The effect of grand maternal nicotine exposure during gestation and lactation on lung integrity of the F2 generation.

BACKGROUND: Maternal nicotine exposure during gestation and lactation adversely affects lung development in the offspring. It has been suggested that the "program" that control long-term maintenance of the structural integrity of the lung may be compromised. The aim of the study was to establish whether the effect of grand-maternal nicotine exposure during gestation and lactation can be transferred to the F2 generation. METHODS: After mating, rats were randomly divided into two groups (F0). One group received nicotine (1 mg/kg body weight/day). The controls receive saline. Body weight (BW), lung volume (Lv), linear intercept (Lm), alveolar wall thickness (Tsept), senescent and proliferating cell numbers were used to evaluate changes in the lung structure of the offspring (F1). The F1 generation was divided into four groups, namely, (1) control (F1 males mated with F1 females, (2) NmCf (F1 nicotine exposed male mated with F1 control female), (3) NfCm (F1 nicotine exposed female mated with F1 control male), and (4) NmNf (F1 male exposed to nicotine mated with F1 female also exposed to nicotine). The F1 nicotine exposed males and females were exposed to nicotine via the placenta and mother's milk (F0 generation) only. The F2 progeny was never exposed to nicotine. DISCUSSION: Grand-maternal nicotine (F0) resulted in parenchymal deterioration and emphysema in the F2 progeny due to increased numbers of premature senescent cells together with a slower cell proliferation. The transfer of premature aging characteristics from the F1 progeny to the F2 progeny is via the male and female germ cell line. CONCLUSION: Grand-maternal nicotine exposure induces structural changes in the lungs of the F2 generation that resembled premature aging.

Perinatal exposure to nicotine and implications for subsequent obstructive lung disease.

Many diseases are due to gene-environment or epigenetic-environment interactions resulting in a change in the program that controls tissue structure and function. Changes in the in utero and external environment during perinatal development due to parental smoking, or nicotine exposure, may reduce the capacity of the offspring to protect themselves against environmental stressors. Nicotine is genotoxic and also induces reactive oxygen species [ROS] production. It also reduces the antioxidant capacity of the lung. The lungs of the offspring are therefore developing in an environment of an oxidant-antioxidant imbalance with the concomitant adverse effects of the oxidants and nicotine on cell integrity. Consequently, they are more prone to develop respiratory diseases such as asthma and emphysema later in life. The use of NRT by pregnant or lactating females is therefore not an appropriate strategy to quit smoking.

Tobacco smoking: patterns, health consequences for adults, and the long-term health of the offspring.

Tobacco use started several centuries ago and increased markedly after the invention of the cigarette making machine. Once people start smoking they find it difficult to quit the habit. This is due to the addictive effect of nicotine in tobacco smoke. Various epidemiologic and laboratory studies clearly showed that smoking is associated with various diseases such as heart diseases, asthma and emphysema and the associated increase in morbidity and mortality of smokers. Several studies implicate nicotine as the causative factor in tobacco smoke. Apart from nicotine, various carcinogens also occur in tobacco smoke resulting in an increase in the incidence of cancer in smokers. While the smoking habit is decreasing in developed countries, tobacco use increases in the developing countries. Smoking prevalence is also highest in poor communities and amongst those with low education levels. It is important to note that, although ther is a decline in the number of smokers in the developed countries, there is a three to four decades lag between the peak in smoking prevalence and the subsequent peak in smoking related mortality. It has been shown that maternal smoking induces respiratory diseases in the offspring. There is also evidence that parental smoking may program the offspring to develop certain diseases later in life. Various studies showed that maternal nicotine exposure during pregnancy and lactation via tobacco smoke of nicotine replacement therapy (NRT), program the offspring to develop compromised lung structure later in life with the consequent compromised lung function. This implies that NRT is not an option to assist pregnant or lactating smokers to quit the habit. Even paternal smoking may have an adverse effect on the health of the offspring since it has been shown that 2nd and 3rd hand smoking have adverse health consequences for those exposed to it.

Life-long programming implications of exposure to tobacco smoking and nicotine before and soon after birth: evidence for altered lung development.

