Gender-specific effects of prenatal and adolescent exposure to tobacco smoke on auditory and visual attention.

Prenatal exposure to active maternal tobacco smoking elevates risk of cognitive and auditory processing deficits, and of smoking in offspring. Recent preclinical work has demonstrated a sex-specific pattern of reduction in cortical cholinergic markers following prenatal, adolescent, or combined prenatal and adolescent exposure to nicotine, the primary psychoactive component of tobacco smoke. Given the importance of cortical cholinergic neurotransmission to attentional function, we examined auditory and visual selective and divided attention in 181 male and female adolescent smokers and nonsmokers with and without prenatal exposure to maternal smoking. Groups did not differ in age, educational attainment, symptoms of inattention, or years of parent education. A subset of 63 subjects also underwent functional magnetic resonance imaging while performing an auditory and visual selective and divided attention task. Among females, exposure to tobacco smoke during prenatal or adolescent development was associated with reductions in auditory and visual attention performance accuracy that were greatest in female smokers with prenatal exposure (combined exposure). Among males, combined exposure was associated with marked deficits in auditory attention, suggesting greater vulnerability of neurocircuitry supporting auditory attention to insult stemming from developmental exposure to tobacco smoke in males. Activation of brain regions that support auditory attention was greater in adolescents with prenatal or adolescent exposure to tobacco smoke relative to adolescents with neither prenatal nor adolescent exposure to tobacco smoke. These findings extend earlier preclinical work and suggest that, in humans, prenatal and adolescent exposure to nicotine exerts gender-specific deleterious effects on auditory and visual attention, with concomitant alterations in the efficiency of neurocircuitry supporting auditory attention.     

Impact of smoking abstinence on working memory neurocircuitry in adolescent daily tobacco smokers

Rationale Efficient function of neurocircuitry that supports working memory occurs within a narrow range of dopamine neurotransmission. Work in rodents has shown that exposure to nicotine during adolescence leads to nicotine withdrawal emergent alterations in cortical and subcortical dopamine neurotransmission. Objectives To test for evidence that the efficiency of neurocircuitry supporting working memory is altered during acute smoking abstinence in adolescent daily tobacco smokers. Materials and methods Fifty-five adolescent daily tobacco smokers were compared with 38 nonsmokers using functional magnetic resonance imaging while subjects performed a verbal working memory task. Smokers were studied during smoking and after 24 h of abstinence from tobacco use. Results Performance of a task with high working memory load in the context of smoking abstinence was associated with greater activation of components of the verbal working memory neurocircuit, including left ventrolateral prefrontal cortex and left inferior parietal lobe, among smokers relative to nonsmokers. During smoking abstinence, smokers failed to exhibit increases in functional connectivity between components of the working memory neurocircuit with increasing working memory load observed in nonsmoking adolescents and in prior studies of adults. Conclusions Smoking abstinence in adolescent smokers is associated with reductions in the efficiency of working memory neurocircuitry and alterations in the functional coordination between components of the working memory neurocircuit. These alterations may stem from effects of nicotine exposure on catecholaminergic systems during adolescent development. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Prenatal nicotine exposure alters the response to nicotine administration in adolescence: effects on cholinergic systems during exposure and withdrawal.

