans deserves study.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.forename: Angela K
authors.initials: AK
authors.lastname: Chua
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Ning-Ai
authors.initials: NA
authors.lastname: Liu
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
mesh_terms: D000728:Androgens / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose; D019175:DNA Methylation; D013196:Dihydrotestosterone / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D011085:Polycystic Ovary Syndrome / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D013739:Testosterone / Q000502:physiology; D015027:Zebrafish
chemical_list: D000728:Androgens; D001786:Blood Glucose; D013196:Dihydrotestosterone; D013739:Testosterone; D005947:Glucose