Alterations in DNA methylation and airway hyperreactivity in response to in utero exposure to environmental tobacco smoke

Abstract

Growing evidence indicates that prenatal exposure to maternal smoking is a risk factor for the development of asthma in children. However, the effects of prenatal environmental tobacco smoke (ETS) exposure on the genome and lung immune cells are unclear. This study aims to determine whether in utero ETS exposure alters DNA methylation patterns and increases airway hyperreactivity (AHR) and inflammation. Pregnant C57BL/6 mice were exposed daily to a concentration of 1.0?mg/m³ ETS. AHR was determined in the 6-week-old offspring by measurement of airway resistance. Global and gene promoter methylation levels in lung DNA from offspring were analyzed by luminometric methylation and pyrosequencing assays, respectively. Offspring exposed to ETS showed a marked increase in the number of alveolar macrophages in the bronchoalveolar lavage fluid and level of IL-13 in the airways compared with offspring of filtered-air exposed dams (controls). ETS exposure significantly augmented AHR compared with controls. In the methylation analysis, ETS-exposed offspring had a significantly lower level of global DNA methylation than the controls. We observed a significant increase in IFN-γ, and significant decrease in IL-13 methylation levels in the ETS group compared with controls. Collectively, these data suggest that in utero ETS exposure increases the risk of pulmonary inflammation and AHR through altered DNA methylation, but additional studies are needed to fully determine the causal link between changes in methylation and cytokines levels, as well as AHR.     

The effect of folic acid on ovine fetuses in utero during late gestation

To investigate whether folic acid would have toxic effects on fetal cardiac, hepatic, and renal functions, this was the first in utero fetal study testing acute effects of folic acid at the last third of gestation. Folic acid (5?mg/day) or 0.9% saline as the control was intragastricly administrated into pregnant ewes. Both maternal and fetal blood were analyzed for pH, PO₂, PCO₂, SO₂%, hemoglobin, hematocrit, glucose, lactic acid, osmolality, Na⁺, and K⁺ concentrations. Maternal and fetal cardiovascular functions were assessed by examining cardiac enzymes and cardiovascular responses in vivo. Fetal hepatic and renal functions were examined by analysis of biochemistry index and renal excretion. Folic acid did not alter the blood values in both ewes and fetuses. Cardiac enzyme activities remained unchanged, and no alteration in cardiovascular responses was observed. Folic acid did not affect fetal urine volume, urine electrolytes, and osmolality. Enzyme activities related to hepatic and renal functions were not changed. In addition, maternal application of folic acid had no effect on maternal and fetal lipid profile. The results showed that folic acid used (5?mg/day) during the last third of gestation did not cause biochemical changes related to cardiac, hepatic, and renal functions in both maternal and fetal sheep, providing new information for use of folic acid during late pregnancy.     

Early life exposure to environmental tobacco smoke alters immune response to asbestos via a shift in inflammatory phenotype resulting in increased disease development

Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual’s lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development.     

Maternal nicotine exposure during gestation and lactation induces cardiac remodeling in rat offspring

The aim of this study was to evaluate the effects of maternal nicotine exposure on heart morphology and fibrosis in rat offspring. Nicotine was administered to pregnant Sprague-Dawley rats by using a subcutaneous osmotic mini-pump at a dose of 6 mg/kg/day from Gestational Days 7–21 or Gestational Day 7 to Postnatal Day 14. A control group received an equal volume of saline by the same route as nicotine. Rats born to prenatal nicotine-treated dams exhibited significantly greater cell width of cardiomyocytes, fewer cardiomyocyte nuclei number, higher β-myosin heavy chain and transforming growth factor (TGF-β1) expression, and higher collagen deposition in heart compared with rats born to normal saline-treated dams on Postnatal Days 7 and 21. Postnatal nicotine exposure further enhances these effects. We conclude that TGF-β1 may be involved in the pathogenesis of cardiac remodeling induced by maternal nicotine exposure during gestation and lactation in rat offspring.     