Maternal smoking during pregnancy increases the likelihood that the offspring will become smokers in adolescence. In the current study, we evaluated effects of prenatal and adolescent nicotine exposure in rats to assess whether there is a biological basis for this relationship. Pregnant rats were given nicotine or vehicle throughout pregnancy and the offspring then again received nicotine or vehicle during adolescence (postnatal days PN30-47.5), using a regimen (6 mg/kg/day by subcutaneous infusion) that produces plasma nicotine levels similar to those in smokers. Evaluations were made in the cerebral cortex and midbrain during adolescent nicotine administration (PN45) and for up to 1 month after the end of treatment. We assessed the magnitude and persistence of nicotinic acetylcholine receptor (nAChR) upregulation; in addition, we evaluated cholinergic synaptic activity by comparing the effects on choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, with those on hemicholinium-3 (HC-3) binding to the presynaptic choline transporter, which is regulated by nerve impulse activity. Prenatal nicotine exposure had only minor effects on nAChRs but produced persistent cholinergic hypoactivity (reduced HC-3 binding relative to ChAT) throughout adolescence and into adulthood (PN75). Adolescent nicotine exposure evoked robust nAChR upregulation and also suppressed cholinergic activity. Prenatal nicotine exposure reduced the upregulation of nAChRs evoked by adolescent nicotine but worsened the cholinergic hypoactivity during withdrawal. Our results indicate that prenatal nicotine exposure alters the subsequent response to nicotine in adolescence, effects that may contribute to the association between maternal smoking during pregnancy and subsequent adolescent smoking in the offspring.     

Abnormal hippocampal neurochemistry in smokers: evidence from proton magnetic resonance spectroscopy at 3 T

OBJECTIVE: In animals, nicotine, the primary psychoactive constituent of tobacco smoke, reduces neurogenesis and increases cell loss in both hippocampus and cortex. Accordingly, tobacco smoking has been linked to reduced performance on cognitive paradigms requiring attention and working memory in humans. However, few prior studies have tested for evidence of structural brain alterations in human tobacco smokers. In this study, proton magnetic resonance spectroscopy was used to assess the effects of chronic smoking on neuronal integrity of the hippocampus and anterior cingulate cortex (ACC). METHODS: Absolute concentrations of N-acetylaspartate, total choline (tCho), and total creatine were measured in the left hippocampus and ACC in 13 chronic tobacco smokers and 13 nonsmokers matched for age, sex, and education. RESULTS: The N-acetylaspartate concentration was significantly reduced in smokers relative to nonsmokers in the left hippocampus but not in the ACC. There were no group differences in the tCho and total creatine concentrations in either voxel. However, ACC tCho concentration was positively correlated with magnitude of lifetime exposure to tobacco smoke (pack-years). CONCLUSION: The results are consistent with prior observations of hippocampal neuronal damage in rodents receiving nicotine and working memory deficits in human tobacco smokers. The positive relationship between tCho and lifetime tobacco exposure suggests that a component of tobacco smoke, presumably nicotine, may increase cortical membrane turnover or modify cell density. Together, these results add to growing evidence that nicotine exerts neurotoxic effects in human brain, although an a priori nature of the findings cannot be ruled out.     

Effects of nicotine on novelty detection and memory recognition performance: double-blind, placebo-controlled studies of smokers and nonsmokers

Rationale  Dependent smokers exhibit deficits in attentional and memory processes when smoking abstinent as compared to when satiated. While nicotine replacement therapy improves attention during abstinence, it is unclear whether this is due to the alleviation of withdrawal-related deficits or inherent beneficial effects of nicotine. Objectives  The primary aim of these studies was to test whether nicotine exerts a beneficial effect on novelty detection and whether such effects occur in nonsmokers as well as habitual smokers. Materials and methods  In two parallel, double-blind, placebo-controlled studies, 24 smokers (study 1) and 24 nonsmokers (study 2) were tested in two counterbalanced sessions: once while wearing a nicotine patch (smokers = 14 mg; nonsmokers = 7 mg) and once while wearing a placebo patch. On each day, participants performed three content-specific oddball tasks (perceptual, semantic, and emotional) that required them to press a button whenever they saw a novel target (20% of stimuli) embedded in a stream of common nontarget stimuli (80% of stimuli). Recognition memory for targets was subsequently tested. Reports of mood, smoking withdrawal, patch side effects, and blind success were collected in each session. Results  Among smokers, compared to placebo, nicotine decreased target reaction time during all oddball tasks. Among nonsmokers, nicotine increased target detection accuracy and subsequent memory recognition. Nicotine’s enhancement on each respective measure was not task-content specific in either sample. Conclusions  These data suggest that acute nicotine administration may exert direct beneficial effects on novelty detection and subsequent memory recognition in both smokers and nonsmokers. Moreover, these effects are not content-specific.     

