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  • br Materials and methods br


    Materials and methods
    Discussion Here, we described a mouse model in which paternal exposure to hyperglycemia leads to metabolic derangement and accumulation of fatty Etoposide in the adult offspring liver. Deregulation of genes related to hepatic lipid metabolism can be explained, in part, by reduced expression of the key factor Ppara. In turn, altered Ppara expression can be partially attributed to changes in DNA methylation in the promoter region mediated by abrogation of SP1 binding. This epigenetic signature was already present in E16.5 fetuses. Hence, our data strongly suggest paternal hyperglycemia alters patterns of liver DNA methylation in early life stages that are subsequently maintained in adult livers, thereby influencing liver lipid metabolism and increasing the risk of metabolic derangement in the offspring. The rapid global rise in the incidence of chronic metabolic diseases such as diabetes, obesity, and cardiovascular disease suggest nongenetic environmental factors are contributors to the disease risk. Disruptions in mother-infant interactions during both prenatal and perinatal periods can have profound consequences for offspring development [40]. Remodeling by environmental factors, which is referred to as “early life reprogramming”, is associated with increased risk of disease, contributing to the transmission of pathologies such as cardiovascular disease, metabolic syndrome, and cognitive impairments through generations [41]. Increasing evidence has confirmed that paternal lifestyle and particular environmental factors, such as stress [17], nutrition [42], and obesity [43] can influence offspring development either through direct care of offspring or even in the absence of direct contact with offspring. Although it has been proven that intrauterine exposure to maternal diabetes conveys high risk for obesity and type 2 diabetes in the offspring [44], the detrimental consequences of paternal hyperglycemia on the offspring's metabolic profile remains obscure. Together with our previous studies, the present investigations have demonstrated hyperglycemia in male rats influences the systemic and liver lipid metabolism in the next generation, increasing their risk for metabolic syndrome, and thus transmits environmentally induced effects to the offspring. This amplification of pathological disaster through generations can, at least in part, explain the rising prevalence of diabetes that mirrors the global increase in the number of people who are overweight or obese. It has been noted that paternal effects on offspring can emerge even in species that are not biparental and where direct contact between fathers and their progeny is absent. Moreover, this phenomenon is unlikely to be attributed to inherited genetic variation as it can also occur in isogenic species [45]. Emerging evidence has proved the role of epigenetic mechanisms in shaping the phenotype of the offspring. Indeed, our findings confirmed that changes in genome-wide epigenetic reprogramming still occurred in the offspring of hyperglycemic fathers, even when the fathers were removed from the cages after fertilization, and parenting provided by fathers was absent, and thus influences evoked by paternal care seemed unlikely. Additionally, MeDIP analysis revealed that the lipid metabolism pathway was highly influenced by epigenetic effects, accompanied by dramatic changes in mRNA and protein expression of genes regulating fatty acid metabolism. All those alterations at the epigenetic and transcriptional levels coincided with a phenotype characterized by liver function that was compromised in terms of lipid metabolism, massive fat deposition in liver and higher hepatic triglyceride levels, thus indicating transgenerational consequences of adverse environmental factors through the paternal lineage. One of the major findings of this study is that paternal hyperglycemia induced changes in DNA methylation patterns of Ppara in both adult and fetal liver of the offspring. Ppara is a key factor in controlling systemic energy balance, including adipocyte differentiation, energy hemostasis, and lipoprotein and glucose metabolism. Many previous findings have confirmed epigenetic modifications of Ppara can mediate the impact of the nutritional environment of parents on offspring development, such as high-fat-diet induced obesity [46], or a protein restricted diet [47], and that ligand-activated Ppara -dependent DNA methylation can regulate the fatty acid β-oxidation genes in the postnatal liver [29]. However, these findings revealing epigenetic alterations as an important link between environment and genes were all based on transmission of deleterious conditions from mothers to their children. Our findings, for the first time, reveal the significance of the adverse impact of fathers, namely, hyperglycemia, on the DNA methylation patterns of Ppara in the offspring liver, exposing them to high risk of devastating metabolic diseases.