Effects Of Prenatal Nicotine Exposure Research Articles

The Increased Apoptosis of Mesenchymal Stem Cells Mediated Osteopenia Due to Prenatal Nicotine Exposure in Female Offspring Rats via IGF1 Pathway.

Nicotine exposure is a common adverse environment during pregnancy and causes developmental toxicity of long bones in offspring. However, the effect of prenatal nicotine exposure (PNE) on bone mass accumulation in female offspring and its mechanism remained to be further investigated. In this study, we constructed a PNE rat model and collected the long bone and the bone marrow mesenchymal stem cells (BMSCs) from female offspring rats for the detection of bone mass, cell apoptosis, and the expressions of osteogenesis- and apoptosis-related genes. The results revealed that PNE induced low bone mass in female offspring rats and was associated with the suppression of osteogenic function. Moreover, the apoptosis of BMSCs derived from the PNE female offspring rats was raised, and the expression ratio of apoptosis marker genes BAX/BCL-2 was significantly increased. Further, PNE inhibited the expression and function of insulin-like growth factor l (IGF1) signaling pathway in BMSCs. However, the exogenous IGF1 treatment partially ameliorated the increased apoptosis of BMSCs derived from the PNE female offspring rats. In conclusion, PNE induced low bone mass in female offspring rats, which was attributed to the increased apoptosis of BMSCs due to functional inhibition of IGF1 signaling pathway.

Effects of Prenatal Nicotine Exposure on Short-Term and Long-Term Memory: A Literature Review

Effects of Prenatal Nicotine Exposure on Short-Term and Long-Term Memory: A Literature Review

Vaporized nicotine in utero results in reduced birthweight, increased locomotion, and decreased voluntary exercise, dependent on sex and diet in offspring.

Rationale Clinical research has shown that prenatal exposure to nicotine may result in increased obesity risk later in life. Preclinical research has corroborated this finding, but few studies have investigated inhaled nicotine or the interaction with diet on obesity risk. Objective The aim of this study was to investigate the effects of prenatal nicotine exposure on both direct and indirect obesity measures, with both sex and diet as factors. Methods Pregnant rats were exposed to either vehicle or nicotine vapor (24mg/mL or 59mg/mL) throughout the entire gestational period. Offspring from each treatment group were given either a normal diet or a high fat diet starting at postnatal day 22. Caloric intake, body weight, spontaneous locomotion, sleep/wake activity, and voluntary exercise were measured throughout adolescence. Pregnancy weight gain and pup birthweights were collected to further measure developmental effects of prenatal nicotine exposure. Results Both maternal weight gain during pregnancy and pup weight at birth were decreased with prenatal nicotine exposure. Early adolescent males showed increased spontaneous activity in the open field following prenatal nicotine exposure compared to vehicle counterparts, particularly those given high-fat diet. Additionally, high dose nicotine prenatal treated males ran significantly less distance on the running wheel in late adolescence compared to vehicle counterparts, in the normal diet group only. Conclusion The results presented here show decreased birthweight, hyperactivity, and decreased voluntary exercise in adolescence following prenatal nicotine exposure in dose, sex, and diet dependent manners, which could lead to increased obesity risk in adulthood.

Effects of prenatal nicotine exposure on vascular endothelial function and structure in offspring rats