Tobacco smoking during pregnancy remains common, especially in indigenous communities, and likely contributes to respiratory illness in exposed offspring. It is now well established that components of tobacco smoke, notably nicotine, can affect multiple organs in the fetus and newborn, potentially with life-long consequences. Recent studies have shown that nicotine can permanently affect the developing lung such that its final structure and function are adversely affected; these changes can increase the risk of respiratory illness and accelerate the decline in lung function with age. In this review we discuss the impact of maternal smoking on the lungs and consider the evidence that smoking can have life-long, programming consequences for exposed offspring. Exposure to maternal tobacco smoking and nicotine intake during pregnancy and lactation changes the genetic program that controls the development and aging of the lungs of the offspring. Changes in the conducting airways and alveoli reduce lung function in exposed offspring, rendering the lungs more susceptible to obstructive lung disease and accelerating lung aging. Although it is generally accepted that prevention of maternal smoking during pregnancy and lactation is essential, current knowledge of the effects of nicotine on lung development does not support the use of nicotine replacement therapy in this group.

Are nicotine replacement therapy, varenicline or bupropion options for pregnant mothers to quit smoking? Effects on the respiratory system of the offspring.

Nicotine occurs in tobacco smoke. It is a habit-forming substance and is prescribed by health professionals to assist smokers to quit smoking. It is rapidly absorbed from the lungs of smokers. It crosses the placenta and accumulates in the developing fetus. Nicotine induces formation of oxygen radicals and at the same time also reduces the antioxidant capacity of the lungs. Nicotine and the oxidants cause point mutations in the DNA molecule thereby changing the program that controls lung growth and maintenance of lung structure. The data available indicate that maternal nicotine exposure induces a persistent inhibition of glycolysis and a drastically increased AMP level. These metabolic changes are thought to contribute to the faster aging of the lungs of the offspring of mothers that are exposed to nicotine via the placenta and mother's milk. The lungs of these animals are more susceptible to damage as shown by the gradual deterioration of the lung parenchyma. The rapid metabolic and structural aging of the lungs of the animals exposed to nicotine via the placenta and mother's milk, and thus during phases of lung development characterized by rapid cell division, is likely due to 'programming' induced by nicotine. Since varenicline, a partial nicotine agonist, has basically the same structure as nicotine, and also binds to acetylcholine receptors in competition with nicotine (but with largely the same effect), it is not advisable to use nicotine or varenicline during gestation and lactation. Furthermore, the use of individual vitamin supplements is also not advisable because of the negative impact on the program that controls maintenance of lung structural and functional integrity and aging. A more appropriate smoking cessation program will also include a mixture of antioxidant nutrients such as in tomato juice.

Nicotine and lung development.

Nicotine is found in tobacco smoke. It is a habit forming substance and is prescribed by health professionals to assist smokers to quit smoking. It is rapidly absorbed from the lungs of smokers. It crosses the placenta and accumulates in the developing fetus. Nicotine induces formation of oxygen radicals and at the same time also reduces the antioxidant capacity of the lungs. Nicotine and the oxidants cause point mutations in the DNA molecule, thereby changing the program that controls lung growth and maintenance of lung structure. The data available indicate that maternal nicotine exposure induces a persistent inhibition of glycolysis and a drastically increased cAMP level. These metabolic changes are thought to contribute to the faster aging of the lungs of the offspring of mothers that are exposed to nicotine via the placenta and mother's milk. The lungs of these animals are more susceptible to damage as shown by the gradual deterioration of the lung parenchyma. The rapid metabolic and structural aging of the lungs of the animals that were exposed to nicotine via the placenta and mother's milk, and thus during phases of lung development characterized by rapid cell division, is likely due to "programming" induced by nicotine. It is, therefore, not advisable to use nicotine during gestation and lactation.

Critical review: nicotine for the fetus, the infant and the adolescent?

The recent expansion of Nicotine Replacement Therapy to pregnant women and children ignores the fact that nicotine impairs, disrupts, duplicates and/or interacts with essential physiological functions and is involved in tobacco-related carcinogenesis. The main concerns in the present context are its fetotoxicity and neuroteratogenicity that can cause cognitive, affective and behavioral disorders in children born to mothers exposed to nicotine during pregnancy, and the detrimental effects of nicotine on the growing organism. Hence, the use of nicotine, whose efficacy in treating nicotine addiction is controversial even in adults, must be strictly avoided in pregnancy, breastfeeding, childhood and adolescence.

Alveolar epithelial cell differentiation and surfactant protein expression after mild preterm birth in sheep.

