Within recent years, fundamental assumptions about genetic inheritance have been revisited [5, 6]. In addition to classical Mendelian genetics, the environment has been shown to contribute to inherited characteristics by placing epigenetic tags on DNA or associated histones that result in modified gene expression. In particular, the prenatal environment can result in reprogramming of the epigenome, as demonstrated by Rehan et al. [4]. They showed that acute daily injections of nicotine throughout pregnancy led to epigenetic modifications of lung tissue in the F1 offspring (Figure 1), with a resulting asthma-like phenotype. When F1 rats were mated, similar changes in lung function were observed in their F2 offspring, even though they had never been exposed to nicotine. Nicotine induction of the asthma phenotype was found to result from a downregulation of mesenchymal peroxisome proliferator-activated receptor-γ (PPARγ), which plays a critical role in the development, homeostasis and repair of the lung [7]. Rosiglitazone, a PPARγ agonist, completely prevented the alterations in lung function, and in H3 acetylation of lung histones, when co-administered with nicotine to the pregnant dam [4].

Although the F2 rats had never been exposed to nicotine, their primordial germ cells were potential targets while the F1 parents were in utero. The finding of nicotine-induced epigenetic changes in both ovarian and testicular tissues from F1 generation rats provides support for this as a possible mechanism for functional changes observed in F2 offspring. Whereas H4 histone acetylation was increased in the gonads of both sexes, DNA methylation was increased in testes but decreased in ovaries. All of these epigenetic changes were eliminated by rosiglitazone, implicating the downregulation of PPARγ as a more universal mechanism of nicotine-induced changes to the epigenome, impacting germ cells as well as lung tissue.

In utero nicotine exposure resulted in alterations to both the somatic and germ cell epigenome. However, the nicotine-induced germ cell epigenetic changes were only examined in the gonads of F1 offspring. The true test of whether nicotine can induce permanent epigenetic changes to the germline, with resulting transgenerational genetic inheritance, will require studies that look at germ cells in the F2 offspring and lung function in subsequent F3 and F4 generations. This issue notwithstanding, however, this preclinical study is critically important in that it provides the first experimental evidence for multigenerational effects of in utero nicotine exposure. Furthermore, it provides a conceptual framework with which to understand the novel clinical observation that grandmothers' smoking patterns are as important as that of the mother in determining pediatric lung function [3].