To clarify the effect of prenatal nicotine exposure (PNE) on vascular endothelial function (VEF) in offspring rats, and to explore whether these effects are long-lasting and sex-dependent. Pregnant Sprague-Dawley rats were randomized into two groups and exposed to either 102 mg/mL nicotine (experimental group) or normal saline (control group) through a subcutaneously implanted osmotic micropump. Vascular rings from the thoracic aorta were collected from offspring rats at 1, 4, and 12 months of age. The specimens were used to determine VEF using functional tests and to observe morphologic and pathologic changes of blood vessels in hematoxylin and eosin-stained samples with light microscopy. The percentage of acetylcholine-induced endothelium-dependent vasorelaxation (EDV) of the thoracic aorta was significantly higher in the experimental group than in the control group in 1-, 4-, and 12-month-old female offspring rats (18.68±2.32 vs. 13.85±6.10, 17.44±3.91 vs. 10.77±5.77, and 30.96±22.26 vs. 18.94±13.61, respectively; P <0.05). The percentage of acetylcholine-induced EDV was significantly lower in the experimental group than in the control group in 1-, 4-, and 12-month-old male offspring rats (10.31±4.05 vs. 16.05±14.80, 5.57±2.81 vs. 12.12±5.62, and 11.98±7.24 vs. 58.87±32.43, respectively; P <0.05). The hematoxylin & eosin-stained vascular rings of the offspring rats displayed an uneven lumen, scattered intimal thickening, partial shedding and vacuolar degeneration of endothelial cells, and inflammatory cell infiltration and phagocytosis in the experimental group. In addition, overt smooth muscle atrophy in tunica media, disordered cell arrangement, and unclear structure of the elastic fiber layer was observed. None of these histopathologic changes were found in the control group. In adult offspring rats, PNE not only affected the VEF of the thoracic aorta but also led to pathologic changes in the vascular structure. Additionally, the effects of PNE on VEF were sex-specific, manifesting primarily as significantly improved VEF in female offspring rats and significantly impaired VEF in male offspring rats, lasting into adulthood.

Mechanisms underlying cognitive impairment induced by prenatal nicotine exposure: a literature review.

Human and animal studies have conclusively shown that prenatal nicotine exposure alters fetal brain development and causes persistent impairment in the cognitive function of offspring. However, the mechanisms underlying the effect of prenatal nicotine exposure on cognitive function in offspring are still unclear. The objective of this review is to discuss the published studies on the mechanisms underlying the effects of prenatal nicotine exposure on cognitive impairment and discuss the potential mechanisms of action. The findings of the reviewed studies show that the main mechanisms involved are alteration in the composition of nicotinic acetylcholine receptor subunits, increase in surface expression of the glutamate receptor subunit GluR2, a reduction in neurogenesis, alteration of Akt and ERK1/2 activity, and mitochondrial dysfunction in the hippocampus and cortex. These pathways could shed light on future molecular markers and therapeutic targets for the prevention and treatment of cognitive dysfunction induced by prenatal nicotine exposure.

Nicotine and Its Downstream Metabolites in Maternal and Cord Sera: Biomarkers of Prenatal Smoking Exposure Associated with Offspring DNA Methylation.

Nicotine is a major constituent of cigarette smoke. Its primary metabolite in maternal and cord sera, cotinine, is considered a biomarker of prenatal smoking. Nicotine and cotinine half-lives are decreased in pregnancy due to their increased rate of metabolism and conversion to downstream metabolites such as norcotinine and 3-hydroxycotinine. Hence, downstream metabolites of nicotine may provide informative biomarkers of prenatal smoking. In this study of three generations (F0-mothers, F1-offspring who became mothers, and F2-offspring), we present a biochemical assessment of prenatal smoking exposure based on maternal and cord sera levels of nicotine, cotinine, norcotinine, and 3-hydroxycotinine. As potential markers of early effects of prenatal smoking, associations with differential DNA methylation (DNAm) in the F1- and F2-offspring were assessed. All metabolites in maternal and cord sera were associated with self-reported prenatal smoking, except for nicotine. We compared maternal self-report of smoking in pregnancy to biochemical evidence of prenatal smoking exposure. Self-report of F0-mothers of F1 in 1989–1990 had more accuracy identifying prenatal smoking related to maternal metabolites in maternal serum (sensitivity = 94.6%, specificity = 86.9%) compared to self-reports of F1-mothers of F2 (2010–2016) associated with cord serum markers (sensitivity = 66.7%, specificity = 78.8%). Nicotine levels in sera showed no significant association with any DNAm site previously linked to maternal smoking. Its downstream metabolites, however, were associated with DNAm sites located on the MYO1G, AHRR, and GFI1 genes. In conclusion, cotinine, norcotinine, and 3-hydroxycotinine in maternal and cord sera provide informative biomarkers and should be considered when assessing prenatal smoking. The observed association of offspring DNAm with metabolites, except for nicotine, may imply that the toxic effects of prenatal nicotine exposure are exerted by downstream metabolites, rather than nicotine. If differential DNA methylation on the MYO1G, AHRR, and GFI1 genes transmit adverse effects of prenatal nicotine exposure to the child, there is a need to investigate whether preventing changes in DNA methylation by reducing the metabolic rate of nicotine and conversion to harmful metabolites may protect exposed children.

