Perinatal nicotine exposure induces asthma in second generation offspring

Abstract

BackgroundBy altering specific developmental signaling pathways that are necessary for fetal lung development, perinatal nicotine exposure affects lung growth and differentiation, resulting in the offsprings' predisposition to childhood asthma; peroxisome proliferator-activated receptor gamma (PPARγ) agonists can inhibit this effect. However, whether the perinatal nicotine-induced asthma risk is restricted to nicotine-exposed offspring only; whether it can be transmitted to the next generation; and whether PPARγ agonists would have any effect on this process are not known.MethodsTime-mated Sprague Dawley rat dams received either placebo or nicotine (1 mg/kg, s.c.), once daily from day 6 of gestation to postnatal day (PND) 21. Following delivery, at PND21, generation 1 (F1) pups were either subjected to pulmonary function tests, or killed to obtain their lungs, tracheas, and gonads to determine the relevant protein markers (mesenchymal contractile proteins), global DNA methylation, histone 3 and 4 acetylation, and for tracheal tension studies. Some F1 animals were used as breeders to generate F2 pups, but without any exposure to nicotine in the F1 pregnancy. At PND21, F2 pups underwent studies similar to those performed on F1 pups.ResultsConsistent with the asthma phenotype, nicotine affected lung function in both male and female F1 and F2 offspring (maximal 250% increase in total respiratory system resistance, and 84% maximal decrease in dynamic compliance following methacholine challenge; P < 0.01, nicotine versus control; P < 0.05, males versus females; and P > 0.05, F1 versus F2), but only affected tracheal constriction in males (51% maximal increase in tracheal constriction following acetylcholine challenge, P < 0.01, nicotine versus control; P < 0.0001, males versus females; P > 0.05, F1 versus F2); nicotine also increased the contractile protein content of whole lung (180% increase in fibronectin protein levels, P < 0.01, nicotine versus control, and P < 0.05, males versus females) and isolated lung fibroblasts (for example, 45% increase in fibronectin protein levels, P < 0.05, nicotine versus control), along with decreased PPARγ expression (30% decrease, P < 0.05, nicotine versus control), but only affected contractile proteins in the male trachea (P < 0.05, nicotine versus control, and P < 0.0001, males versus females). All of the nicotine-induced changes in the lung and gonad DNA methylation and histone 3 and 4 acetylation were normalized by the PPARγ agonist rosiglitazone except for the histone 4 acetylation in the lung.ConclusionsGermline epigenetic marks imposed by exposure to nicotine during pregnancy can become permanently programmed and transferred through the germline to subsequent generations, a ground-breaking finding that shifts the current asthma paradigm, opening up many new avenues to explore.

A study of the consequences of early gestational ethanol and/or nicotine exposure in the mouse

“…Specifically, a number of phenotypes have previously been associated with other models of prenatal nicotine exposure, including those of alterations in behaviour (Klein et al, 2003;Pauly et al, 2004), respiratory function (Rehan et al, 2012), and immune function (Basta et al, 2000). These phenotypes have largely been identified following nicotine exposure either for the entirety of gestation, or late in gestation.…”

“…Following in vivo gestational nicotine exposure in rats, the offspring at postnatal day 21 were found to have global changes in the level of DNA methylation (testicular and ovarian tissue), histone 3 acetylation (lung and testicular tissue), and histone 4 acetylation (lung, testicular, and ovarian tissue) (Rehan et al, 2012). Another study identified downregulation of angiotensin type 2 mRNA in male postnatal day 10 rat pups, which was correlated to increased methylation at the promoter region of this gene, following gestational exposure to nicotine (Li et al, 2012).…”

“…Prenatal exposure to nicotine has been reported to result in changes to offspring growth (Wang et al, 2008), metabolic outcomes (Gao et al, 2005;Holloway et al, 2005;Somm et al, 2008Somm et al, , 2009Ma et al, 2014;Xu et al, 2015), cognitive behaviour (Ernst et al, 2001;Alkam et al, 2013), locomotor activity (Pauly et al, 2004), nicotine preference (Klein et al, 2003), genital development (Gyekis et al, 2010), vulnerability to hypoxia (Li et al, 2012), asthma (Rehan et al, 2012), neuroanatomy (Chen et al, 2005;Mychasiuk et al, 2014), and immune function (Basta et al, 2000). Given the increasing usage of nicotine substitutes within the Australian population, it is imperative to better establish the safety, or lack thereof for the use of these products during pregnancy.…”

Uncertain Inheritance: Transgenerational Effects of Environmental Exposures

“…But, similarly to an earlier study extending to F 2 offspring, the effects were sex-specific, with total airway system resistance significantly greater in males than females, due in part to tracheal constriction, which was detected only in males. 5,6 What's still unclear (and a subject of his current research), Rehan says, is whether the transgenerational effect is being carried through the male or female germ line.…”

“…Most of these findings come from rodent studies. 4,5,6,7 But preliminary evidence that chemical effects can carry over generations in humans is also emerging, although no F 3 data have been published yet. Given the challenges of tracking effects over multiple human lifespans, the evidence is more difficult to interpret, particularly with respect to potential mechanisms, says Tessa Roseboom, a professor of early development and health at the Academic Medical Center in Amsterdam, the Netherlands.…”