110-OR: Paternal Metabolism Modulates the Metabolome of Offspring during the Early Embryonic Period

Introduction & Objective: Obesity in females and males of reproductive age may impact health of offspring. Data indicate that paternal metabolism can contribute to intergenerational disease risk, likely via epigenetic modification. This study investigated the impact of paternal obesity and hyperglycemia on metabolomes of pre-implantation embryos.

Methods: C57BL/6J male mice (6 weeks) were fed low fat diet (LFD; 10% calories from fat) or high fat diet (HFD; 60% from fat) ad lib to induce obesity. After 4 weeks, HFD-fed mice were separated, creating 4 groups: (1) continued LFD, (2) continued HFD, (3) HFD with SGLT2i canagliflozin (CANA, 25 mg/kg/day), or (4) HFD with 15-30% caloric restriction (CR) to achieve weight matched to HFD-CANA (n=16/group). HFD-CANA and HFD-CR had lower weight and glucose vs. HFD (P<0.05). At 16 weeks, males were bred with chow-fed females. After pregnancy confirmation, day 3.5 blastocysts were isolated, and pools from each of the 4 groups were analyzed using mass spectrometry; metabolomic data were analyzed using Metaboanalyst.

Results: Blastocysts derived from HFD males had reductions in acetyl-CoA, α-ketoglutarate (α-KG), and S-adenosyl-L-methionine (SAM) (P<0.05), while decarboxylated-SAM (dc-SAM) (P<0.05) was increased vs. LFD. This pattern was largely reversed in blastocysts derived from HFD-CANA males, with increased acetyl-CoA, α-KG and SAM and decreased dc-SAM (P<0.05) vs. HFD. Changes in HFD-CR shared some features with HFD-CANA, including reduced dc-SAM (P<0.05) and increased spermidine and spermine (P<0.05).

Conclusion: Paternal HFD and interventions to improve paternal metabolism can modulate the blastocyst metabolome. Top-ranking regulated metabolites are key constituents of one-carbon metabolism and cofactors for epigenetic regulation including DNA methylation and histone modification; thus, changes in the early-embryo metabolome could contribute to sustained differences in epigenetic control and offspring phenotypes.