Effect Of Paternal Preconception Inflammation On Growth Performance And Hepatic Glucose Metabolism In Offspring And Its Mechanisms

Changes of the internal and external environment experienced by the parent can influence the phenotype of the offspring.In mammals,influences of maternal exposure on progeny have been widely reported.Now more studies have shown that paternal stress can also change the phenotype of offspring.Paternal obesity,nutritional stress and psychological stress may increase the risk of metabolic diseases in offspring.Variety of factors such as pathogen infection can trigger animal inflammatory response,but it is not clear whether it affects the phenotype of the offspring.The aim of this study was to investigate the effects of male animal inflammation on growth and hepatic glucose metabolism in offspring and its epigenetic mechanism.1 Effects of inflammation on sperm motility,tsRNA abundance and fecundity in male miceTo investigate the effect of inflammation on sperm motility,tsRNA abundance and fecundity in male mice,male mice were injected with lipopolysaccharides(LPS)as an inflammation model.After LPS treatment,the total sperm motility of mice decreased significantly(P<0.01),but the difference of the of high-motility sperm was not significant.Compared with the control group,LPS group had no significant difference in the number of births,sex ratio,mortality,number of litter size and pregnancy rate.Sperm tRNA-derived small RNAs(tsRNA)contribute to intergenerational inheritance of an acquired metabolic disorder.The results shown that,the abundance of tsRNAGlu and tsRNAVal was significantly increased in the caput epididymis of LPS-treatment mice(P<0.05).Also,the expression of ANG1 which induced tsRNA generation was up-regulated(P<0.05),and tRNA methyltransferase Dnmt2 mRNA expression was down-regulated(P<0.01)2 Effect of paternal preconception inflammation on growth performance and hepatic glucose metabolism in offspringTo investigate the effect of paternal inflammation on growth performance and hepatic glucose metabolism in offspring,male mice were injected with lipopolysaccharides(LPS)as an inflammation model.Then,male mice were mated with normal female mice.There was no significant change in the birth weight of offspring between LPS treatment group control group.At 6-7 weeks of age,the average body weight of offspring from LPS treatment group was significantly higher than that of control group(P<0.01).The body weight of 8-week-age offspring male mice from LPS treatment group was significantly higher than that of control group.The weight of liver,gastrocnemius muscle and epididymal fat of male offspring from LPS treatment group were significantly heavier than those in the control group,but there was no significant difference in organ weight ratio.There was no significant difference in female offspring organ weight and organ weight ratio.Compared with control group,the level of fasting blood glucose in male offspring from LPS-treated group was significantly increased(P<0.05)in 7 weeks age,and the area under curve of the GTT was significantly increased(P<0.01),which implies glucose intolerance.There was no significant difference in the female offspring.Taken together,paternal inflammation promoted growth and glucose intolerance in male offspring.3 Effect of paternal preconception inflammation on liver IGF2 expression and gluconeogenesis in offspringThe abundance of tsRNA in serum was increased in the inflammatory mice,but the relationship between parental inflammation and offspring metabolism and the underlying molecular mechanism were not clear.Insulin-like growth factor 2(IGF2)is a key regulator of animal growth.Studies have shown that IGF2,as an imprinted gene,participates in the process of parental stress affecting the growth and metabolism of offspring.The mRNA levels of PC and PCK1 which are rate-limiting enzymes in gluconeogenesis were significantly increased(P<0.05).Meanwhile,the nuclear transcription factor FoxO1 nucleation increased in the liver,which was consistent with the hyperglycemia phenotype.Compared with control group,IGF2 mRNA and protein abundance were significantly up-regulated in the male offspring liver of LPS treatment group(P<0.01).Further analysis revealed that the methylation level in the ICR region of the liver IGF2 gene was significantly up-regulated,these characteristics are consistent with the growth acceleration of male individuals.To sum up,phenotypes such as accelerated growth and glucose intolerance of male offspring may be mediated by increased sperm tsRNA and methylation level up-regulation of IGF2 gene ICR region in male offspring liver,and the specific mechanism needs to be further studied.