Dataset Information

Prenatal nicotine exposure alters lung function and airway geometry through ?7 nicotinic receptors.

ABSTRACT: Maternal smoking during pregnancy has been associated with adverse effects on respiratory health. Whereas the epidemiologic link is incontrovertible, the mechanisms responsible for this association are still poorly understood. Although cigarette smoke has many toxic constituents, nicotine, the major addictive component in cigarette smoke, may play a more significant role than previously realized. The objectives of this study were to determine whether exposure to nicotine prenatally leads to alterations in pulmonary function and airway geometry in offspring, and whether ?7 nicotinic acetylcholine receptors (nAChRs) mediate these effects. In a murine model of in utero nicotine exposure, pulmonary function, airway size and number, methacholine response, and collagen deposition were examined. Exposure periods included Gestation Days 7-21, Gestation Day 14 to Postnatal Day 7, and Postnatal Days 3-15. Prenatal nicotine exposure decreases forced expiratory flows in offspring through ?7 nAChR-mediated signals, and the critical period of nicotine exposure was between Prenatal Day 14 and Postnatal Day 7. These physiologic changes were associated with increased airway length and decreased diameter. In addition, adult mice exposed to prenatal nicotine exhibit an increased response to methacholine challenge, even in the absence of allergic sensitization. Collagen expression was increased between adjacent airways and vessels, which was absent in ?7 nAChR knockout mice. These observations provide a unified mechanism of how maternal smoking during pregnancy may lead to lifelong alterations in offspring pulmonary function and increased risk of asthma, and suggest potential targets to counteract those effects.

SUBMITTER: Wongtrakool C

PROVIDER: S-EPMC3359906 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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Prenatal nicotine exposure alters lung function and airway geometry through α7 nicotinic receptors.

Wongtrakool Cherry C Wang Ningshan N Hyde Dallas M DM Roman Jesse J Spindel Eliot R ER

American journal of respiratory cell and molecular biology 20120112 5

Maternal smoking during pregnancy has been associated with adverse effects on respiratory health. Whereas the epidemiologic link is incontrovertible, the mechanisms responsible for this association are still poorly understood. Although cigarette smoke has many toxic constituents, nicotine, the major addictive component in cigarette smoke, may play a more significant role than previously realized. The objectives of this study were to determine whether exposure to nicotine prenatally leads to alte ...[more]

PMID: 22246862

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Project description:Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl(2) (10ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2weeks of age. At 7weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-? production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4(+)FoxP3(+)CD25(+) (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8(+)CD223(+) T cells were markedly decreased in the spleens in all offspring at 7weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can result in long term detrimental effects on the immune system of the offspring and these effects are to some extent sex-specific.

Project description:Technological advances have led to the discovery of genetic variants that contribute to many illnesses including nicotine dependence. A multi-stage model of the development of nicotine dependence underlies these genetic studies, and it includes a progression through several stages of smoking behavior from never smoking to nicotine dependence. The final step in this model of dependence is the progression from established smoking behavior to the development of nicotine dependence. Contrasting individuals who smoke only a few cigarettes per day, or "chippers", to heavy smoking, nicotine dependent subjects, focuses a genetic study on the transition from smoking to nicotine dependence. This approach has identified distinct genetic variants that contribute to nicotine dependence on chromosome 15 in the region of the alpha5-alpha3-beta4 family of nicotinic receptor genes. This region of association includes an amino acid change in the alpha5 nicotinic receptor protein, which is most likely a biological variant altering the risk of developing dependence. There is also evidence that other variants alter alpha5 nicotinic receptor gene expression and potentially the risk of smoking. The discovery of these genetic variants and their contribution to the development of nicotine dependence highlight some of the many challenges in genetic studies. The first is that the prevalence of risk alleles can vary across populations so that a genetic risk factor can have a larger or small effect in a population depending on its frequency. The second challenge is that the risk that each genetic variant contributes in the development of a disorder is small and so it is many genes along with environmental risk factors that contribute to the development of a disorder. Interestingly, recent genetic studies of lung cancer and chronic obstructive pulmonary disease demonstrate that this same region has an important genetic influence on these disorders. Finally, there are differences in the risk of developing nicotine dependence based on gender and socioeconomic status. As our understanding of the genetic contributions of nicotine dependence increases, we may improve and personalize our treatments for smoking cessation and enhance our knowledge of other smoking related diseases in those who are at high risk for the many adverse consequences of smoking.

Dataset Information

Prenatal nicotine exposure alters lung function and airway geometry through ?7 nicotinic receptors.

Publications

Prenatal nicotine exposure alters lung function and airway geometry through α7 nicotinic receptors.

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