Abstract
BackgroundPaternal obesity has been associated with reduced live birth rates. It could lead to inheritance of metabolic disturbances to the offspring through epigenetic mechanisms. However, obesity is a multifactorial disorder with genetic or environmental causes. Earlier we had demonstrated differential effects of high-fat diet-induced obesity (DIO) and genetically inherited obesity (GIO) on metabolic, hormonal profile, male fertility, and spermatogenesis using two rat models. The present study aimed to understand the effect of DIO and GIO on DNA methylation in male germline, and its subsequent effects on the resorbed (post-implantation embryo loss) and normal embryos. First, we assessed the DNA methylation enzymatic machinery in the testis by Real-Time PCR, followed global DNA methylation levels in spermatozoa and testicular cells by ELISA and flow cytometry, respectively. Further, we performed Methylation Sequencing in spermatozoa for both the groups. Sequencing data in spermatozoa from both the groups were validated using Pyrosequencing. Expression of the differentially methylated genes was assessed in the resorbed and normal embryos sired by the DIO group using Real-Time PCR for functional validation.ResultsWe noted a significant decrease in Dnmt transcript and global DNA methylation levels in the DIO group and an increase in the GIO group. Sequencing analysis showed 16,966 and 9113 differentially methylated regions in the spermatozoa of the DIO and GIO groups, respectively. Upon pathway analysis, we observed genes enriched in pathways involved in embryo growth and development namely Wnt, Hedgehog, TGF-beta, and Notch in spermatozoa for both the groups, the methylation status of which partially correlated with the gene expression pattern in resorbed and normal embryos sired by the DIO group.ConclusionOur study reports the mechanism by which diet-induced and genetically inherited obesity causes differential effects on the DNA methylation in the male germline that could be due to a difference in the white adipose tissue accumulation. These differences could either lead to embryo loss or transmit obesity-related traits to the offspring in adult life.
Highlights
Paternal obesity has been associated with reduced live birth rates
We observed a significant increase in the Dnmt1, Dnmt3a, and Dnmt3b expression levels in the testis of the WNIN/Ob group compared to the Calorie-restricted WNIN/Ob (CROb) and LEAN groups, respectively (Fig. 2b)
We identified a total of 16,966, 9113, 9249 and 16,471 differentially methylated CpG sites in the spermatozoa of the high-fat diet (HFD) group compared to the control diet (CD) group, WNIN/Ob group compared to the CROb group, WNIN/Ob group compared to the LEAN group and CROb group compared to the LEAN group respectively
Summary
Paternal obesity has been associated with reduced live birth rates. It could lead to inheritance of metabolic disturbances to the offspring through epigenetic mechanisms. Several reports have indicated that children born to Deshpande et al Clin Epigenet (2020) 12:179 obese fathers are at higher risk of developing metabolic syndrome in adult life [2, 3]. This evidence supports the notion that paternal obesity has a heritability component responsible for the transmission of obesity-related traits to the offspring, which is carried by the spermatozoa of obese fathers. Obesity is multifactorial in nature and could have the involvement of the environmental and/or genetic component [8] The effects of these components individually on the epigenome of the male germline have not been explored earlier
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