Tobacco smoking
Smoking is one of the best-established carcinogenic hazards. Of note is that previous studies on childhood cancer epidemiology have mostly shown null associations between maternal smoking and risk of childhood cancer, which is in line with the results of the present umbrella review. By contrast, paternal smoking during pregnancy has been more consistently reported as potential risk factor of childhood cancer, especially ALL, which was also supported by the herein results; the magnitude of this effect was calculated at 1.20 summary random effects estimate. Our study also found suggestive evidence for paternal ever smoking, even before pregnancy in relation to childhood leukemia. IARC considered the evidence from different studies as sufficient to suggest a causal link between paternal smoking and childhood cancers. Exposure to mutagenic polycyclic aromatic compounds from tobacco smoke can increase the formation of DNA adducts in sperm. Smoking also induces the generation of reactive oxygen species and reduces levels of antioxidant cellular defenses, thus contributing to oxidative stress and DNA damage. Oxidative DNA damage is not randomly distributed in mature human spermatozoa but occurs preferentially in unpackaged, protein-free regions of the genome in close proximity to the nuclear membrane, which are especially vulnerable to oxidative stress. Overall, tobacco smoke may cause genetic changes through the germline that may make children more susceptible to developing cancer[NO_PRINTED_FORM]. Indeed, paternal smoking may contribute up to 1.3 million extra cases of aneuploid pregnancies per generation due to smoking-induced de novo germline mutations transmitted from fathers to offspring. In addition, recent epigenome-wide association studies (EWASs) suggest that tobacco affects the genomic DNA methylation profiles. Smoking-related cytosine-phosphate-guanine (CpG) sites have been identified in various genes, such as AHRR , F2RL3 and GPR15 , which could be used as predictors of smoking-related health risks. Tobacco-related products may induce specific differences in the spermatozoal microRNA content, which subsequently mediate pathways vital for healthy sperm and normal embryo development, particularly cell death and apoptosis. Smoking may also alter genomic imprinting due to DNA hypomethylation and reduce sperm cytosine methyl transferase messenger RNA levels, which may, in turn, lead to the expression of normally silent paternal alleles.