Gestational atrazine exposure: effects on male reproductive development and metabolite distribution in the dam, fetus, and neonate

Few studies have investigated the long-term effects of atrazine (ATR) following in utero exposure. We evaluated the effects of gestational exposure of Sprague Dawley dams to ATR (0, 1, 5, 20, or 100 mg/kg-d) on the reproductive development of male offspring. We also quantified the distribution of ATR and its chlorinated metabolites in maternal, fetal, and neonatal fluid and tissue samples following gestational and/or lactational exposure. Dose-dependent levels of chlorotriazines, primarily diamino-s-chlorotriazine, were present in most samples analyzed, including fetal tissue. In utero exposure to 1-20 mg/kg-d ATR did not alter testosterone production, the timing of puberty, play behavior, or other androgen-dependent endpoints of male offspring. Significant maternal toxicity and postnatal mortality were observed at 100 mg/kg-d. We conclude that, although levels of chlorotriazines within the fetus were considerable, gestational exposures of 1-20 mg/kg-d do not lead to alterations in the measures of male development examined in this study.     

The genotoxic effect of nicotine on chromosomes of human fetal cells: The first report described as an important study

Context: Recent studies have suggested a direct contribution of nicotine ? the addictive component of tobacco and tobacco smoke ? to human carcinogenesis, and it remains the most common harmful substance to which pregnant women are exposed. Also, it has deleterious effects on the fetus. The sperm of smoking fathers and newborns of smoking mothers have elevated frequencies of chromosome translocations and DNA strand breaks.

Objective: We tried to understand the genotoxic effect of nicotine in pregnancies of active or passive smoking mothers. For this reason, we provide the evidence that nicotine exposure in vitro has detrimental effects on fetal cells.

Materials and methods: We examined the effect of nicotine sulphate on amniotic cells by designing an experimental setting consisting fetal cells grown in nicotine containing medium (25?ng/mL) in study group and fetal cells grown in control medium, which did not contain nicotine.

Results: According to our findings, there is a significant difference of chromosomal aberrations (CAs) between nicotine containing medium grown cells and control medium grown cells, determined by the χ2 test (P <0.001). We found CAs in 21.5% of cells analyzed. The 19.4% of the all cells had numerical aberrations. Chromosomes 21, 22, 8, 15 and 20 related numerical abnormalities were found to be the most frequent numerical abnormalities.

Conclusion: Results of this study confirm that the nicotine leads to significant direct genotoxic effects in human fetal cells in vitro. We speculate that there is an association between prenatal exposure to cigarette smoke and in utero aneuploidies.     

Maternal exposure to Δ9-tetrahydrocannabinol impairs female offspring glucose homeostasis and endocrine pancreatic development in the rat

Recent reports indicate that 7% of pregnant mothers in North America use cannabis. This is concerning given that in utero exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive component in cannabis, causes fetal growth restriction and may alter replication and survival of pancreatic β-cells in the offspring. Accordingly, we hypothesized that maternal exposure to Δ9-THC during pregnancy would impair postnatal glucometabolic health of offspring. To test this hypothesis, pregnant Wistar rats were treated with daily intraperitoneal injections of either 3 mg/kg Δ9-THC or vehicle from gestational day 6 to birth. Offspring were subsequently challenged with glucose and insulin at 5 months of age to assess glucose tolerance and peripheral muscle insulin sensitivity. Female offspring exposed to Δ9-THC in utero were glucose intolerant, associated with blunted insulin response in muscle and increased serum insulin concentration 15 min after glucose challenge. Additionally, pancreata from male and female offspring were harvested at postnatal day 21 and 5 months of age for assessment of endocrine pancreas morphometry by immunostaining. This analysis revealed that gestational exposure to Δ9-THC reduced the density of islets in female, but not male, offspring at postnatal day 21 and 5 months, culminating in reduced β-cell mass at 5 months. These results demonstrate that fetal exposure to Δ9-THC causes female-specific impairments in glucose homeostasis, raising concern regarding the metabolic health of offspring, particularly females, exposed to cannabis in utero.     

Visuospatial memory deficits emerging during nicotine withdrawal in adolescents with prenatal exposure to active maternal smoking.

