Abstract
BackgroundAlthough paternal exposure to cigarette smoke may contribute to obesity and metabolic syndrome in offspring, the underlying mechanisms remain uncertain.MethodsIn the present study, we analyzed the sperm DNA-methylation profiles in tobacco-smoking normozoospermic (SN) men, non-tobacco-smoking normozoospermic (N) men, and non-smoking oligoasthenozoospermic (OA) men. Using a mouse model, we also analyzed global methylation and differentially methylated regions (DMRs) of the DLK1 gene in paternal spermatozoa and the livers of progeny. In addition, we quantified DLK1 expression, executed an intra-peritoneal glucose tolerance test (IPGTT), measured serum metabolites, and analyzed liver lipid accumulation in the F1 offspring.ResultsGlobal sperm DNA-methylation levels were significantly elevated (p < 0.05) in the SN group, and the methylation patterns were different among N, SN, and OA groups. Importantly, the methylation level of the DLK1 locus (cg11193865) was significantly elevated in the SN group compared to both N and OA groups (p < 0.001). In the mouse model, the group exposed to cigarette smoke extract (CSE) exhibited a significantly higher global methylation DNA level in spermatozoa (p < 0.001) and on the DMR sites of Dlk1 in 10-week-old male offspring (p < 0.05), with a significant increase in Dlk1 expression in their livers (p < 0.001). In addition, IPGTT and LDL levels were significantly altered (p < 0.001), with elevated liver fat accumulation (p < 0.05) in F1 offspring.ConclusionPaternal exposure to cigarette smoke led to increased global methylation of sperm DNA and alterations to the DMR of the DLK1 gene in the F1 generation, which may be inherited parentally and may perturb long-term metabolic function.
Highlights
There is growing evidence to support the hypothesis that paternal exposure to various contaminants, nutrients, and lifestyle-related conditions can influence an offspring’s future health—including increasing the risks for obesity, diabetes, and other chronic non-genetic diseases [1]
The principal component analysis (PCA) showed that the global methylation profiles of N, smoking normozoospermic (SN) and OA subjects were highly heterogeneous as they had extensive variation even within groups (Fig. 1a, b)
Our results showed that the DNA-methylation level of the delta-like homolog 1 (DLK1) locus in the men’s sperm was significantly elevated in normozoospermic men who were (See figure on page.) Fig. 2 Methylation and Dlk1 expression levels in paternal sperm and the F1 generation of the mouse model. a Model of the CpG site in the IG-differentially methylated regions (DMRs) at the Dlk1/Gtl2 locus in mouse. b Global DNA-methylation level (5-mC) in paternal sperm cells. c Expression level of Dlk1 in liver from 10-week-old F1 offspring. d Methylation levels of the IG-DMR in paternal sperm cells. e Methylation levels of IG-DMR in F2 liver cells
Summary
There is growing evidence to support the hypothesis that paternal exposure to various contaminants, nutrients, and lifestyle-related conditions can influence an offspring’s future health—including increasing the risks for obesity, diabetes, and other chronic non-genetic diseases [1]. Liu et al Epigenetics & Chromatin (2022) 15:3 son-specific obesity [2], and that the degree increased with age [3]. Another epidemiologic study revealed an association between paternal smoking and an offspring’s overweight/obesity that was more marked for boys [4]. Imprinted genes play important roles in metabolic regulation, and associations between abnormalities in these genes and metabolic disease risk have been widely reported [7,8,9]. The DLK1 gene is an important paternal imprinting gene that regulates offspring metabolism. Paternal exposure to cigarette smoke may contribute to obesity and metabolic syndrome in offspring, the underlying mechanisms remain uncertain
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