Are adolescent smokers dependent on nicotine? A review of the evidence

This paper reviews the empirical literature on adolescent nicotine dependence, withdrawal, and their associated features. Data documenting nicotine dependence scores, diagnoses, and individual features among adolescents are reviewed in detail and compared to observations based on adult smokers. These data are derived from a broad variety of sources, including national surveys, school-based surveys, and smoking cessation studies. Overall, results indicate that one to three out of five adolescent smokers is dependent on nicotine, with some adolescent groups clearly at higher risk for dependence (those who are incarcerated, in vocational schools, daily smokers, and/or heavy smokers). Across studies, data consistently indicate that a large majority (two-thirds or more) of adolescent smokers report experiencing withdrawal symptoms during attempts to quit or reduce their smoking. Craving or strong desire to smoke was the most commonly reported withdrawal symptom in every study reviewed. Although analyses of concurrent validity generally support the dependence and withdrawal findings among adolescents, data on the predictive validity of measures used are needed. Moreover, studies of adolescent tobacco withdrawal rely almost exclusively on retrospective self-report data. Recommendations for enhancing methodology and advancing our understanding of adolescent nicotine dependence and withdrawal are offered.     

The nicotine withdrawal assessment for youth: initial instrument validation and psychometric properties

Within the field of adolescent tobacco use, there does not exist a consistently used and validated measure of adolescent nicotine withdrawal symptoms. The purpose of this study was to evaluate the psychometric properties of the Nicotine Withdrawal Assessment for Youth (N-WAY), a new measure of adolescent nicotine withdrawal symptoms. Smokers and nonsmokers, ranging from 13 to 19 years old, were administered the N-WAY and other smoking information questionnaires in order to examine its reliability and validity. The N-WAY demonstrated satisfactory test-retest reliability (r=0.74-88) and internal consistency (Cronbach's α=0.90-0.92). Its total symptom score accurately discriminated current smokers from nonsmokers. The N-WAY was demonstrated to measure a construct different than nicotine dependence symptoms while correlates of nicotine withdrawal symptoms, such as number of daily cigarettes smoked and prior quit attempts, accurately predicted total N-WAY symptom and impact scores. Preliminary results indicate the N-WAY is a reliable and valid assessment of adolescent nicotine withdrawal symptoms among current smokers.     

Sex differences in the cognitive effects of tobacco abstinence: a pilot study

Despite significant research demonstrating the deleterious effects of tobacco abstinence on memory, and research showing substantial sex differences in nicotine withdrawal and memory processes, there has been scant work on how males and females might differ in the effects of tobacco abstinence on memory and cognition. Using a standard recognition memory task, we conducted a pilot study to examine how 24 hours of tobacco abstinence in moderate to heavy smokers would affect memory in males and females. Twenty-five moderate to heavy smokers were tested following a period of smoking normally and following 24 hours of tobacco abstinence. At each session, participants completed a recognition memory task in which items were studied under full- and divided-attention conditions (a standard manipulation of memory encoding) as well as tests of passive short-term and working memory (forward and backward digit span). Tobacco abstinence significantly reduced memory performance under full attention conditions for males but not for females. A significant main effect of smoking status in which abstinence significantly reduced performance, as well as a main effect of encoding condition (divided attention < full attention), were found. Our results demonstrate that there may be substantial sex differences in the cognitive effects of tobacco abstinence. While preliminary, the data suggest the need for further, more extensive study of how males and females differ during tobacco abstinence. Such information will inform the best strategies for tobacco cessation efforts.     