Optical coherence tomography angiography to evaluate murine fetal brain vasculature changes caused by prenatal exposure to nicotine.

Maternal smoking causes several defects ranging from intrauterine growth restriction to sudden infant death syndrome and spontaneous abortion. While several studies have documented the effects of prenatal nicotine exposure in development and behavior, acute vasculature changes in the fetal brain due to prenatal nicotine exposure have not been evaluated yet. This study uses correlation mapping optical coherence angiography to evaluate changes in fetal brain vasculature flow caused by maternal exposure to nicotine during the second trimester-equivalent of gestation in a mouse model. The effects of two different doses of nicotine were evaluated. Results showed a decrease in the vasculature for both doses of nicotine, which was not seen in the case of the sham group.

Effects of Prenatal Nicotine Exposure on the Dental Health of Laboratory Rats (Rattus norvegicus)

Nicotine, regarded as the active ingredient in cigarette smoke, is known to directly or indirectly interfere with cellular metabolic pathways including angiogenesis, osteogenesis, and collagen synthesis. Though smoking remains common, relatively little studies focus on nicotine’s role in dental development.The objective of this project was to assess the effect of prenatal nicotine exposure on dental development using rats (Rattus norvegicus) as an animal model. We hypothesized that maternal prenatal exposure to nicotine would have a long lasting negative effects on dental development even after nicotine withdrawal.To test these hypotheses, 12 female and six male Long Evans rats were purchased and bred. Dams were randomly divided into four groups (n=3, per group) and injected subcutaneously with different concentrations of nicotine hydrogen tartrate (Sigma CAS Number 65‐31‐6) as follows; Control Group (saline), Low Dose (1 mg/kg), Medium Dose (2 mg/kg), and High Dose (4 mg/kg). Pups were raised under normal laboratory conditions. We additionally monitored the weights and food intake levels of mothers during pregnancy.Incisor Growth Measurement: Offspring were anesthetized with a 2L/m oxygen flow with 5% isoflurane. Grooves were made above the gum line of mandibular incisors using an electronic dremel. After 7 days, incisor length measurement was made by measuring the distance between the gum tissue boundary and the groove. A new groove was made at the gum line. Measurements were taken every 7 days for eight weeks. Upon completion of the study, the animals were euthanized by carbon dioxide inhalation followed by bilateral thoracotomy. All procedures used on live animals were approved by St. Olaf College Institutional Animal Care and Use Committee.The differences among groups on incisor growth rate, maternal food intake, weight gain and litter size were determined by analysis of variance. P values ≤ 0.05 were considered significant.Nicotine injection during pregnancy is associated with reduced food intake and weight growth of the mothers. Prenatal exposure to nicotine also altered incisor growth rates among their offspring. Our results have shown that the mean dental growth of male offspring in the control, low, medium, and high doses were 4.8 mm, 4.0 mm, 4.4 mm, and 4.4 mm, respectively; the mean dental growth of female offspring in the control, low, medium, and high doses were 4.7 mm, 3.9 mm, 4.1 mm, and 4.4 mm, respectively. According to our two factor ANOVA, the result rejects the hypothesis that there is a correlation between sex and dental growth differences among the groups. On the other hand, the Tukey‐Kramer test suggested that there were statistically significant differences between the control and low groups, control and medium groups, and low and high groups in regard to dental growth rates. However, the correlation between nicotine dosage and dental growth in statistically significant groups is not dosage dependent, In conclusion, maternal nicotine uptake does not affect dental growth rate in a dose dependent pathway.Support or Funding InformationSt. Olaf Biology Department