As the transition to extrauterine life at birth alters the proportions of type I and II alveolar epithelial cells (AECs), our aim was to determine the effect of mild preterm birth on AECs and surfactant protein (SP) gene expression. Preterm lambs were born at approximately 133 d of gestational age (DGA); controls were born at term (approximately 147 DGA). Lungs were collected from preterm lambs at term-equivalent age (TEA; approximately 2 wk after preterm birth) and 6 wk post-TEA. Control lung tissue was collected from fetuses (at 132 DGA), as well as from lambs at approximately 6 h (normal term) and 2, 6, and 8 wk of postnatal age (PNA). In controls, the proportion of type I AECs decreased from 65.1 +/- 3.9% at term to 50.9 +/- 3.3%, while the proportion of type II AECs increased from 33.7 +/- 3.9% to 48.5 +/- 3.3% at 6 wk PNA. At 2 wk after preterm birth, the proportions of type I and II AECs were similar in preterm lambs compared to 132-d fetal levels and term controls but differed from control values at 2 wk PNA; differences between control and preterm lambs persisted at 8 wk PNA. At approximately 2 wk after preterm birth, SP-A and SP-B, but not SP-C, mRNA levels were significantly reduced in preterm lambs compared with term controls, but these differences did not persist at 2 and 6 wk PNA. We conclude that mild preterm birth alters the normal postnatal changes in type I and II cell proportions but does not severely affect SP gene expression.

Early developmental origins of impaired lung structure and function.

Epidemiological studies show that exposure to factors that restrict fetal growth or lead to low birthweight can alter lung development and have later adverse effects on lung function and respiratory health. The major causal factors include reduced nutrient and oxygen availability, nicotine exposure via maternal tobacco smoking and preterm birth, each of which can affect critical stages of lung development. Experimental studies show that these environmental insults can permanently alter lung structure and hence lung function, increasing the risk of respiratory illness and accelerating the rate of lung aging. Further studies are required that address the molecular and cellular mechanisms by which these factors adversely affect lung development and whether such effects can be blocked or reversed. Ultimately however, a major goal should be to prevent prenatal compromises through clinical monitoring, and in the case of smoking through education, thereby ensuring that each fetus has the best possible environment in which to develop.

Postnatal expression of cytochrome P450 1A1, 2A3, and 2B1 mRNA in neonatal rat lung: influence of maternal nicotine exposure.

A critical factor contributing to the etiology or modification of respiratory disease is the ability of the lung tissue to activate or inactivate chemicals. In this study, the authors investigated the effect of maternal nicotine exposure during gestation and lactation on the expression mRNA of cytochrome P450 (CYP) CYP1A1, CYP2A3, and CYP2B1. Fetal rats were exposed to nicotine via maternal administration of nicotine (1 mg/kg body weight/day, subcutaneously); after birth, neonatal rats were exposed to nicotine via the mother's milk. Lung tissue of 1-, 7-, 14-, 21-, and 49-day-old rat pups were used. From weaning on postnatal day 21 up to postnatal day 49, the offspring received no nicotine. Using RNA dot-blot techniques, our results show that CYP mRNA expression in lung tissue increased with age after birth. Maternal nicotine exposure had no influence on CYP1A1 mRNA, but resulted in a marked increase in the expression of CYP2A3 mRNA and CYP2B1 mRNA. The higher levels of CYP2A3 mRNA and CYP2B1 mRNA were maintained after weaning.

Fetal growth restriction has long-term effects on postnatal lung structure in sheep.

We have previously shown that fetal growth restriction (FGR) during late gestation in sheep affects lung development in the near-term fetus and at 8 wk after birth. In the present study, our aim was to determine the effects of FGR on the structure of the lungs at 2 y after birth; our hypothesis was that changes observed at 8 wk after birth would persist until maturity. FGR was induced in sheep by umbilicoplacental embolization, which was maintained from 120 d until delivery at term (approximately 147 d); birth weights of FGR lambs were 41% lower than in controls. At 2 y after birth, body and lung weights were not different, but there were 28% fewer alveoli and alveoli were significantly larger than in controls; hence there was a 10% reduction in the internal surface area relative to lung volume in FGR sheep compared with controls. The lungs of FGR sheep, compared with controls, had thicker interalveolar septa as a result of increased extracellular matrix deposition; the alveolar blood-air barrier was also thicker, largely because of an 82% increase in basement membrane thickness. These changes are qualitatively similar to those observed at 8 wk. Our data show that structural alterations in the lungs induced by FGR that were apparent at 8 wk were still evident at 2 y after birth, indicating that FGR may result in permanent changes in the structure of the lungs of the offspring and may affect respiratory health and lung aging later in life.