Schizophrenia and tobacco smoking comorbidity: nAChR agonists in the treatment of schizophrenia-associated cognitive deficits

Tobacco smoking is a preventable cause of morbidity and mortality throughout the world. Very high rates of tobacco smoking are seen in patients with schizophrenia. Importantly, smokers with schizophrenia generally have higher nicotine dependence scores, experience more severe withdrawal symptoms upon smoking cessation, have lower cessation rates than healthy individuals, and suffer from significant smoking-related morbidity and premature mortality compared with the general population. Interestingly, significant disturbances in cholinergic function are reported in schizophrenia patients. The high smoking-schizophrenia comorbidity observed in schizophrenia patients may be an attempt to compensate for this cholinergic dysfunction. Cholinergic neurotransmission plays an important role in cognition and is hypothesized to play an important role in schizophrenia-associated cognitive deficits. In this review, preclinical evidence highlighting the beneficial effects of nicotine and subtype-selective nicotinic receptor agonists in schizophrenia-associated cognitive deficits, such as working memory and attention, is discussed. Furthermore, some of the challenges involved in the development of procognitive medications, particularly subtype-selective nicotinic receptor agonists, are also discussed. Amelioration of schizophrenia-associated cognitive deficits may help in the treatment of schizophrenia-smoking comorbidity by promoting smoking cessation and thus help in the better management of schizophrenia patients.     

Does prenatal nicotine exposure sensitize the brain to nicotine-induced neurotoxicity in adolescence?

Offspring of women who smoke during pregnancy are themselves more likely to take up smoking in adolescence. We evaluated neurotoxicant effects of prenatal and adolescent nicotine exposure in developing rats to evaluate whether these contribute to a biological basis for this relationship. Rats were given nicotine or vehicle throughout pregnancy and the offspring then again received nicotine or vehicle during adolescence (postnatal days PN30-47.5); this regimen reproduces the plasma nicotine levels found in smokers. Indices of neural cell number (DNA concentration and content), cell size (protein/DNA ratio), and cell membrane surface area (membrane/total protein) were then evaluated in brain regions during adolescent nicotine administration (PN45) and up to 1 month post-treatment. By itself, prenatal nicotine administration produced cellular alterations that persisted into adolescence, characterized by net cell losses in the midbrain and to a lesser extent, in the cerebral cortex, with corresponding elevations in the membrane/total protein ratio. The hippocampus showed a unique response, with increased DNA content and regional enlargement. Adolescent nicotine treatment alone had similar, albeit smaller effects, but also showed sex-dependence, with effects on protein biomarkers preferential to females. When animals exposed to nicotine prenatally were then given nicotine in adolescence, the net outcome was worsened, largely representing summation of the two individual effects. Our results indicate that prenatal nicotine exposure alters parameters of cell development lasting into adolescence, where the effects add to those elicited directly by adolescent nicotine; neurotoxicant actions may thus contribute to the association between maternal smoking and subsequent smoking in the offspring.     

Working memory deficits predict short-term smoking resumption following brief abstinence

As many as one-half of smokers relapse in the first week following a quit attempt, and subjective reports of cognitive deficits in early abstinence are associated with increased relapse risk. This study examined whether objective cognitive performance after 3 days of abstinence predicts smoking resumption in a 7-day simulated quit attempt. Sixty-seven treatment-seeking smokers received either varenicline or placebo (randomized double-blind) for 21 days. Following medication run-up (days 1–10), there was a 3-day mandatory (biochemically confirmed) abstinence period (days 11–13) during which working memory (Letter-N-Back Task) and sustained attention (Continuous Performance Task) were assessed (day 13). Participants were then exposed to a scheduled smoking lapse and instructed to try to remain abstinent for the next 7 days (days 15–21). Poorer cognitive performance (slower correct reaction time on Letter-N-Back task) during abstinence predicted more rapid smoking resumption among those receiving placebo (p = 0.038) but not among those receiving varenicline. These data lend further support for the growing recognition that cognitive deficits involving working memory are a core symptom of nicotine withdrawal and a potential target for the development of pharmacological and behavioral treatments.     

