Maternal obesity in rats results in male-specific increases in genome-wide DNA methylation in postnatal offspring liver

Male-specific peripubertal DNA demethylation in the liver has been reported in mouse. Here we investigated whether it also occurs in rats, the influence of maternal obesity and whether DNA demethylation changes contribute to observed sex-specific effects of maternal obesity in offspring. Female rats were fed a high-fat, high-sugar 'cafeteria' (Caf) diet before mating with standard chow-fed males. Offspring liver methylome and transcriptome was examined. Body weight was higher in Caf-fed dams prior to mating, during gestation and at parturition. Male and female offspring from Caf-fed dams had lower birth weights but higher adult weight and adiposity than offspring from chow-fed dams. Comparison of DNA methylation in 3-week-old weaner males versus female siblings from Chow-fed dams did not reveal the male-specific DNA demethylation that was previously reported in mouse. However, strong maternal diet effects in male weaner offspring methylation were observed. Comparison of female weaners from Chow- versusCaf-fed dams showed a range of differences, with 39% of Differentially Methylated Regions (DMRs) having higher methylation in Caf offspring and 61% of DMRs having higher methylation in Chow offspring. In stark contrast, 99% of maternal diet-induced DMRs in male weaner offspring had higher methylation in offspring from Caf-fed dams. This suggests maternal obesity induces widespread hypermethylation in their male offspring liver at weaning. However, comparison with RNA-seq data revealed limited transcriptional changes at this developmental stage, or in adult offspring. While these data highlight how environmentally-sensitive DNA methylation is in the male rodent peri-natal period, these methylation changes may not be a major contributor to sex-differences in developmentally-programmed liver disease.