Dataset Information

Perinatal nicotine exposure induces asthma in second generation offspring.

ABSTRACT:

Background

By 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 (PPAR?) 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 PPAR? agonists would have any effect on this process are not known.

Methods

Time-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.

Results

Consistent 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 PPAR? 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 PPAR? agonist rosiglitazone except for the histone 4 acetylation in the lung.

Conclusions

Germline 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.

SUBMITTER: Rehan VK

PROVIDER: S-EPMC3568737 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Publications

Perinatal nicotine exposure induces asthma in second generation offspring.

Rehan Virender K VK Liu Jie J Naeem Erum E Tian Jia J Sakurai Reiko R Kwong Kenny K Akbari Omid O Torday John S JS

BMC medicine 20121030

<h4>Background</h4>By 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 gen ...[more]

PMID: 23106849

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Project description:Introduction. Environmental exposure of the developing offspring to cigarette smoke or nicotine is an important predisposing factor for many chronic respiratory conditions, such as asthma, emphysema, pulmonary fibrosis, and so forth, in the exposed offspring. Studies showed that electroacupuncture (EA) applied to maternal "Zusanli" (ST36) acupoints during pregnancy and lactation protects against perinatal nicotine exposure- (PNE-) induced lung damage. However, the most effective time period, that is, prenatal vs. postnatal, to attain this effect has not been determined. Objective:To determine the most effective developmental timing of EA's protective effect against PNE-induced lung phenotype in the exposed offspring. Methods:Pregnant rats were given (1) saline ("S" group); (2) nicotine ("N" group); (3) nicotine?+?EA, exclusively prenatally ("Pre-EA" group); (4) nicotine?+?EA, exclusively postnatally ("Post-EA," group); and (5) nicotine?+?EA, administered both prenatally and postnatally ("Pre- and Post-EA" group). Nicotine was injected once daily (1?mg/kg, 100??l) and EA was administered to bilateral ST36 acupoints once daily during the specified time-periods. At the end of the experimental periods, key hypothalamic pituitary adrenal (HPA) axis markers in pups and dams, and lung function, morphometry, and the central molecular markers of lung development in the offspring were determined. Results:After nicotine exposure, alveolar mean linear intercept (MLI) increased, but mean alveolar number (MAN) decreased and lung PPAR? level decreased, but glucocorticoid receptor (GR) and serum corticosterone (Cort) levels increased, in line with the known PNE-induced lung phenotype. In the nicotine exposed group, maternal hypothalamic corticotropin releasing hormone (CRH) level decreased, but pituitary adrenocorticotropic hormone (ACTH) and serum Cort levels increased. In the "Pre- and Post-EA" groups, PNE-induced alterations in lung morphometry, lung development markers, and HPA axis were blocked. In the "Pre-EA" group, PNE-induced changes in lung morphometry, GR, and maternal HPA axis improved; lung PPAR? level decreased, but glucocorticoid receptor (GR) and serum corticosterone (Cort) levels increased, in line with the known PNE-induced lung phenotype. In the nicotine exposed group, maternal hypothalamic corticotropin releasing hormone (CRH) level decreased, but pituitary adrenocorticotropic hormone (ACTH) and serum Cort levels increased. In the "Pre- and Post-EA" groups, PNE-induced alterations in lung morphometry, lung development markers, and HPA axis were blocked. In the "Pre-EA" group, PNE-induced changes in lung morphometry, GR, and maternal HPA axis improved; lung PPAR. Conclusions:Maternal EA applied to ST36 acupoints during both pre- and postnatal periods preserves offspring lung structure and function despite perinatal exposure to nicotine. EA applied during the "prenatal period" affords only limited benefits, whereas EA applied during the "postnatal period" is ineffective, suggesting that the EA's effects in modulating PNE-induced lung phenotype are limited to specific time-periods during lung development.

Project description:IntroductionSecond generation electronic nicotine delivery systems (ENDS; also known as e-cigarettes, vaporizers or vape pens) are designed for a customized nicotine delivery experience and have less resemblance to regular cigarettes than first generation "cigalikes." The present study examined whether they generalize as a conditioned cue and evoke smoking urges or behavior in persons exposed to their use.MethodsData were analyzed in N = 108 young adult smokers (?5 cigarettes per week) randomized to either a traditional combustible cigarette smoking cue or a second generation ENDS vaping cue in a controlled laboratory setting. Cigarette and e-cigarette urge and desire were assessed pre- and post-cue exposure. Smoking behavior was also explored in a subsample undergoing a smoking latency phase after cue exposure (N = 26).ResultsThe ENDS vape pen cue evoked both urge and desire for a regular cigarette to a similar extent as that produced by the combustible cigarette cue. Both cues produced similar time to initiate smoking during the smoking latency phase. The ENDS vape pen cue elicited smoking urge and desire regardless of ENDS use history, that is, across ENDS na?ve, lifetime or current users. Inclusion of past ENDS or cigarette use as covariates did not significantly alter the results.ConclusionsThese findings demonstrate that observation of vape pen ENDS use generalizes as a conditioned cue to produce smoking urge, desire, and behavior in young adult smokers. As the popularity of these devices may eventually overtake those of first generation ENDS cigalikes, exposure effects will be of increasing importance.ImplicationsThis study shows that passive exposure to a second generation ENDS vape pen cue evoked smoking urge, desire, and behavior across a range of daily and non-daily young adult smokers. Smoking urge and desire increases after vape pen exposure were similar to those produced by exposure to a first generation ENDS cigalike and a combustible cigarette, a known potent cue. Given the increasing popularity of ENDS tank system products, passive exposures to these devices will no doubt increase, and may contribute to tobacco use in young adult smokers.