Increased anxiety-like behavior in adult rats exposed to nicotine as adolescents

OBJECTIVE: Twenty percent of adolescents between 12 and 18 years old are regular smokers. Recently developed animal models demonstrate that adolescent nicotine exposure produces behavioral and electrophysiological changes, which persist into adulthood. The purpose of this study was to further define the behavioral effects of nicotine exposure during adolescence. METHODS: Male 31-36-day-old adolescent rats were administered 5.0 mg/kg/day nicotine using transdermal Nicoderm CQ patches (SmithKline Beecham). During nicotine exposure, motor activity was assessed. Behavior in both standard open field and modified open field was examined 2-3 weeks after exposure ended. RESULTS: Nicotine exposure significantly enhanced motor activity in nicotine-exposed rats compared with controls, demonstrating the acute stimulatory effects of transdermal nicotine. Two to three weeks after nicotine exposure ended, significantly lower levels of exploratory activity were observed relative to controls in the standard open field. Rats exposed to nicotine during adolescence also retreated to the perimeter of the open field more quickly than control rats. In a modified open field, nicotine exposure reduced approaches to food, contact with food and food intake. CONCLUSIONS: Taken together, these data suggest that adolescent nicotine exposure may induce an anxiogenic profile, which persists beyond acute nicotine withdrawal. Given the hypothesized role of stress and anxiety in the maintenance of smoking, it could be speculated that anxiety associated with smoking abstinence may play an important role in continued adolescent tobacco use.     

Nicotine derived from the electronic cigarette improves time-based prospective memory in abstinent smokers

Rationale

It is well established that nicotine improves, and deprivation impairs, cognitive performance and mood in smokers. Prospective memory (PM), remembering to execute a delayed intention at a given time point, is under-explored in smokers. Whilst a handful of studies have shown improved PM with nicotine, the effects of nicotine delivered via the electronic cigarette (e-cigarette) have not been investigated.

Objective

This study explores whether, by comparison with placebo, nicotine delivered via the e-cigarette can improve PM, tobacco withdrawal symptoms and desire to smoke in abstinent smokers.

Methods

Twenty smokers, abstinent for 8–10 h, each completed two experimental sessions under nicotine (18 mg) and placebo (0 mg) e-cigarette conditions. Participants completed a single-item desire-to-smoke scale and the Mood and Physical Symptoms Scale. PM was measured using the Cambridge Prospective Memory Test.

Results

Compared with placebo, the nicotine e-cigarette reduced the desire to smoke and tobacco withdrawal symptoms, and improved time-based but not event-based PM. There was a moderate, marginally significant negative correlation between PM performance during abstinence and nicotine dependence.

Conclusions

This is the first study to show that nicotine derived via e-cigarette can improve PM in abstinent smokers, suggesting efficient nicotine delivery. The finding that the effect of nicotine was restricted to time-based rather than event-based PM is consistent with the view that nicotine acts to improve performance on strategic (effortful) rather than automatic processing. These findings add to the growing body of evidence that the e-cigarette can replace some of the effects of nicotine derived from tobacco smoking, thus highlighting its potential for smoking cessation.     

Is prenatal tobacco exposure a risk factor for early adolescent smoking? A follow-up study

Recent reports indicate a relation between prenatal tobacco exposure (PTE) and offspring smoking. Many of these reports have been retrospective or have not included important variables such as other prenatal substance exposures, maternal and child psycho-social characteristics, mother's current smoking, and friends' smoking. No prior study has examined the timing of PTE. In this prospective study of a birth cohort of 567 14-year-olds, we examined the relation between trimester-specific PTE, offspring smoking, and other correlates of adolescent smoking. Average age of the adolescents was 14.8 years (range: 13.9-16.6 years), 51% were female, 54% were African-American. Data on maternal tobacco and other substance use were collected both prenatally and postnatally, 51% of the mothers were prenatal smokers and 53% smoked when their children were 14 years. PTE in the third trimester significantly predicted offspring smoking (ever/never, smoking level, age of onset) when demographic and other prenatal substances were included in the analyses. PTE remained a significant predictor of the level of adolescent smoking when maternal and child psychological characteristics were added to the model. When more proximal measures of the child's smoking were included in the model, including mother's current smoking and friends' smoking, PTE was no longer significant. Significant predictors of adolescent smoking at age 14 were female gender, Caucasian race, child externalizing behavior, maternal anxiety, and child depressive symptoms. Although direct effects of PTE on offspring smoking behavior have previously been reported from this study and by others, by early-adolescence, this association is not significant after controlling for the more proximal covariates of adolescent smoking such as mother's current smoking and peer smoking.     

