Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

Abstract

Prenatal stress (PS) can lead to neuroendocrine and emotional disorders later in adolescence. Sexual dimorphism in these neurodevelopmental outcomes have been observed; however, the underlying mechanisms are not fully understood. To address this issue, we investigated whether there are sex differences in epigenetic reprogramming in rats exposed to PS. Pregnant female rats were subjected to chronic restraint stress from gestational day (G)12 to G18. From postnatal day (P)38 to P45, subgroups of offspring including both males and females were subjected to behavioral testing and brain tissue specimens were analyzed by DNA pyrosequencing, western blotting, and Golgi staining to assess changes in methylation pattern of glucocorticoid receptor (GR) gene, expression of DNA methyltransferase (DNMT) and DNA demethylase, and dendrite morphology, respectively. The DNA methyltransferase inhibitor decitabine was administered to rats prior to PS to further evaluate the role of methylation in the sexually dimorphic effects of PS. The results showed that PS increased anxiety-like behavior in offspring, especially in females, while depression-like behavior was increased in male offspring compared to control littermates. The methylation pattern in the promoter region of the GR gene differed between males and females. Sex-specific changes in the expression of DNMTs (DNMT1 and DNMT3a) and DNA demethylase (Tet methylcytosine dioxygenase 2) were also observed. Interestingly, decitabine alleviated the behavioral disorder caused by PS and restored dendrite density and morphology in female but not male rats. These findings suggest that different change patterns of DNMT and demethylase in the two sexes after PS are responsible for the sexually dimorphism, which could have implications for the clinical management of stress-related disorders.

A Glimpse Into the Sexual Dimorphisms in Major Depressive Disorder Through Epigenetic Studies

“…However, most studies explore general epigenetic abnormalities in MDD, lacking the sexual and behavioral specificity. Various rodent models provide powerful tools to ameliorate specific aspects of different depression-like phenotypes ( Catale et al, 2020 ; Chang et al, 2020 ; Lei et al, 2020 ; Kronman et al, 2021 ). For example, social deficits in MDD are easily and superiorly recapitulated in the ELS models with maternal separation and social isolation paradigms.…”

“…Recently, it was found that prenatal stress on offspring triggered more display of anxiety-like behaviors in females and more depression-like behaviors in males. These behavioral differences are correlated with sexually different methylation patterns on the promotor region of GR genes, levels of DNA methyltransferases (Dnmt1 and Dnmt3a), and DNA demethylase (Tet methylcytosine dioxygenase 2) ( Lei et al, 2020 ). In general, ELS models recapitulate social deficits induced by early life adversity and are good models to investigate sex differences in epigenetic modifications in MDD.…”

Sex Differences in Anxiety and Depression: What Can (and Cannot) Preclinical Studies Tell Us?

“…Lei found that exposure to prenatal stress increased anxiety-like behavior in female offspring, while male offspring exhibited more depressive-like behavior. Sex-specific epigenetic differences were observed, such as the methylation pattern in the promoter region of the GR gene, and changes in the expression of deoxyribonucleic acid (DNA) methyltransferase and DNA demethylase [109].…”

Trends in Research of Prenatal Stress From 2011 to 2021: A Bibliometric Study

“…In other words, PS is the stress experienced by pregnant women before giving birth ( 3 ). Exposure to adverse stimuli during pregnancy can cause perpetual negative effects on emotion and cognition, thereby increasing the risk of psychiatric disorders in offspring ( 4 , 5 ). Maternal stress has been described as an important component in the development of offspring's cerebrum, altering the susceptibility to diseases in later life ( 6 ).…”