Active maternal smoking during pregnancy elevates the risk of cognitive deficits and tobacco smoking among offspring. Preclinical work has shown that combined prenatal and adolescent exposure to nicotine produces more pronounced hippocampal changes and greater deficits in cholinergic activity upon nicotine withdrawal than does prenatal or adolescent exposure to nicotine alone. Few prior studies have examined the potential modifying effects of gestational exposure to active maternal smoking on cognitive or brain functional response to tobacco smoking or nicotine withdrawal in adolescents. We examined visuospatial and verbal memory in 35 adolescent tobacco smokers with prenatal exposure to active maternal smoking and 26 adolescent tobacco smokers with no prenatal exposure to maternal smoking who were similar in age, educational attainment, general intelligence, and baseline plasma cotinine. Subjects were studied during ad libitum smoking and after 24 h of abstinence from smoking. A subset of subjects from each group also underwent functional magnetic resonance imaging while performing a visuospatial encoding and recognition task. Adolescent tobacco smokers with prenatal exposure experienced greater nicotine withdrawal-related deficits in immediate and delayed visuospatial memory relative to adolescent smokers with no prenatal exposure. Among adolescent smokers with prenatal exposure, nicotine withdrawal was associated with increased activation of left parahippocampal gyrus during early recognition testing of visuospatial stimuli and increased activation of bilateral hippocampus during delayed recognition testing of visuospatial stimuli. These findings extend prior preclinical work and suggest that, in human adolescent tobacco smokers, prenatal exposure to active maternal smoking is associated with alterations in medial temporal lobe function and concomitant deficits in visuospatial memory.     

Respiratory dysfunctions induced by prenatal nicotine exposure

• 1 Maternal tobacco smoking is the principal risk factor associated with sudden infant death syndrome (SIDS), a leading cause of death of infants under 1 year of age. Victims of SIDS show a higher incidence of respiratory control abnormalities, including central apnoeas, delayed arousal responses and diminished ventilatory chemoreflexes.
• 2 Nicotine is likely the link between maternal tobacco smoking and SIDS. Prenatal nicotine exposure can alter the breathing pattern and can reduce hypoxia‐ and hypercarbia‐induced ventilatory chemoreflexes. In vitro approaches have revealed that prenatal nicotine exposure impairs central chemosensitivity, switching the cholinergic contribution from a muscarinic to a nicotinic receptor‐based drive. In addition, serotonergic, noradrenergic, GABAergic, glycinergic and glutamatergic, among others, are affected by prenatal nicotine.
• 3 Here we propose that prenatal nicotine affects the respiratory network through two main processes: (i) reorganization of neurotransmitter systems; and (ii) remodelling of neural circuits. These changes make breathing more vulnerable to fail in early postnatal life, which could be related to the pathogenesis of SIDS.

     

The effect of maternal exposure to di‐(2‐ethylhexyl)‐phthalate on fetal cardiac development in mice

Accumulating evidence has suggested a link between maternal di‐(2‐ethylhexyl)‐phthalate (DEHP) exposure and various developmental abnormalities. However, the evidence regarding the effect of maternal DEHP exposure on fetal cardiac development is scarce. The present study aimed to determine the effect of maternal DEHP exposure on fetal cardiac development in mice and explore the possible involved mechanism preliminarily. The C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 250 mg kg^–1 DEHP group (n = 15), 500 mg kg^–1 DEHP group (n = 20) and 1 g kg^–1 DEHP group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from embryonic day (E)6.5 to E14.5. Maternal weights were monitored every day and samples were collected at E15.5. Hematoxylin and eosin staining was used to examine fetal cardiac malformations. Real‐time quantitative polymerase chain reaction and western blot were applied to detect peroxisome proliferator‐activated receptor (PPAR)α/PPARγ/Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. Maternal DEHP exposure significantly decreased maternal body weight, fetal weight and placental weight, and remarkably elevated fetal cardiac malformations rate. The phenotypes of cardiac anomalies mainly include septal defects, ventricular myocardium noncompaction and cardiac hypoplasia. Higher doses DEHP (500 mg kg^–1 and 1 g kg^–1) could significantly decreased fetal cardiac Gata4/Mef2c/Chf1 expression, while PPARγ expression was upregulated. Maternal exposure to higher doses of DEHP could result in fetal cardiac development malformations in mice and it might have resulted from the inhibition of cardiac GATA4/Mef2c/Chf1 expression via PPARγ activation.     