Prenatal nicotine exposure alters the responses to subsequent nicotine administration and withdrawal in adolescence: Serotonin receptors and cell signaling.

Offspring of women who smoke during pregnancy are themselves more likely to take up smoking in adolescence, effects that are associated with a high rate of depression and increased sensitivity to withdrawal symptoms. To evaluate the biological basis for this relationship, we assessed effects on serotonin (5-hydroxytryptamine, 5HT) receptors and 5HT-mediated cellular responses in rats exposed to nicotine throughout prenatal development and then given nicotine in adolescence (postnatal days PN30-47.5), using regimens that reproduce plasma nicotine levels found in smokers. Evaluations were then made during the period of adolescent nicotine treatment and for up to one month after the end of treatment. Prenatal nicotine exposure, which elicits damage to 5HT projections in the cerebral cortex and striatum, produced sex-selective changes in the expression of 5HT(1A) and 5HT2 receptors, along with induction of adenylyl cyclase (AC), leading to sensitization of heterologous inputs operating through this signaling pathway. Superimposed on these effects, the AC response to 5HT was shifted toward inhibition. By itself, adolescent nicotine administration, which damages the same pathways, produced similar effects on receptors and the 5HT-mediated response, but a smaller overall induction of AC. Animals exposed to prenatal nicotine showed a reduced response to nicotine administered in adolescence, results in keeping with earlier findings of persistent desensitization. Our results indicate that prenatal nicotine exposure alters parameters of 5HT synaptic communication lasting into adolescence and changes the response to nicotine administration and withdrawal in adolescence, actions which may contribute to a subpopulation especially vulnerable to nicotine dependence.     

Late emerging effects of prenatal and early postnatal nicotine exposure on the cholinergic system and anxiety-like behavior

Animal models of prenatal nicotine exposure clearly indicate that nicotine is a neuroteratogen. Some of the persisting effects of prenatal nicotine exposure include low birth weight, behavioral changes and deficits in cognitive function, although few studies have looked for neurobehavioral and neurochemical effects that might persist throughout the lifespan. Pregnant rats were given continuous infusions of nicotine (0.96 mg/kg/day or 2.0 mg/kg/day, freebase) continuing through the third trimester equivalent, a period of rapid brain development. Because the third trimester equivalent occurs postnatally in the rat (roughly the first week of life) nicotine administration to neonate pups continued via maternal milk until postnatal day (P) 10. Exposure to nicotine during pre- and early postnatal development had an anxiogenic effect on adult rats (P75) in the elevated plus maze (EPM), and blocked extinction learning in a fear conditioning paradigm, suggesting that pre- and postnatal nicotine exposure affect anxiety-like behavior and cognitive function well into adulthood. In contrast, nicotine exposure had no effect on anxiety-like behaviors in the EPM in adolescent animals (P30). Analysis of mRNA for the α4, α7, and β2 subunits of nicotinic acetylcholine receptors revealed lower expression of these subunits in the adult hippocampus and medial prefrontal cortex following pre- and postnatal nicotine exposure, suggesting that nicotine altered the developmental trajectory of the brain. These long-term behavioral and neurochemical changes strengthen the case for discouraging cigarette smoking during pregnancy and clearly indicate that the use of the patch as a smoking cessation aid during pregnancy is not a safe alternative.     

Effects of nicotine nasal spray on cognitive function in schizophrenia.

