Prenatal Synthetic Glucocorticoid Treatment Changes DNA Methylation States in Male Organ Systems: Multigenerational Effects

Abstract

Prenatal synthetic glucocorticoids (sGC) are administered to pregnant women at risk of delivering preterm, approximately 10% of all pregnancies. Animal studies have demonstrated that offspring exposed to elevated glucocorticoids, either by administration of sGC or as a result of maternal stress, are at increased risk of developing behavioral, endocrine, and metabolic abnormalities. DNA methylation is a covalent modification of DNA that plays a critical role in long-lasting programming of gene expression. Here we tested the hypothesis that prenatal sGC treatment has both acute and long-term effects on DNA methylation states in the fetus and offspring and that these effects extend into a subsequent generation. Pregnant guinea pigs were treated with sGC in late gestation, and methylation analysis by luminometric methylation assay was undertaken in organs from fetuses and offspring across two generations. Expression of genes that modify the epigenetic state were measured by quantitative real-time PCR. Results indicate that there are organ-specific developmental trajectories of methylation in the fetus and newborn. Furthermore, these trajectories are substantially modified by intrauterine exposure to sGC. These sGC-induced changes in DNA methylation remain into adulthood and are evident in the next generation. Furthermore, prenatal sGC exposure alters the expression of several genes encoding proteins that modulate the epigenetic state. Several of these changes are long lasting and are also present in the next generation. These data support the hypothesis that prenatal sGC exposure leads to broad changes in critical components of the epigenetic machinery and that these effects can pass to the next generation.

Dexamethasone Induces Cardiomyocyte Terminal Differentiation via Epigenetic Repression of Cyclin D2 Gene

“…Furthermore glucocorticoid exposure is associated with both methylation and demethylation of promoter and enhancer regions, illustrating a potentially complex regulatory pathway (Crudo et al, 2013;Thomassin et al, 2001). Crudo et al (2012) demonstrated that the endogenous glucocorticoid surge alters the expression of methylation specific genes such as DNA (cytosine-5)-methyltransferase 3b and methyl-CpG-binding domain protein 2 and is instrumental in defining DNA methylation patterns in an organ-specific manner (Crudo et al, 2012). The effects of glucocorticoids on methylation patterns are long lasting and are sustained into adulthood and even in subsequent generations (Crudo et al, 2012(Crudo et al, , 2013.…”

“…Crudo et al (2012) demonstrated that the endogenous glucocorticoid surge alters the expression of methylation specific genes such as DNA (cytosine-5)-methyltransferase 3b and methyl-CpG-binding domain protein 2 and is instrumental in defining DNA methylation patterns in an organ-specific manner (Crudo et al, 2012). The effects of glucocorticoids on methylation patterns are long lasting and are sustained into adulthood and even in subsequent generations (Crudo et al, 2012(Crudo et al, , 2013. In the present study, we found that treatment with dexamethasone was not associated with changes in global DNA methylation.…”

Developmental Programming and Transgenerational Transmission of Obesity

“…However, these effects were resolved in the F3 generation [18]. Experimental models in the guinea pig (maternal DEX and low-protein diet) have shown DNA methylation changes, altered hypothalamic-pituitary axis function and cardiovascular impairment as well as delayed neurodevelopment in the F2 offspring [25,26]. Maternal diets deficient in micronutrients have also been shown to result in F2 phenotypes including vitamin D and zinc deficiencies [27,28,29].…”

Prenatal Treatment of Congenital Adrenal Hyperplasia: Long-Term Effects of Excess Glucocorticoid Exposure

“…A transgenerational effect of the epigenetic changes has also been proposed. The second-generation offspring (F2) of guinea pigs treated during pregnancy with multiple doses of betamethasone showed reduced methylation of genomic DNA globally and of specific genes involved in the methylation process per se [49, 87]. …”