Maternal nicotine exposure and fetal programming of vascular oxidative stress in adult offspring

Abstract

Despite the well-known harmful effects, many women continue to smoke throughout pregnancy. Consequently, nicotine replacement therapy (NRT) – which has been developed as a pharmacotherapy for smoking cessation – has been used as an alternative to smoking during pregnancy. However, like cigarette smoking, NRT results in biologically significant levels of nicotine crossing the placenta, leading to both fetal and neonatal exposure to nicotine, and yet, NRT safety during pregnancy has not been extensively evaluated. There is now evidence from studies in rats that maternal nicotine exposure throughout gestation results in fetal programming of vascular oxidative stress in the offspring during adulthood. This phenomenon involves vascular dysfunction mediated by reactive oxygen species in association with decreased superoxide dismutase activity and increased Nox2-NADPH oxidase expression in the vascular wall. If this phenomenon also occurs in humans, either smoking or NRT use during pregnancy may represent a novel risk factor for the unborn that results in accelerated cardiovascular disease in their adulthood.

LINKED ARTICLE

This article is a commentary on Xiao et al., pp. 1400–1409 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2011.01437.x

Despite readily available literature on the harmful effects of smoking during pregnancy, as many as 20% of women continue to smoke throughout pregnancy (Andres and Day, 2000). Obstetrical and fetal complications associated with cigarette smoking include stillbirth (Hogberg and Cnattingius, 2007), placental abruption (Ananth et al., 1999), spontaneous abortion (George et al., 2006) and sudden infant death syndrome (Mitchell and Milerad, 2006). Consequently, nicotine replacement therapy (NRT) has been developed as a pharmacotherapy for smoking cessation and may be used during pregnancy. However, the clinical safety of NRT use during pregnancy has only been evaluated in a small number of short-term human trials. Data from animal studies suggest that nicotine may be a crucial component of cigarette smoke responsible for many long-term effects associated with maternal cigarette smoking on the offspring, such as impaired fertility, type 2 diabetes, obesity, hypertension, neurobehavioural defects and respiratory dysfunction. This subject was recently reviewed in detail by Bruin et al. (2007).

Experimental and, ultimately, clinical research into developmental origins of disease could provide parents with new information to assist in lifestyle choices that have significant impact on their offspring. For example, a study of milk quality in lactating rats found that exposure to tobacco smoke altered glucose homeostasis and hormonal profiles in feeding pups. Thus, serum from pups born to smoke-exposed mothers had lower blood glucose levels, as well as lower adrenal catecholamine and serum corticosterone (Santos-Silva et al., 2011). An earlier study of in utero and neonatal rat exposure to second-hand tobacco smoke demonstrated reduced endothelium-dependent relaxation in aortas of 4-week-old offspring (Hutchison et al., 1998). In non-human primates, perinatal exposure to second-hand smoke (from day 40 of gestation to 1 year of age) increased aortic levels of 3-nitrotyrosine and 2,4-dinitrophenylahydrazine, accompanied by reduced aortic superoxide dismutase protein expression and activity, as well as increased mitochondrial DNA lesions, as seen in human smokers (Westbrook et al., 2010). Smoking during pregnancy results in biologically significant levels of nicotine crossing the placenta (range 3.3–28 ng·g⁻¹) in amniotic fluid (range 1.5–23 ng·mL⁻¹) and in fetal serum (range 0.5–25 ng·mL⁻¹) (Luck et al., 1985). Nicotine concentrates in fetal blood and amniotic fluid and is detectable in breast milk (Luck and Nau, 1985; Jordanov, 1990; Lambers and Clark, 1996). As such, like smoking, maternal use of NRT results in both fetal and neonatal exposure to nicotine.

In this issue, Xiao and colleagues report the first evidence of an impact of maternal nicotine exposure on fetal programming of vascular oxidative stress in adult offspring (Xiao et al., 2011). Remarkably, administration of nicotine to pregnant rats throughout gestation resulted in augmented angiotensin II-induced vasoconstriction and impaired endothelium-dependent NO-mediated vasodilatation in their 5-month-old male offspring. These functional abnormalities could be abrogated by acute treatment of the vessels with the NADPH oxidase inhibitor, apocynin, or the superoxide dismutase mimetic, tempol, consistent with a detrimental effect of reactive oxygen species generated acutely in the vascular wall. Furthermore, the changes in vascular function were associated with decreased superoxide dismutase activity and increased Nox2, malondialdehyde, superoxide and nitrotyrosine levels in the vascular wall. The authors have previously reported that prenatal nicotine exposure leads to altered vascular reactivity in male adult offspring (Xiao et al., 2007) associated with increased AT₁ angiotensin II receptors but decreased AT₂ receptor levels (Xiao et al., 2008). Together with the current findings of enhanced vascular oxidative stress, it would therefore be anticipated that antenatal nicotine exposure increases the risk of hypertension and vascular disease, at least in male adult offspring. An important goal of future studies will thus be to carefully test this hypothesis, and if ultimately proven in humans, this important work will have revealed a novel cardiovascular risk factor that can only be modified before birth.

While these present findings have major implications for cardiovascular health, the fundamental processes that underlie oxidative stress and the resulting cellular dysfunction are likely to exist in other organ systems, and thus should also be carefully evaluated. Indeed, maternal nicotine exposure during pregnancy and lactation in Wistar rats has been reported to exert a direct effect on the nicotinic acetylcholine receptor in the developing pancreas to induce oxidative stress and subsequent beta cell loss (Bruin et al., 2008), a scenario that is associated with increased risk of developing type 2 diabetes later in life (Leahy, 2005; Rhodes, 2005).

There is some information available regarding the ontogeny of chromatin remodelling to the onset of adult metabolic syndrome; however, the epigenetic changes during fetal development that result in adult vascular oxidative stress and dysfunction remain unknown. Fetal epigenetic changes following maternal nicotine exposure are an important aspect of fetal programming that needs to be studied in detail as DNA methylation is greatest during fetal life. Glucocorticoids have a demethylating action (Zhavoronkova and Vaniushin, 1987), which might modulate expression of genes involved in vascular structure and functional development, while reactive oxygen species can modify methylation, leading to changes in gene transcription and protein expression (Cerda and Weitzman, 1997; Valinluck et al., 2004). Furthermore, modifications of histones H3 and H4 have been described in experimental intrauterine growth retardation associated with impaired development of pancreatic beta cells and insulin resistance, as a result of progressive epigenetic silencing of Pdx1 (Park et al., 2008).

A reduction in the cost of health care will rely heavily on the birth of healthy children who are less likely to develop cardiovascular disease and metabolic syndromes later in life. Xiao et al. (2011) have here provided a further glimpse into a mechanism by which NRT-mediated maternal exposure to nicotine may programme the fetus to increased cardiovascular risk. Future epigenetic studies in experimental mouse models, and especially in humans, are needed to bolster our understanding of the complex fundamental biological processes of fetal programming affected by the prenatal and perinatal exposure to nicotine, received either through smoking or from the use of NRT.

Glossary

Abbreviations

NADPH

nicotinamide adenine dinucleotide phosphate

NRT

nicotine replacement therapy

Conflicts of interest

None.