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Updated: Oct 15, 2025
Long-term Behavioral and Reproductive Consequences of Embryonic Exposure to Low-dose Toxicants
Published on: March 6, 2018
Prenatal dexamethasone exposure programs the decreased testosterone synthesis in offspring rats by low level of
Min Liu1,2, Yi Liu1, Lin-Guo Pei1,2
1Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China.
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.
Insights
Prenatal dexamethasone exposure (PDE) in rats impairs male offspring testosterone production by altering epigenetic mechanisms. This study reveals how low-level endogenous glucocorticoids disrupt testicular development and function long-term.
Area of Science:
- Endocrinology
- Developmental Biology
- Epigenetics
Background:
- Prenatal dexamethasone exposure (PDE) in rats is known to cause testicular dysplasia in male offspring.
- The underlying mechanisms of low-level endogenous glucocorticoid-mediated testicular dysfunction remain unclear.
- Understanding intrauterine epigenetic programming is crucial for addressing developmental reproductive issues.
Purpose of the Study:
- To investigate low-level endogenous glucocorticoid-mediated testicular dysplasia in PDE offspring rats.
- To elucidate the intrauterine epigenetic programming mechanisms responsible for PDE-induced effects.
- To assess the impact of PDE on testosterone synthesis and related gene expression.
Main Methods:
- Pregnant rats received dexamethasone injections during specific gestational days.
- Offspring blood and testes were collected at various developmental stages for analysis.
- In vitro studies cultured Leydig cells treated with varying corticosterone concentrations.
Main Results:
- PDE induced abnormal testicular morphology and significantly decreased testosterone synthesis and related gene expression.
- Serum corticosterone, IGF1 expression, and H3K14ac levels in the testis were significantly reduced in PDE offspring.
- Corticosterone treatment in vitro inhibited GRα and miR-124-3p, increased HDAC5, and reduced IGF1 H3K14ac and expression.
Conclusions:
- Prenatal dexamethasone exposure causes persistent inhibition of testosterone synthesis in male offspring rats.
- Low-level endogenous glucocorticoids disrupt testicular development via the GRα/miR-124-3p/HDAC5 pathway, affecting IGF1.
- Intrauterine epigenetic programming by glucocorticoids leads to long-term reproductive dysfunction.
