As these GEITP pages have often stated, any trait (phenotype) reflects contributions of: genetics (differences in DNA sequence); epigenetic factors (chromosomal events independent of DNA sequence: DNA methylation, RNA interference, histone modifications, and chromatin remodeling); environmental effects (smoking, diet, lifestyle); endogenous influences (kidney or cardiopulmonary disorders); and each person’s microbiome. The topic today fits well with the theme of gene-environment interactions. The environmental “signal” is cigarette smoke exposure — in the father’s lungs. The genes (actually, in this case, an epigenetic factor = DNA methylation) that “respond to this signal” are in the children — of the offspring that had been exposed in utero (!!). This phenonmenon is called transgenerational imprinting, and there are known examples reported in humans as well as mice.
Paternal cigarette smoking has been linked to increased risk of several diseases in the father’s offspring, as well as his grandchildren (e.g. obesity, cancer, behavioral disorders), but the mechanisms by which this occurs remain unclear. How does cigarette smoke exposure, originating in the father’s lungs, lead to heritable (i.e. passed on to the subsequent generation) health problems from the offspring that had been in the mother’s uterus at the time? Authors [see attached article] found that paternal cigarette smoke exposure causes significant changes in gene expression and DNA methylation in the brains of the unexposed grandchildren.
Authors hypothesized that the observed heritable impacts were likely associated with systemic oxidative stress. When they examined epigenetic and gene expression patterns in mice that were null for the Nfe2l2 (alias = Nrf2) gene (a mouse model known to be hypersensitive to oxidative stress), many of the observed outcomes from paternal cigarette-smoke exposure were reiterated — including impacts on epigenetic marks and gene expression. Male mice comprised two groups (cigarette-smoking exposed vs nonexposed), and the experimental group was exposed to the body mass-adjusted equivalent of 10–20 cigarettes per day, 5 days per week over a period of 60 days (corresponding to two complete cycles of spermatogenesis). The cigarette-smoke-exposed offspring (and control mice) were then bred to unexposed females, and their offspring were analyzed for phenotypic and molecular measures.
The nuclear factor (erythroid-derived-2)-like-2 (NFE2L2) pathway is one of the primary cellular defenses against cytotoxic effects of oxidative stress; thus, to investigate the mode by which cigarette-smoke-induced epigenetic changes occur, authors used the Nfe2l2-null mouse model, which has compromised antioxidant capacity. Consistent with previous papers in the literature, both wild-type (WT) and Nfe2l2(-/-) offspring — whose fathers had been exposed to cigarette smoke — weighed significantly less than non-exposed control animals. Sperm concentration and motility were not significantly affected by cigarette-smoke exposure, but sperm concentration was lower in Nfe2l2(-/-) than WT males, and conception was significantly delayed in cigarette-smoke-exposed Nfe2l2(-/-) mice compared with unexposed
Authors thus found that paternal smoking is associated with changes in the methylated DNA (DNAme) pattern and gene expression pattern in prefrontal cortex of the offspring’s offspring. Importantly, paternal sperm DNAme changes are distinctly different from the DNAme changes that were detected in prefrontal cortex of the grandchildren, indicating that the observed DNAme changes in sperm are not directly inherited, but rather via additional steps in the process of transgenerational imprinting. In addition, the changes in sperm DNAme associated with cigarette-smoke exposure were not observed in sperm of unexposed offspring — suggesting that the effects are likely not maintained across multiple generations. These results suggest that oxidative stress is an important mechanism by which heritable negative impacts of paternal cigarette smoking arise.
[P.S. This publication takes the record — in this PLoS Genet journal — for the poorest-ever-written and least-clear descriptions of what these TWELVE authors had actually carried out versus how they explained what they had done.] ☹
Plos Genet June 2020; 16: e1008756