Effects of prenatal nicotine exposure on hepatic glucose and lipid metabolism in offspring rats and its hereditability

Prenatal nicotine exposure (PNE) could induce an increased susceptibility to multiple chronic diseases in adult offspring, that mainly caused by intrauterine maternal glucocorticoid (GC) over-exposure. We investigated the changes and inheritability of hepatic glucose and lipid metabolism caused by PNE, to decipher the possible intrauterine programming mechanism. Pregnant Wistar rats were administered subcutaneously with 2 mg/kg·d nicotine from gestational day (GD) 9∼20, and second-generation (F2) were set according to the mating between control females and PNE males. The results showed that serum phenotypes and hepatic enzymes of glucose and lipid metabolism were lower in F1 fetal rats of PNE but higher in the F1 adult rats. Meanwhile, the activated states of hepatic glucocorticoid-activation system, including type 1 and type 2 11β-hydroxysteroid dehydrogenases (Hsd11b1/2), nuclear receptor subfamily 3, group C, member 1 (Nr3c1) and CCAAT enhancer binding protein α (Cebpa), were positively correlated with serum corticosterone levels but negatively correlated with the histone acetylation (H3K27ac) and expression levels of insulin-like growth factor 1 (Igf1) before and after birth. Furthermore, serum phenotypes and hepatic enzymes of glucose and lipid metabolism were lower in both F2 fetal and adult rats of PNE, which were consistent with the hepatic changes of GC-IGF1 axis and the glucocorticoid-activation system. In conclusion, PNE could lead to inheritable changes of hepatic glucose and lipid metabolism, which are related to the intrauterine programming of GC-IGF1 axis induced by the glucocorticoid-activation system.

Effects of Prenatal Nicotine Exposure on the Dental Development of Laboratory Rats (Rattus norvegicus)

Cigarette smoking is extremely common among pregnant women. The main active ingredient in cigarettes is nicotine. Nicotine is known to have negative effects on the cardiovascular system, respiratory system and birth weight among others. Maternal smoking during pregnancy has also been found to affect dental development in the offspring. The objective of this project was to assess the dose dependent effect of prenatal nicotine exposure on dental development in humans using rats (Rattus norvegicus) as an animal model. We hypothesized that maternal prenatal exposure to nicotine would affect dental development in the offspring. We also hypothesized that nicotine exposure in the early developmental stages would have long lasting negative effects on dental development. Rats are an ideal animal model for this study because of their short lifespan and continuously growing incisors.To test these hypotheses, 12 female and six male Long Evans rats were purchased and bred. During the 21 days of pregnancy, dams were randomly divided into four groups (n=2, per group) and injected subcutaneously with different concentrations of nicotine hydrogen tartrate (Sigma CAS Number 65‐31‐6) as follows; group 1 received a low dose of 1 mg/kg, group 2 received a medium dose of 2 mg/kg and group 3 received a high dose of 4 mg/kg. Maternal food intake and weight gain were monitored during pregnancy. At birth, pups were raised under normal laboratory conditions and weaned after three weeks.Teeth measurements are ongoing. Measurements are taken once a week and will continue for a period of 8 weeks. The rats are anaesthetized by ether. Grooves are then made on the labial surface of the right mandibular incisor teeth by means of a jeweller's file; this procedure is repeated whenever the grooves are abraded. The distance between the groove and the free gingival margin covering the interincisal septum is measured by vernier calipers, the latter being taken as the datum point. This is repeated at intervals of 2 and 7 days.Statistical analysisThe differences among groups on maternal food intake, weight gain and litter size were determined by analysis of variance. P values ≤ 0.05 were considered significant.ResultsThere was a significant difference between the experimental groups in terms of maternal weight gain (p≤0.05). However, there was no difference among the four groups when it came to food intake. Analysis of dental development is ongoing and results will be available and ready for presentation at the annual meeting.ConclusionFrom the current data, high dose nicotine treatment negatively impacted weight gain during pregnancy. Compared to the control group, the high dose treatment group gained the least amount of weight and had the smallest litter size. However nicotine treatment did not seem to affect food intake. More research is underway to determine the mechanisms underlying these observations.Support or Funding InformationNone Food Intake During PregnancyimageFood Intake During Pregnancy Weight Gain During PregnancyimageWeight Gain During PregnancyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Synergistic effects of prenatal nicotine exposure and post-weaning high-fat diet on hypercholesterolaemia in rat offspring of different sexes.