Developmental programming: Sex‐specific programming of growth upon prenatal bisphenol A exposure

In both human and animals, in utero exposure to bisphenol A (BPA), an endocrine‐disrupting chemical used in the production of plastics and epoxy resins, has been shown to affect offspring reproductive and metabolic health during adult life. We hypothesized that the effect of prenatal exposure to environmentally relevant doses of BPA will be evident during fetal organogenesis and fetal/postnatal growth trajectory. Pregnant ewes were administered BPA subcutaneously from 30 to 90 days of gestation (term 147 days). Fetal organ weight, anthropometric measures, maternal/fetal hormones and postnatal growth trajectory were measured in both sexes. Gestational BPA administration resulted in higher accumulation in male than female fetuses only at fetal day 65, with minimal impact on fetal/maternal steroid milieu in both sexes at both time points. BPA‐treated male fetuses were heavier than BPA‐treated female fetuses at fetal day 90 whereas this sex difference was not evident in the control group. At the organ level, liver weight was reduced in prenatal BPA‐treated female fetuses, while heart and thyroid gland weights were increased in BPA‐treated male fetuses relative to their sex‐matched control groups. Prenatal BPA treatment also altered the postnatal growth trajectory in a sex‐specific manner. Males grew slower during the early postnatal period and caught up later. Females, in contrast, demonstrated the opposite growth trend. Prenatal BPA‐induced changes in fetal organ differentiation and early life growth strongly implicate translational relevance of in utero contributions to reproductive and metabolic defects previously reported in adult female offspring.     

Cross-Fostering Study of Methyl Mercury Retention,Demethylation and Excretion in the Neonatal Hamster

Abstract: The cross-fostering technique was used in order to compare methyl mercury (MeHg) metabolism in hamsters following prenatal (in utero) and neonatal (lactational) exposure. Pregnant Syrian golden hamsters were administered radiolabeled MeHg on day 12 of gestation. The offspring was nursed by foster mothers unexposed to MeHg, while the pups from the unexposed animals were nursed by the MeHg-administered animals. Under these conditions, each pup in the litter received a dose of MeHg in utero corresponding to 0.9% of the maternal dose. The average amount of mercury found in the pups exposed via milk corresponded to 4.5% of the total body burden of the foster dam at the onset of lactation. This was about half the amount received by the pups exposed in utero. The total body burden of mercury, and the amount of mercury in the liver, brain and kidney of the pups exposed in utero began to decrease at seven days of age. The rate of decrease differed among the tissues and was lowest in the kidney. The amount of mercury in pups exposed via milk reached a peak level when the pups were 10-15 days old. The total body burden of mercury showed a slow decrease while the liver, brain and kidney levels decreased rapidly. In both groups of animals, up to 80% of the total body burden of mercury was found in the pelt. These data show that milk may be a significant exposure route for mercury and that neonatal hamsters are unable to demethylate MeHg and excrete mercury in urine and faeces.     

Lymphoma and lung cancer in offspring born to pregnant mice dosed with dibenzo[a,l]pyrene: the importance of in utero vs. lactational exposure

The fetus and neonate cannot be viewed as “little adults”; they are highly sensitive to toxicity from environmental chemicals. This phenomenon contributes to the fetal basis of adult disease. One example is transplacental carcinogenesis. Animal models demonstrate that environmental chemicals, to which pregnant women are daily exposed, can increase susceptibility of the offspring to cancer. It is uncertain to what degree in utero vs. lactational exposure contributes to cancer, especially for hydrophobic chemicals such as polyhalogenated biphenyls, ethers, dioxins, furans, etc., which can partition into breast milk. We developed a pregnant mouse model in which exposure to the polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), during late gestation, produces an aggressive T-cell lymphoma in offspring between 3 and 6 months of age. Survivors exhibit multiple lung and liver (males) tumors. Here, we adopt a cross-foster design with litters born to dams treated with DBP exchanged with those born to dams treated with vehicle. Exposure to DBP in utero (about 2 days) produced significantly greater mortality than residual DBP exposure only through breast milk (3 weeks of lactation). As previously observed pups in all groups with an ahr^b-1/d (“responsive”) genotype were more susceptible to lymphoma mortality than ahr^d/d (“non-responsive”) siblings. At termination of the study at 10 months, mice exposed in utero also had greater lung tumor multiplicity than mice exposed only during lactation. Our results demonstrate that short exposure to DBP during late gestation presents a greater risk to offspring than exposure to this very hydrophobic PAH following 3 weeks of nursing.     