Project description:Bisphenol A (BPA) accumulates in the maturing gut and liver in utero and is known to alter gut bacterial profiles in offspring. Gut bacterial dysbiosis may contribute to chronic colonic and systemic inflammation. We hypothesized that perinatal BPA exposure-induced intestinal (and liver) inflammation in offspring is due to alterations in the microbiome and colonic metabolome. The 16S rRNA amplicon sequencing analysis revealed differences in beta diversity with a significant reduction in the relative abundances of short-chain fatty acid (SCFA) producers such as Oscillospira and Ruminococcaceae due to BPA exposure. Furthermore, BPA exposure reduced fecal SCFA levels and increased systemic lipopolysaccharide (LPS) levels. BPA exposure-increased intestinal permeability was ameliorated by the addition of SCFA in vitro. Metabolic fingerprints revealed alterations in global metabolism and amino acid metabolism. Thus, our findings indicate that perinatal BPA exposure may cause gut bacterial dysbiosis and altered metabolite profiles, particularly SCFA profiles, leading to chronic colon and liver inflammation. IMPORTANCE Emerging evidence suggests that environmental toxicants may influence inflammation-promoted chronic disease susceptibility during early life. BPA, an environmental endocrine disruptor, can transfer across the placenta and accumulate in fetal gut and liver. However, underlying mechanisms for BPA-induced colonic and liver inflammation are not fully elucidated. In this report, we show how perinatal BPA exposure in rabbits alters gut microbiota and their metabolite profiles, which leads to colonic and liver inflammation as well as to increased gut permeability as measured by elevated serum lipopolysaccharide (LPS) levels in the offspring. Also, perinatal BPA exposure leads to reduced levels of gut bacterial diversity and bacterial metabolites (short-chain fatty acids [SCFA]) and elevated gut permeability-three common early biomarkers of inflammation-promoted chronic diseases. In addition, we showed that SCFA ameliorated BPA-induced intestinal permeability in vitro. Thus, our study results suggest that correcting environmental toxicant-induced bacterial dysbiosis early in life may reduce the risk of chronic diseases later in life.

Project description:Due to the active inhibition of the adipogenic programming, the default destiny of the developing lung mesenchyme is to acquire a myogenic phenotype. We have previously shown that perinatal nicotine exposure, by down-regulating PPAR? expression, accentuates this property, culminating in myogenic pulmonary phenotype, though the underlying mechanisms remained incompletely understood. We hypothesized that nicotine-induced PPAR? down-regulation is mediated by PPAR? promoter methylation, controlled by DNA methyltransferase 1 (DNMT1) and methyl CpG binding protein 2 (MeCP2), two known key regulators of DNA methylation. Using cultured alveolar interstitial fibroblasts and an in vivo perinatal nicotine exposure rat model, we found that PPAR? promoter methylation is strongly correlated with inhibition of PPAR? expression in the presence of nicotine. Methylation inhibitor 5-aza-2'-deoxycytidine restored the nicotine-induced down-regulation of PPAR? expression and the activation of its downstream myogenic marker fibronectin. With nicotine exposure, a specific region of PPAR? promoter was significantly enriched with antibodies against chromatin repressive markers H3K9me3 and H3K27me3, dose-dependently. Similar data were observed with antibodies against DNA methylation regulatory factors DNMT1 and MeCP2. The knock down of DNMT1 and MeCP2 abolished nicotine-mediated increases in DNMT1 and MeCP2 protein levels, and PPAR? promoter methylation, restoring nicotine-induced down regulation of PPAR? and upregulation of the myogenic protein, fibronectin. The nicotine-induced alterations in DNA methylation modulators DNMT1 and MeCP2, PPAR? promoter methylation, and its down-stream targets, were also validated in perinatally nicotine exposed rat lung tissue. These data provide novel mechanistic insights into nicotine-induced epigenetic silencing of PPAR? that could be exploited to design novel targeted molecular interventions against the smoke exposed lung injury in general and perinatal nicotine exposure induced lung damage in particular.

Dataset Information

Perinatal nicotine exposure induces asthma in second generation offspring.

Background

Methods

Results

Conclusions

Publications

Perinatal nicotine exposure induces asthma in second generation offspring.

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