Hypercholesterolaemia is considered a disease with intrauterine origin. Recently, we reported that prenatal nicotine exposure (PNE) induced an abnormal level of total cholesterol in rat offspring before and after birth. However, there were little data about sex differences in serum cholesterol level in PNE offspring. In addition, many previous studies reported that blood cholesterol is associated with daily diet. This study was designed to analyse the interaction among PNE, high-fat diet (HFD) and sex on cholesterol metabolism in the rat. Pregnant Wistar rats were administered 2mg/kg nicotine subcutaneously from gestational day (GD) 11 until parturition. After weaning, pups were fed with normal diet or HFD till 24weeks, and then, serum cholesterol phenotypes and hepatic cholesterol metabolism-related genes were tested. Results showed that PNE manifested a distinct programming effect on cholesterol phenotype and cholesterol metabolism-related genes. HFD aggregated PNE-induced hypercholesterolaemia in adult offspring and exacerbated liver cholesterol metabolism dysfunction in PNE offspring. There was no sex difference in serum cholesterol level, but there were interactions among PNE, HFD and sex on cholesterol metabolic genes in adult offspring, which indicates that cholesterol metabolism in female offspring is more likely to be affected by PNE and HFD. In conclusion, HFD exacerbated PNE-induced hypercholesterolaemia, and sex differences existed in liver cholesterol metabolic genes in PNE- or HFD-treated offspring.

Prenatal nicotine exposure induces thymic hypoplasia in mice offspring from neonatal to adulthood

Clinical study showed that smoking during pregnancy deceased the thymus size in newborns. However, the long-term effect remains unclear. This study was aimed to observe the effects of prenatal nicotine exposure (PNE) on the development of thymus and the T-lymphocyte subpopulation in mice offspring from the neonatal to adulthood. Both the thymus weight and cytometry data indicated that PNE caused persistent thymic hypoplasia in male offspring from neonatal to adult period and transient changes in female offspring from neonatal to prepuberal period. Flow cytometry analysis disclosed a permanent decreased proportion and number of mature CD4 single-positive (SP) T cells in thymus of both sex. In addition, the PNE male offspring showed a more serious thymus atrophy in the ovalbumin (OVA)-sensitized model. Moreover, increased autophagic vacuole and elevated mRNA expression of Beclin 1 were noted in PNE fetal thymus. In conclusion, PNE offspring showed thymus atrophy and CD 4 SP T cell reduction at different life stages. Mechanically, PNE induced excessive autophagy in fetal thymocytes might be involved in these changes. All the results provided evidence for elucidating the PNE-induced programmed immune diseases.

Prenatal nicotine exposure alters postsynaptic AMPA receptors and glutamate neurotransmission within the laterodorsal tegmentum (LDT) of juvenile mice