Schizophrenics have among the highest rates of cigarette smoking. Some studies indicate that cigarette smoking or nicotine may ameliorate some of the cognitive or theoretically related neurophysiological deficits seen in schizophrenic patients. This study investigated the effects of nicotine nasal spray on measures of attention, verbal memory, and visual-spatial memory in schizophrenic patients who were chronic smokers, using a double-blind placebo-controlled pre-post experimental design. Compared to placebo, active nicotine spray significantly decreased reaction time on the Conner's CPT and improved scores on a measure purported to reflect spatial working memory on a dot task. There were trends for the increased number of hits and decreased number of errors in pre-post comparisons on the CPT task in the active nicotine session. There were no effects of active nicotine nasal spray on verbal memory. Our results suggest that nicotine may modestly enhance attention and spatial working memory in schizophrenic patients who are cigarette smokers and have been abstinent overnight.     

Do adolescent smokers experience withdrawal effects when deprived of nicotine?

This is the first controlled prospective study of the effects of nicotine deprivation in adolescent smokers. Heart rate and subjective withdrawal symptoms were measured over an 8-hr period while participants smoked normally. Seven days later, participants were randomized to wear a 15-mg (16-hr) nicotine patch or a placebo patch for 8 hr, and they refrained from smoking during the session. Those wearing the placebo experienced a decrease in heart rate across sessions and an increase in subjective measures of nicotine withdrawal. Those wearing the active patch also reported significant increases for some subjective symptoms. Expectancy effects were also observed. The findings indicate that adolescent smokers experience subjective and objective changes when deprived of nicotine. As in previous research with adults, expectancies concerning the effects of nicotine replacement also influenced perceptions of withdrawal.     

Does early exposure to maternal smoking affect future fertility in adult males?

Animal data suggest that prenatal exposure to certain tobacco smoke components such as nicotine may affect the development of the male gonadal axis, which may in turn affect future adult fertility. There are no previous epidemiologic studies on the potential effects of early (prenatal and childhood) exposure to maternal smoking on the reproductive system in adult male offspring. To investigate this question, we used data from a follow-up study of reproductive function and fertility among young adult sons of mothers who had participated in a randomized clinical trial of diethylstilbestrol use during pregnancy. We observed no significant effects of early exposure to maternal smoking on conventional semen characteristics, hormone levels (follicle stimulating hormone [FSH], luteinizing hormone [LH] and testosterone), urogenital abnormalities and diseases, or perceived infertility problems. Current active smoking by the men was, however, associated with a significant decrease in the percentage of sperm with normal morphology.     

Assessment of prenatal smoke exposure by determining nicotine and its metabolites in maternal and neonatal urine

Urine specimens were collected from 75 pregnant women before childbirth and from their newborns within 48 postnatal hours. A high-performance liquid chromatography (HPLC) method was used to determine urinary nicotine and its metabolites, cotinine and trans-3'-hydroxycotinine (OH-cotinine) to objectivise prenatal smoke exposure. Using the sum of nicotine metabolites as a marker, 34 women were classed as not exposed to smoke ( < 15 nmol/l), 18 as passive smokers (15-400 nmol/l), and 23 as active smokers ( > 400 nmol/1). The newborns of active smokers exhibited significantly (P < 0.001) higher nicotine metabolite concentrations than did those of either non-exposed women or passive smokers. A close correlation was found to exist between maternal and neonatal nicotine and cotinine concentrations (r=0.8968 and r=0.9205, respectively). For OH-cotinine, this correlation was particularly close when maternal, but not neonatal, OH - cotinine was adjusted to creatinine (r=0.9792). The neonatal/maternal urine concentration ratios for cotinine and OH-cotinine were noted to not significantly depend on the time of postpartal urine collection. Within the first two postnatal days, the extent of current prenatal smoke exposure attributable to active smoking of the mother was best reflected by the urinary concentrations of cotinine plus OH-cotinine without adjustment to creatinine.