Developmental Effects Associated with Exposure to Xylene: A Review

ABSTRACT

Data obtained from rodents indicates that maternal exposure to mixed xylenes or individual xylene isomers can have adverse effects on the conceptus. Fetotoxic effects were reported following maternal inhalation exposure to mixed xylenes; altered enzyme activities were also found in rat pups. Dermal application resulted in apparent changes in fetal enzyme activities, while oral treatment was followed by prenatal mortality, growth inhibition, and malformations, primarily cleft palate. Maternal inhalation of individual isomers was associated with all of the above mentioned effects, with the exception of cleft palate. The o^- and p^- isomers appeared more hazardous to offspring than did the m-isomer. Malformations (i.e., cleft palate) associated with mixed or individual isomers were primarily reported at maternally toxic doses. Thus, a clear case for a selective teratogenic effect due to exposure to xylene has yet to be presented.     

Increased nicotine self-administration following prenatal exposure in female rats

There is a significant association between maternal cigarette smoking during pregnancy and greater subsequent risk of smoking in female offspring. In animal models, prenatal nicotine exposure causes persistent alterations in cholinergic and monoaminergic systems, both of which are important for nicotine actions underlying tobacco addiction. Accordingly, the current study was conducted to determine if there is a cause-and-effect relationship between prenatal nicotine exposure and nicotine self-administration starting in adolescence. Pregnant rats were administered nicotine (6 mg/kg/day) by osmotic minipump infusion throughout gestation and then, beginning in adolescence and continuing into adulthood, female offspring were given access to nicotine via a standard operant IV self-administration procedure (0.03 mg/kg/infusion). Gestational nicotine exposure did not alter the initial rate of nicotine self-administration. However, when animals underwent one week of forced abstinence and then had a second opportunity to self-administer nicotine, the prenatally-exposed animals showed a significantly greater rate of self-administration than did the controls. Prenatal nicotine exposure causes increased nicotine self-administration, which is revealed only when the animals are allowed to experience a period of nicotine abstinence. This supports a cause-and-effect relationship between the higher rates of smoking in the daughters of women who smoke cigarettes during pregnancy and implicates a role for nicotine in this effect. Our results further characterize the long-term liabilities of maternal smoking but also point to the potential liabilities of nicotine-based treatments for smoking cessation during pregnancy.     

In utero exposure to nicotine and chlorpyrifos alone, and in combination produces persistent sensorimotor deficits and Purkinje neuron loss in the cerebellum of adult offspring rats