Despite dissemination of information regarding the harm on fetal development of smoking while pregnant, the number of pregnancies associated with nicotine exposure appears to have stagnated. Presence of nicotine during neural formulation is associated with a higher susceptibility of drug dependence, suggesting an altered development of neurons in circuits involved in saliency and motivation. The laterodorsal tegmental nucleus (LDT) plays a role in coding stimuli valence via afferents to mesolimbic nuclei. Accordingly, alterations in development of neural mechanisms in the LDT could be involved in vulnerability to drug dependency. Therefore, we examined the effect of prenatal nicotine exposure (PNE) on glutamatergic functioning of LDT neurons in mouse brain slices using whole-cell, patch clamp concurrent with fluorescence-based calcium imaging. PNE was associated with larger amplitudes of AMPA-induced currents, and greater AMPA-mediated rises in intracellular calcium. AMPA/NMDA ratios and the AMPA-current rectification index were lower and higher, respectively, consistent with changes in the functionality of AMPA receptors in the PNE, which was substantiated by a greater inhibition of evoked and spontaneous glutamatergic synaptic events by a selective inhibitor of GluA2-lacking AMPA receptors. Paired pulse ratios showed a decreased probability of glutamate release from presynaptic inputs, and fluorescent imaging indicated a decreased action potential-dependent calcium increase associated with PNE. When taken together, our data suggest that PNE alters LDT glutamatergic functioning, which could alter output to mesolimbic targets. Such an alteration could play a role in altered coding of relevancy of drug stimuli that could enhance risk for development of drug dependency.

α7 nAChR mediated Fas demethylation contributes to prenatal nicotine exposure-induced programmed thymocyte apoptosis in mice

This study aimed to investigate the effects of prenatal nicotine exposure (PNE) on thymocyte apoptosis and postnatal immune impairments in vivo and further explore the epigenetic mechanisms of the pro-apoptotic effect of nicotine in vitro. The results showed that PNE caused immune impairments in offspring on postnatal day 49, manifested as increased IL-4 production and an increased IgG1/IgG2a ratio in serum. Enhanced apoptosis of total and CD4+SP thymocytes was observed both in fetus and in offspring. Further, by exposing thymocytes to 0–100 μM of nicotine in vitro for 48 h, we found that nicotine increased α7 nicotinic acetylcholine receptor (nAChR) expression, activated the Fas apoptotic pathway, and promoted thymocyte apoptosis in concentration-dependent manners. In addition, nicotine could induce Tet methylcytosine dioxygenase (TET) 2 expression and Fas promoter demethylation, which can be abolished by TET2 siRNA transfection. Moreover, the α7 nAChR specific antagonist α-bungarotoxin can abrogate nicotine-induced TET2 increase, and the following Fas demethylation and Fas-mediated apoptosis. In conclusion, our findings showed, for the first time, that α7 nAChR activation could induce TET2-mediated Fas demethylation in thymocytes and results in the upregulation of Fas apoptotic pathway, which provide evidence for elucidating the PNE-induced programmed thymocyte apoptosis.

Sex Dependent Effects of Prenatal Nicotine Exposure on Cardiovascular Reactivity: Are Males at a Greater Risk for Cardiovascular Disease?

Prenatal nicotine exposure (PNE) has been linked to an increased incidence of anxiety‐disorders, risk of nicotine use, and dysregulation of the hypothalamic orexin system. Recent data link dysregulation of the orexin system to cardiovascular disease. The aim of this study was to evaluate cardiovascular reactivity of adult offspring exposed to nicotine in utero and correlate differences with changes in orexin system gene expression in the hypothalamus and amygdala. Pregnant Sprague Dawley rats had an osmotic mini‐pump filled with nicotine implanted on day 6 of pregnancy (exposure dose 3 mg/kg). At 12 weeks of age (n=4–6/group) offspring were instrumented with arterial catheters and tested 2 days later. PNE male and female weighed ~20% more than controls (P<0.05) but resting mean arterial pressure (MAP) was not significantly different between groups. After an acute dose of nicotine (0.37mg/kg), MAP increased ~ 9 mm Hg in females and 6 mm Hg in male within 2 min. of a subcutaneous (sc) injection, independent of prenatal treatment At 18 minutes' post nicotine injection, MAP in both male and female controls and PNE females decreased significantly below baseline (−9 mmHg) while the MAP of PNE males returned to baseline. There was a strong trend (P<0.07) for the pressor response to angiotensin II (10 microg/kg) to be greater in the PNE males compared to control but not for the PNE females when compared to sex‐matched controls. In the hypothalamus orexin‐type 1 receptor gene expression was increased significantly in PNE males compared to controls (P<0.006). Alternatively, in the amygdala a decrease in orexin‐type 2 receptors in PNE females compared to controls (P<0.03) was identified These results suggest that male offspring exposed to nicotine in utero may be more susceptible to the negative cardiovascular consequences of nicotine when compared to females due to sex‐dependent changes in orexin‐receptor gene expression in the brain.Support or Funding InformationFlorida Department of Health‐James and Esther King Biomedical Research Program

Prenatal nicotine exposure decreases the release of dopamine in the medial frontal cortex and induces atomoxetine-responsive neurobehavioral deficits in mice.

