CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depression‐like behavior across 2 generations

Abstract

Pregnant women at risk of preterm labor usually receive synthetic glucocorticoids (sGCs) to promote fetal lung development. Emerging evidence indicates that antenatal sGC increases the risk of affective disorders in offspring. Data from animal studies show that such disorders can be transmitted to the second generation. However, the molecular mechanisms underlying the intergenerational effects of prenatal sGC remain largely unknown. Here we show that prenatal dexamethasone (Dex) administration in late pregnancy induced depression-like behavior in first-generation (F1) offspring, which could be transmitted to second-generation (F2) offspring with maternal dependence. Moreover, corticotropin-releasing hormone (CRH) and CRH receptor type 1 (CRHR1) expression in the hippocampus was increased in F1 Dex offspring and F2 offspring from F1 Dex female rats. Administration of a CRHR1 antagonist to newborn F1 Dex offspring alleviated depression-like behavior in these rats at adult. Furthermore, we demonstrated that increased CRHR1 expression in F1 and F2 offspring was associated with hypomethylation of CpG islands in Crhr1 promoter. Our results revealed that prenatal sGC exposure could program Crh and Crhr1 gene expression in hippocampus across 2 generations, thereby leading to depression-like behavior. Our study indicates that prenatal sGC can cause epigenetic instability, which increases the risk of disease development in the offspring's later life.-Xu, Y.-J., Sheng, H., Wu, T.-W., Bao, Q.-Y., Zheng, Y., Zhang, Y.-M., Gong, Y.-X., Lu, J.-Q., You, Z.-D., Xia, Y., Ni, X. CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depression-like behavior across 2 generations.

Treadmill Exercise Ameliorates Depression-Like Behavior in the Rats With Prenatal Dexamethasone Exposure: The Role of Hippocampal Mitochondria

“…It has been reported that increased hypothalamic–pituitary–adrenal (HPA) activity contributes to depression-like behavior induced by prenatal GC exposure (Shoener et al, 2006; Xu et al, 2018). We therefore examined circulating corticosterone level in offspring with prenatal Dex exposure.…”

“…Emerging epidemiological evidence has indicated that prenatal exposure to increased amounts of sGCs causes increased susceptibility to neuropsychiatric disorders, such as anxiety and depression, in adulthood (Khalife et al, 2013; Braithwaite et al, 2017). Many animal studies have also demonstrated that repeated exposure to sGCs in late gestation leads to depression-like behavior and other modified behavior in adult offspring (Hiroi et al, 2016; Conti et al, 2017; Xu et al, 2018). Although a number of genes have been found to be associated with depression-like behavior (McCoy et al, 2017; Xu et al, 2018), the mechanisms underlying the prenatal GC programming of depression-like behavior remain largely unknown.…”

“…Many animal studies have also demonstrated that repeated exposure to sGCs in late gestation leads to depression-like behavior and other modified behavior in adult offspring (Hiroi et al, 2016; Conti et al, 2017; Xu et al, 2018). Although a number of genes have been found to be associated with depression-like behavior (McCoy et al, 2017; Xu et al, 2018), the mechanisms underlying the prenatal GC programming of depression-like behavior remain largely unknown.…”

Prenatal programming of stress responsiveness and behaviours: Progress and perspectives

“…Importantly, the association was significant in F 2 offspring of famine-exposed F 1 women, but not men. 119 Epigenetic marks transmitted via the maternal lineage have been investigated. In guinea pigs, exposure to repeated stress from early to mid-pregnancy resulted in F 2 males that exhibited increased fecal cortisone concentrations and this occurred following both maternal and paternal transmission.…”

“…These effects were associated with increased hippocampal expression of Crh and Crhr, as well as hypomethylation of CpG islands in the Crhr1 promoter. 119 Epigenetic marks transmitted via the maternal lineage have been investigated. In humans, grandchildren of maternal grandmothers who were exposed to community or domestic violence during pregnancy exhibited modified DNA methylation in CFTR (cystic fibrosis transmembrane conductance regulator), CORIN, and BARX1 (BARX homeobox 1) genes (involved in cardiovascular diseases and embryonic development) in saliva.…”