This study was carried out to investigate the effect of in utero exposure to the cholinotoxicants, nicotine and chlorpyrifos, alone or in combination on neurobehavioral alterations and neuronal morphology latter in adult age. In the present study, 90 days old (corresponding to a human adult age) male and female offspring rats were evaluated for neurobehavioral, and neuropathological alterations following maternal, gestational exposure to nicotine and chlorpyrifos (O,O-diethyl-O-3,5,6-trichloro-2-pyridinyl phosphorothioate), alone and in combination. Female Sprague-Dawley rats (300–350 g) with timed-pregnancy were treated with nicotine (3.3 mg/kg/day, in bacteriostatic water via s.c. implantation of mini osmotic pump), chlorpyrifos (1.0 mg/kg, daily, dermal, in 75% ethanol, 1.0 ml/kg) or a combination of both chemicals, on gestational days (GD) 4–20. Control animals received bacteriostatic water via s.c. implantation of mini osmotic pump and dermal application of 70% ethanol. The offspring at postnatal day (PND) 90 were evaluated for neurobehavioral performance, changes in the activity of plasma butyrylcholinesterase (BChE) and acetylcholinesterase (AChE), and neuropathological alterations in the brain. Neurobehavioral evaluations included beam-walk score, beam-walk time, incline plane performance and forepaw grip time. Male and female offspring from mothers treated with nicotine and CPF, alone or in combination showed impairments in the performance of neurobehavioral tests, indicating sensorimotor deficits. Female offspring from mothers treated with a combination of nicotine and chlorpyrifos showed significant increase in plasma BChE activity. Brain regional AChE activity showed differential increases in male and female offspring. Brainstem and cerebellum of female offspring from mothers treated with nicotine or chlorpyrifos, alone or in combination showed increased AChE activity, whereas brainstem of male offspring from mothers treated with nicotine alone or a combination of nicotine and chlorpyrifos showed increase in AChE activity. Also, male offspring exposed in utero to nicotine exhibited increased AChE activity. Histopathological evaluations using cresyl violet staining showed a decrease in surviving Purkinje neurons in the cerebellum in offspring of all treatments groups. An increase in glial fibrillary acidic protein (GFAP) immuno-staining was observed in cerebellum white matter as well as granular cell layer (GCL) of cerebellum following all exposures. These results indicate that in utero exposure to nicotine and chlorpyrifos, alone and in combination produced significant sensorimotor deficits in male and female offspring, differential increase in brain AChE activity, a decrease in the surviving neurons and an increased expression of GFAP in cerebellum in adult offspring rats at a corresponding human adult age. Collectively, this study demonstrates that maternal exposure to environmental neurotoxic chemicals, i.e., nicotine and chlorpyrifos leads to developmental abnormalities in the offspring that persist latter into adulthood.     

Environmental Endocrine Modulators and Human Health: An Assessment of the Biological Evidence

Recently, a great deal of attention and interest has been directed toward the hypothesis that exposure, particularly in utero exposure, to certain environmental chemicals might be capable of causing a spectrum of adverse effects as a result of endocrine modulation. In particular, the hypothesis has focused on the idea that certain organochlorine and other compounds acting as weak estrogens have the capability, either alone or in combination, to produce a variety of adverse effects, including breast, testicular and prostate cancer, adverse effects on male reproductive tract, endometriosis, fertility problems, alterations of sexual behavior, learning disability or delay, and adverse effects on immune and thyroid function. While hormones are potent modulators of biochemical and physiological function, the implication that exposure to environmental hormones (e.g., xenoestrogens) has this capability is uncertain. While it is reasonable to hypothesize that exposure to estrogen-like compounds, whatever their source, could adversely affect human health, biological plausibility alone is an insufficient basis for concluding that environmental endocrine modulators have adversely affected humans. Diethylstilbestrol (DES) is a potent, synthetic estrogen administered under a variety of dosing protocols to millions of women in the belief (now known to be mistaken) that it would prevent miscarriage. As a result of this use, substantial in utero exposure to large numbers of male and female offspring occurred. Numerous studies have been conducted on the health consequences of in utero DES exposure among the adult offspring of these women. There are also extensive animal data on the effects of DES and there is a high degree of concordance between effects observed in animals and humans. The extensive human data in DES-exposed cohorts provide a useful basis for assessing the biological plausibility that potential adverse effects might occur following in utero exposure to compounds identified as environmental estrogens. The effects observed in both animals and humans following in utero exposure to sufficient doses of DES are consistent with basic principles of dose response as well as the possibility of maternal dose levels below which potential non-cancer effects may not occur. Significant differences in estrogenic potency between DES and chemicals identified to date as environmental estrogens, as well as an even larger number of naturally occurring dietary phytoestrogens, must be taken into account when inferring potential effects from in utero exposure to any of these substances. The antiestrogenic properties of many of these same exogenous compounds might also diminish net estrogenic effects. Based on the extensive data on DES-exposed cohorts, it appears unlikely that in utero exposure to usual levels of environmental estrogenic substances, from whatever source, would be sufficient to produce many of the effects (i.e., endometriosis, adverse effects on the male reproductive tract, male and female fertility problems, alterations of sexual behavior, learning problems, immune system effects or thyroid effects) hypothesized as potentially resulting from exposure to chemicals identified to date as environmental estrogens.     

Early life programming of cardiometabolic disease in the Western Australian pregnancy cohort (Raine) study

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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.