Increased risk of attention-deficit/hyperactivity disorder (AD/HD) is partly associated with the early developmental exposure to nicotine in tobacco smoke. Emerging reports link tobacco smoke exposure or prenatal nicotine exposure (PNE) with AD/HD-like behaviors in rodent models. We have previously reported that PNE induces cognitive behavioral deficits in offspring and decreases the contents of dopamine (DA) and its turnover in the prefrontal cortex (PFC) of offspring It is well known that the dysfunction of DAergic system in the brain is one of the core factors in the pathophysiology of AD/HD. Therefore, we examined whether the effects of PNE on the DAergic system underlie the AD/HD-related behavioral changes in mouse offspring. PNE reduced the release of DA in the medial PFC (mPFC) in mouse offspring. PNE reduced the number of tyrosine hydroxylase (TH)-positive varicosities in the mPFC and in the core as well as the shell of nucleus accumbens, but not in the striatum. PNE also induced behavioral deficits in cliff avoidance, object-based attention, and sensorimotor gating in offspring. These behavioral deficits were attenuated by acute treatment with atomoxetine (3mg/kg, s.c.) or partially attenuated by acute treatment with MPH (1mg/kg, s.c.). Taken together, our findings support the notion that PNE induces neurobehavioral abnormalities in mouse offspring by disrupting the DAergic system and improve our understanding about the incidence of AD/HD in children whose mothers were exposed to nicotine during their pregnancy.

Increased Fetal Thymocytes Apoptosis Contributes to Prenatal Nicotine Exposure-induced Th1/Th2 Imbalance in Male Offspring Mice.

Nicotine, a definite risk factor during pregnancy, is an immunomodulator. This study was designed to investigate the effects of prenatal nicotine exposure (PNE) on the balance of Th1/Th2 in offspring, and further explore the developmental origin mechanisms from the perspective of fetal thymocytes apoptosis. Pregnant Balb/c mice were administered 1.5 mg/kg nicotine subcutaneously twice per day from gestational day (GD) 9 to GD18. Results showed that PNE could cause a Th2 shift in male offspring, manifested as increased ratio of IgG1/IgG2a, IL-4 production in serum, and IL-4/IFN-γ expression ratio in spleen. Increased apoptosis of total thymocytes and CD4SP and reduced cell proportion of CD4SP were found in PNE male offspring on postnatal day (PND) 14 and PND 49. In the fetuses, decreased body weight and organ index of fetal thymus, histological changes in fetal thymus, reduced CD4SP proportion and increased fetal thymocyte apoptosis were observed in nicotine group. The increased mRNA expression of genes involved in Fas-mediated apoptotic pathway and protein expression of Fas were also detected. In conclusion, PNE could cause a Th2 shift in male offspring mediated by reduced CD4+ T cells output, which may result from the increasing apoptosis of total thymocytes and CD4SP.

Effects of Prenatal Nicotine Exposure on Infant Language Development: A Cohort Follow Up Study.

