Sex-differential RXRα gene methylation effects on mRNA and protein expression in umbilical cord of the offspring rat exposed to maternal obesity

Maternal obesity (MO) induces negative consequences in the offspring development. Adiposity phenotype is associated with maternal diet at early pregnancy and DNA methylation marks in the RXR alpha promotor at birth. Glucocorticoids play an important role in the regulation of metabolism through the activation of nuclear hormone receptors such as the RXR alpha protein. The aim of the study was to analyze steroid hormone changes at the end of pregnancy in the obese mother and RXR alpha gene methylation in the umbilical cord. For this purpose, in a well-established MO model, female Wistar rats were fed either standard chow (controls: C) or high-fat obesogenic diet (MO) before and during pregnancy to evaluate at 19 days of gestation (19 dG): 1) maternal concentration of circulating steroid hormones in MO and C groups, 2) maternal and fetal weights, 3) analysis of correlation between hormones concentration and maternal and fetal weights, 4) DNA methylation status of a single locus of RXR alpha gene near the early growth response (EGR-1) protein DNA binding site, and 5) RXR alpha mRNA and protein expressions in umbilical cords. Our results demonstrate that at 19 dG, MO body weight before and during pregnancy was higher than C; MO progesterone and corticosterone serum concentrations were higher and estradiol lower than C. There were not differences in fetal weight between male and female per group, therefore averaged data was used; MO fetal weight was lower than C. Positive correlations were found between progesterone and corticosterone with maternal weight, and estradiol with fetal weight, while negative correlation was observed between corticosterone and fetal weight. Additionally, male umbilical cords from MO were hypermethylated in RXR alpha gene compared to male C group, without differences in the female groups; mRNA and protein expression of RXR alpha were decreased in F1 male but not in female MO compared to C. In conclusion, MO results in dysregulation of circulating steroid hormones of the obese mothers and low fetal weight in the F1, modifying DNA methylation of RXR alpha gene as well as RXR alpha mRNA and protein expression in the umbilical cord in a sex-dependent manner.

Automated summary

Maternal obesity has negative consequences on offspring development due to changes in steroid hormones and DNA methylation marks. Glucocorticoids play a role in metabolism regulation, and in this study, obese mothers had higher concentrations of progesterone and corticosterone, while lower levels of estradiol. Fetal weight was lower in maternal obesity, and male umbilical cords showed increased methylation of the RXR alpha gene and decreased mRNA and protein expression compared to control.