Abstract
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 IGF1/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.
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Acknowledgements
This work was supported by grants from the National Key Research and Development Program of China (No. 2020YFA0803900), National Natural Science Foundation of China (Nos. 81673524, 82030111), the Major Technological Innovation Projects of Hubei Province (No. 2019ACA140), Hubei Province’s Outstanding Medical Academic Leader Program, and Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University (No. TFJC2018001).
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ML: Conceptualization, Investigation, Writing-Original Draft; YL: Conceptualization, Investigation, Writing-Original Draft; LGP: Investigation; QZ: Supervision; HX: Supervision; YWC: Supervision; HW: Supervision, Project administration, Funding acquisition, Writing - Review and Editing.
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Liu, M., Liu, Y., Pei, Lg. et al. Prenatal dexamethasone exposure programs the decreased testosterone synthesis in offspring rats by low level of endogenous glucocorticoids. Acta Pharmacol Sin 43, 1461–1472 (2022). https://doi.org/10.1038/s41401-021-00789-z
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DOI: https://doi.org/10.1038/s41401-021-00789-z
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