Diet-induced- and genetic- obesity differentially alters male germline histones.

Obesity, an established risk factor for male subfertility or infertility, is primarily due to genetic and environmental causes. Our earlier studies have shown differential effects of high fat diet-induced- (DIO) and genetically inherited- (GIO) obesity on DNA methylation in male germline and its subsequent effect on fertility. Here, we hypothesized that the effects of DIO and GIO on histone modifications in male germline could also contribute to fertility defects. We observed that DIO affected both active (H3K4me3, H3ac, and H4ac) and repressive (H3K9me3 and H3K27me3) histone marks in testis and their cell types, whereas GIO solely altered acetylated histones. This correlated with deregulation of histone-modifying enzymes in testis of both obese groups. Further, we also observed a decrease in chromatin remodelers in testis of DIO group, which were increased in GIO group. Besides, there was an increase in core histones and a decrease in histone marks along with protamine deficiency in spermatozoa of DIO group, whereas only H3K4me3 levels were increased in spermatozoa of GIO group. Moreover, we observed alterations in the expression and enrichment patterns of a few developmental genes harbored by the active histone mark in resorbed embryos sired by the DIO rats. Together these epigenetic defects in male germline could alter sperm quality and cause fertility defects in these obese groups. Differential changes in two obese groups could also be attributed to differences in their pathophysiological variations. Our study highlights epigenetic differences between DIO and GIO in male germline and its subsequent impact on male fertility.