Objectives To study the longitudinal effects of prenatal nicotine exposure on cognitive development, taking into consideration prenatal and postnatal second-hand smoke exposure. Methods A cohort follow up study was carried out. One hundred and fifty-eight pregnant women and their infants were followed during pregnancy and infant development (at 6, 12, 30months). In each trimester of pregnancy and during postnatal follow-up, a survey was administered to obtain sociodemographic data and the details of maternal and close familial toxic habits. Obstetric and neonatal data were obtained from hospital medical records. To assess cognitive development, the Bayley Scales of Infant Development were applied at 6, 12 and 30months; to assess language development, the MacArthur-Bates Communicative Development Inventories were applied at 12months and the Peabody Picture Vocabulary Test at 30months. Results After adjustment for confounding variables, the results showed that infants prenatally exposed to cigarette smoke recorded poor cognitive development scores. Language development was most consistently affected, specifically those aspects related to auditory function (vocalizations, sound discrimination, word imitation, prelinguistic vocalizations, and word and sentence comprehension). Conclusions for Practice Irrespective of prenatal, perinatal and sociodemographic data (including infant postnatal nicotine exposure), prenatal exposure to cigarette smoke and second-hand smoke affect infant cognitive development, especially language abilities.

Interacting effect of MAOA genotype and maternal prenatal smoking on aggressive behavior in young adulthood.

Findings on the etiology of aggressive behavior have provided evidence for an effect both of genetic factors, such as variation in the monoamine oxidase A (MAOA) gene, and adverse environmental factors. Recent studies have supported the existence of gene×environment interactions, with early experiences playing a key role. In the present study, the effects of prenatal nicotine exposure, MAOA genotype and their interaction on aggressive behavior during young adulthood were examined. In a sample of 272 young adults (129 males, 143 females) from an epidemiological cohort study, smoking during pregnancy was measured with a standardized parent interview at the offspring's age of 3months. Aggressive behavior was assessed between the ages of 19 and 25years using the Young Adult Self-Report. DNA was genotyped for the MAOA 5' untranslated region variable number of tandem repeats polymorphism (VNTR). Results revealed a significant interaction between MAOA and smoking during pregnancy, indicating higher levels of aggressive behavior in young adults carrying the MAOA low-expressing genotype who had experienced prenatal nicotine exposure (n=8, p=.025). In contrast, in carriers of the MAOA high-expressing genotype, maternal smoking during pregnancy had no effect on aggressive behavior during young adulthood (n=20, p=.145). This study extends earlier findings demonstrating an interaction between MAOA genotype and prenatal nicotine exposure on aggressive behavior into young adulthood. The results point to the long-term adverse effects of smoking during pregnancy on the offspring's mental health, possibly underlining the importance of smoking cessation during pregnancy. According to the nature of the study (particularly sample size and power), analyses are exploratory and results need to be interpreted cautiously.

DNA hypermethylation of acetoacetyl-CoA synthetase contributes to inhibited cholesterol supply and steroidogenesis in fetal rat adrenals under prenatal nicotine exposure.

Prenatal nicotine exposure is a risk factor for intrauterine growth retardation (IUGR). Steroid hormones synthesized from cholesterol in the fetal adrenal play an important role in the fetal development. The aim of this study is to investigate the effects of prenatal nicotine exposure on steroidogenesis in fetal rat adrenals from the perspective of cholesterol supply and explore the underlying epigenetic mechanisms. Pregnant Wistar rats were administered 1.0mg/kg nicotine subcutaneously twice a day from gestational day (GD) 7 to GD17. The results showed that prenatal nicotine exposure increased IUGR rates. Histological changes, decreased steroid hormone concentrations and decreased cholesterol supply were observed in nicotine-treated fetal adrenals. In the gene expression array, the expression of genes regulating ketone metabolic process decreased in nicotine-treated fetal adrenals. The following conjoint analysis of DNA methylation array with these differentially expressed genes suggested that acetoacetyl-CoA synthetase (AACS), the enzyme utilizing ketones for cholesterol supply, may play an important role in nicotine-induced cholesterol supply deficiency. Moreover, the decreased expression of AACS and increased DNA methylation in the proximal promoter of AACS in the fetal adrenal was verified by real-time reverse-transcription PCR (RT-PCR) and bisulfite sequencing PCR (BSP), respectively. In conclusion, prenatal nicotine exposure can cause DNA hypermethylation of the AACS promoter in the rat fetal adrenal. These changes may result in decreased AACS expression and cholesterol supply, which inhibits steroidogenesis in the fetal adrenal.