Epigenome-wide association of father’s smoking with offspring DNA methylation: a hypothesis-generating study

Abstract

Epidemiological studies suggest that father’s smoking might influence their future children’s health, but few studies have addressed whether paternal line effects might be related to altered DNA methylation patterns in the offspring. To investigate a potential association between fathers’ smoking exposures and offspring DNA methylation using epigenome-wide association studies. We used data from 195 males and females (11–54 years) participating in two population-based cohorts. DNA methylation was quantified in whole blood using Illumina Infinium MethylationEPIC Beadchip. Comb-p was used to analyse differentially methylated regions (DMRs). Robust multivariate linear models, adjusted for personal/maternal smoking and cell-type proportion, were used to analyse offspring differentially associated probes (DMPs) related to paternal smoking. In sensitivity analyses, we adjusted for socio-economic position and clustering by family. Adjustment for inflation was based on estimation of the empirical null distribution in BACON. Enrichment and pathway analyses were performed on genes annotated to cytosine-phosphate-guanine (CpG) sites using the gometh function in missMethyl. We identified six significant DMRs (Sidak-corrected P values: 0.0006–0.0173), associated with paternal smoking, annotated to genes involved in innate and adaptive immunity, fatty acid synthesis, development and function of neuronal systems and cellular processes. DMP analysis identified 33 CpGs [false discovery rate (FDR) < 0.05]. Following adjustment for genomic control (λ = 1.462), no DMPs remained epigenome-wide significant (FDR < 0.05). This hypothesis-generating study found that fathers’ smoking was associated with differential methylation in their adolescent and adult offspring. Future studies are needed to explore the intriguing hypothesis that fathers’ exposures might persistently modify their future offspring’s epigenome.

Associations of Preconception Exposure to Air Pollution and Greenness with Offspring Asthma and Hay Fever

“…In a study by Svanes et al [ 25 ], the age of smoking onset in the parents was an important risk factor for asthma in their offspring, even after adjustment for the number of cigarettes they had smoked before conception. Moreover, a recent epigenome-wide association study showed associations between pre-conception paternal smoking and DNA methylation characteristics in adult and adolescent offspring—independent of the amount smoked [ 49 ]. Our findings suggest that the same patterns may be present for air pollution exposures as for smoking exposures.…”

Sperm DNA methylation altered by THC and nicotine: Vulnerability of neurodevelopmental genes with bivalent chromatin

“…Initial epigenetic studies by our group have shown that male cannabis use, and male rat exposure to THC, cause widespread DNA methylation changes in sperm 16 . Furthermore, others have shown that cigarette smoking significantly alters DNA methylation patterns in male sperm 63 , 64 , showing that there are also genome-wide epigenetic effects of this exposure. The significance and impact of these changes in sperm on offspring health and development are only beginning to be explored—yet results may provide important information and critical opportunities for preventive interventions to reduce risk to future children.…”

“…The father’s health prior to conception and the exposures he incurs during this time may also impact offspring health and development. Studies show that exposure to cannabis and tobacco products alter sperm DNA methylation 15 – 17 . There is an urgent need to determine whether these effects are heritable, especially given that men are the predominant cannabis and tobacco product consumers 18 – 20 , and their use is increasing 18 , 19 .…”

Parents’ smoking onset before conception as related to body mass index and fat mass in adult offspring: Findings from the RHINESSA generation study

“…Although increased adipose tissue does not necessarily translate into metabolic abnormalities, both BMI and FMI are regarded important determinants of metabolic health at the population level [ 40 , 41 ], and childhood adiposity has been reported to be associated with increased risk of adult type 2 diabetes mellitus [ 42 ]. In a recent epigenome-wide association study, we found that adult offspring with smoking fathers had differential methylation in regions related to innate immune system pathways and fatty acid bio-synthesis [ 43 ]. These are inflammatory signalling pathways and metabolic signals that have been linked to obesity [ 44 ].…”