Petropoulos Sophie, Matthews Stephen G, Szyf Moshe
Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada.
Biol Reprod. 2014 Feb 27;90(2):43. doi: 10.1095/biolreprod.113.115899. Print 2014 Feb.
Synthetic glucocorticoids (sGCs) are commonly prescribed for the management of inflammatory and endocrine disorders. However, nothing is known regarding the effects of sGC on adult germline methylome and whether these effects can be transmitted to the next generation. We hypothesized that administration of sGC to adult male mice alters DNA methylation in mature sperm and modifies the transcription and methylation of steroid receptors in male F1 offspring. Adult C57BL/6 males (n = 10/group) were injected on five consecutive days with 1 mg/kg sGC (i.e., dexamethasone) or vehicle and euthanized 35 or 60 days after initial treatment or bred with control females (60 days postinitial treatment; n = 5/group). A significant increase in global non-CpG methylation was observed in F0 sperm 60 days following sGC treatment. In the hippocampus and kidney of Postnatal Day 50 (PND50) and PND240 male offspring derived from fathers exposed to sGC, significant differences in mineralocorticoid receptor (Nr3c2; Mr), estrogen alpha receptor (Nr3a1; Ers1), and glucocorticoid receptor (Nr3c1; Gr) expression were observed. Furthermore, significant demethylation in regulatory regions of Mr, Gr, and Esr1 was observed in the PND50 kidney derived from fathers exposed to sGC. This is the first demonstration that paternal pharmacological exposure to sGC can alter the expression and DNA methylation of nuclear steroid receptors in brain and somatic tissues of offspring. These findings provide proof of principle that adult male exposure to sGC can affect DNA methylation and gene expression in offspring, indicating the possibility that adult experiences that evoke increases in endogenous glucocorticoid (i.e., stress) might have similar effects.
合成糖皮质激素（sGCs）常用于治疗炎症和内分泌疾病。然而，关于sGC对成年生殖系甲基化组的影响以及这些影响是否能传递给下一代，我们一无所知。我们假设给成年雄性小鼠施用sGC会改变成熟精子中的DNA甲基化，并改变雄性F1后代中类固醇受体的转录和甲基化。成年C57BL/6雄性小鼠（每组n = 10）连续五天注射1 mg/kg sGC（即地塞米松）或赋形剂，并在初始治疗后35天或60天实施安乐死，或者与对照雌性小鼠交配（初始治疗后60天；每组n = 5）。sGC治疗60天后，在F0精子中观察到整体非CpG甲基化显著增加。在来自暴露于sGC的父亲的出生后第50天（PND50）和PND240雄性后代的海马体和肾脏中，观察到盐皮质激素受体（Nr3c2；Mr）、雌激素α受体（Nr3a1；Ers1）和糖皮质激素受体（Nr3c1；Gr）表达存在显著差异。此外，在来自暴露于sGC的父亲的PND50肾脏中，观察到Mr、Gr和Esr1调控区域存在显著去甲基化。这是首次证明父本药理学暴露于sGC可改变后代大脑和体细胞组织中核类固醇受体的表达和DNA甲基化。这些发现提供了原理证明，即成年雄性暴露于sGC可影响后代的DNA甲基化和基因表达，表明引发内源性糖皮质激素增加（即应激）的成年经历可能具有类似影响。
