Fathers’ preconception smoking and offspring DNA methylation

Rationale Experimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are however limited. We aim to identify epigenetic marks in offspring associated with father’s preconception smoking. Methods We conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort on father’s any preconception smoking (N=875 offspring) and father’s pubertal onset smoking <15 years (N=304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, maternal smoking and personal smoking. EWAS of maternal and offspring personal smoking were performed for replication. Results Father’s smoking commencing preconception was associated with methylation of blood DNA in offspring at two Cytosine-phosphate-Guanine sites (CpGs) (False Discovery Rate (FDR) <0.05) in PRR5 and CENPP. Father’s pubertal onset smoking was associated with 19 CpGs (FDR <0.05) mapped to 14 genes (TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1 and CSF1R). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (P< 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses. Conclusion Father’s preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underly epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.

[1]  M. Pembrey,et al.  Grandmaternal smoking during pregnancy is associated with differential DNA methylation in peripheral blood of their grandchildren , 2022, European Journal of Human Genetics.

[2]  M. Pembrey,et al.  Human transgenerational observations of regular smoking before puberty on fat mass in grandchildren and great-grandchildren , 2022, Scientific reports.

[3]  J. Holloway,et al.  Preconceptional smoking alters spermatozoal miRNAs of murine fathers and affects offspring’s body weight , 2021, International Journal of Obesity.

[4]  D. Jarvis,et al.  Prenatal and prepubertal exposures to tobacco smoke in men may cause lower lung function in future offspring: a three-generation study using a causal modelling approach , 2021, European Respiratory Journal.

[5]  P. Tsai,et al.  Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects , 2021, Clinical epigenetics.

[6]  Y. Murakami,et al.  TLR9–IL-2 axis exacerbates allergic asthma by preventing IL-17A hyperproduction , 2020, Scientific Reports.

[7]  Matthew Smith-Raska,et al.  Evidence for germline non-genetic inheritance of human phenotypes and diseases , 2020, Clinical epigenetics.

[8]  C. Janson,et al.  Parents’ smoking onset before conception as related to body mass index and fat mass in adult offspring: Findings from the RHINESSA generation study , 2020, PloS one.

[9]  M. Lagisz,et al.  Mapping the past, present and future research landscape of paternal effects , 2020, BMC biology.

[10]  E. Regan,et al.  DNA Methylation is Predictive of Mortality in Current and Former Smokers. , 2020, American journal of respiratory and critical care medicine.

[11]  J. Holloway,et al.  Epigenome-wide association of father’s smoking with offspring DNA methylation: a hypothesis-generating study , 2019, Environmental epigenetics.

[12]  Kuender D Yang,et al.  Paternal Tobacco Smoke Correlated to Offspring Asthma and Prenatal Epigenetic Programming , 2019, Front. Genet..

[13]  M. Pembrey,et al.  Investigating Possible Trans/Intergenerational Associations With Obesity in Young Adults Using an Exposome Approach , 2019, Front. Genet..

[14]  Vivi Schlünssen,et al.  Time and age trends in smoking cessation in Europe , 2019, PloS one.

[15]  Gautier Koscielny,et al.  Open Targets Platform: new developments and updates two years on , 2018, Nucleic Acids Res..

[16]  M. Montenarh,et al.  The status of global DNA methylation in the spermatozoa of smokers and non-smokers. , 2018, Reproductive biomedicine online.

[17]  D. Jarvis,et al.  Trends in smoking initiation in Europe over 40 years: A retrospective cohort study , 2018, PloS one.

[18]  D. Jarvis,et al.  A three-generation study on the association of tobacco smoking with asthma , 2018, International journal of epidemiology.

[19]  G. Robert,et al.  IL-34 and CSF-1 display an equivalent macrophage differentiation ability but a different polarization potential , 2018, Scientific Reports.

[20]  Senyeong Kao,et al.  Validation of Self-reported Smoking with Urinary Cotinine Levels and Influence of Second-hand Smoke among Conscripts , 2017, Scientific Reports.

[21]  David F Alonso,et al.  Cigarette smoking significantly alters sperm DNA methylation patterns , 2017, Andrology.

[22]  Wei Wu,et al.  Gene Expression Correlated with Severe Asthma Characteristics Reveals Heterogeneous Mechanisms of Severe Disease , 2017, American journal of respiratory and critical care medicine.

[23]  Vivi Schlünssen,et al.  Father's environment before conception and asthma risk in his children: a multi-generation analysis of the Respiratory Health In Northern Europe study. , 2016, International journal of epidemiology.

[24]  T. Noda,et al.  Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity , 2016, Nature Communications.

[25]  Paolo Vineis,et al.  Epigenetic Signatures of Cigarette Smoking , 2016, Circulation. Cardiovascular genetics.

[26]  Christian M. Metallo,et al.  Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism , 2016, Nature Communications.

[27]  Charles Auffray,et al.  DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis. , 2016, American journal of human genetics.

[28]  James F. Thrasher,et al.  Evaluating the validity of self-reported smoking in Mexican adolescents , 2015, BMJ Open.

[29]  J. Trasler,et al.  Developmental windows of susceptibility for epigenetic inheritance through the male germline. , 2015, Seminars in cell & developmental biology.

[30]  S. Ozanne,et al.  Intergenerational epigenetic inheritance in models of developmental programming of adult disease. , 2015, Seminars in cell & developmental biology.

[31]  T. Spector,et al.  Variants Close to NTRK2 Gene Are Associated With Birth Weight in Female Twins , 2014, Twin Research and Human Genetics.

[32]  S. Drăghici,et al.  Increased Interaction With Insulin Receptor Substrate 1, a Novel Abnormality in Insulin Resistance and Type 2 Diabetes , 2014, Diabetes.

[33]  M. Pembrey,et al.  Prepubertal start of father's smoking and increased body fat in his sons: further characterisation of paternal transgenerational responses , 2014, European Journal of Human Genetics.

[34]  C. Maloney,et al.  Paternal high‐fat diet consumption induces common changes in the transcriptomes of retroperitoneal adipose and pancreatic islet tissues in female rat offspring , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  M. Skinner,et al.  Environmentally Induced Transgenerational Epigenetic Reprogramming of Primordial Germ Cells and the Subsequent Germ Line , 2013, PloS one.

[36]  H. Shin,et al.  Association between colony-stimulating factor 1 receptor gene polymorphisms and asthma risk , 2010, Human Genetics.

[37]  J. Salles,et al.  LEPROT and LEPROTL1 cooperatively decrease hepatic growth hormone action in mice. , 2009, The Journal of clinical investigation.

[38]  P. Ferguson,et al.  Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice. , 2009, Blood.

[39]  Frank D. Gilliland,et al.  Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. , 2009, American journal of respiratory and critical care medicine.