Prenatal dexamethasone exposure(PDE)can decrease maternal endogenous glucocorticoid level and induce testicular dysplasia in male offspring rats.In this study we investigated low level endogenous glucocorticoid-mediated testicular dysplasia in PDE offspring and elucidated the intrauterine epigenetic programming mechanisms.Pregnant rats were injected with dexamethasone(0.2 mg·kg-1·d-1,sc)on gestational day(GD)9-20.The offspring rat blood and testis were collected after euthanasia on GD20,postnatal week(PW)12 or PW28.We showed that PDE induced abnormal morphology of testis and significantly decreased the expression of testosterone synthesis-related genes as well as testosterone production before and after birth.Meanwhile,serum corticosterone,the expression and histone 3 lysine 14 acetylation(H3K14ac)of testicular insulin-like growth factor 1(IGF1)were significantly decreased.After the pregnant rats were subjected to chronic stress for 2 weeks(PW10-12),serum corticosterone level was increased in the adult PDE offspring,and the above-mentioned other indicators were also improved.Cultured Leydig cells(TM3)were treated with corticosterone(62.5-500 nM)in vitro.We showed that corticosterone concentration-dependently inhibited glucocorticoid receptor α(GRα)and miR-124-3p expression,increased histone deacetylase 5(HDAC5)expression,and decreased IGF1 H3K14ac level and the expression of IGF 1/steroidogenic acute regulatory protein(StAR),suggesting that corticosterone at lower than physiological level(＜500 nM)inhibited testosterone synthesis by reducing H3K14ac and the expression level of IGF1 through GRα/miR-124-3p/HDAC5 pathway.In conclusion,PDE can cause persistent inhibition of testosterone synthesis before and after birth in the offspring rats by low level of endogenous glucocorticoids.

Min Liu;Yi Liu;Lin-guo Pei;Qi Zhang;Hao Xiao;Ya-wen Chen;Hui Wang

Department of Pharmacology,Wuhan University School of Basic Medical Sciences,Wuhan 430071,China;Hubei Provincial Key Laboratory of Developmentally Originated Disease,Wuhan 430071,China

中国药理学报（英文版）

[1]Min Liu;Yi Liu;Lin-guo Pei;Qi Zhang;Hao Xiao;Ya-wen Chen;Hui Wang-.Prenatal dexamethasone exposure programs the decreased testosterone synthesis in offspring rats by low level of endogenous glucocorticoids)[J].中国药理学报（英文版）,2022(06):1461-1472

PW28,H3K14ac,PW10

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