Prenatal Nicotine Exposure Research Articles

Drinking or Smoking While Breastfeeding and Later Cognition in Children.

Although prenatal alcohol and nicotine exposure are associated with reduced cognition in children, associations between consumption of alcohol during lactation and cognition have not been examined. We aimed to examine whether drinking or smoking while breastfeeding lowers children's cognitive scores. We hypothesized that increased drinking or smoking would be associated with dose-dependent cognitive reductions. Data were sourced from Growing Up in Australia: The Longitudinal Study of Australian Children. Participants were 5107 Australian infants recruited in 2004 and assessed every 2 years. Multivariable linear regression analyses assessed relationships between drinking and smoking habits of breastfeeding mothers and children's Matrix Reasoning, Peabody Picture Vocabulary Test-Third Edition and Who Am I? scores at later waves. Increased or riskier wave 1 maternal alcohol consumption was associated with reductions in Matrix Reasoning scores at age 6 to 7 years in children who had been breastfed (B = -0.11; SE = 0.03; 95% confidence interval: -0.18 to -0.04; P = .01). This relationship was not evident in infants who had never breastfed (B = -0.02; SE = 0.10; 95% confidence interval = -0.20 to 0.17; P = .87). Smoking during lactation was not associated with any outcome variable. Exposing infants to alcohol through breastmilk may cause dose-dependent reductions in their cognitive abilities. This reduction was observed at age 6 to 7 years but was not sustained at age 10 to 11 years. Although the relationship is small, it may be clinically significant when mothers consume alcohol regularly or binge drink. Further analyses will assess relationships between alcohol consumption or tobacco smoking during lactation and academic, developmental, physical, and behavioral outcomes in children.

Combined early life stressors: Prenatal nicotine and maternal deprivation interact to influence affective and drug seeking behavioral phenotypes in rats

Early life stress (ELS) increases the risk for later cognitive and emotional dysfunction, and has been implicated in the etiology of multiple psychiatric disorders. We hypothesize that combined insults during gestation and infancy, critical periods of neural development, could exacerbate neuropsychiatric outcomes in later life. Thus, we investigated the effects of maternal deprivation (MD) stress alone or combined with prenatal nicotine exposure (PNE) on negative affective states, ethanol drinking, and development of mesolimbic loci that regulate depression and drug dependence. On the elevated plus maze (EPM), MD rats exhibited ∼50% increase in risk-taking behavior/decreased anxiety when compared to control, but the combined MD + PNE did not affect this specific behavior. In the open field test, however, both MD and MD + PNE groups showed 2-fold greater locomotor activity. Furthermore, whereas MD showed greater latency to fall at 40 RPM on the rotarod compared to control, the MD + PNE animals’ latency to fall was significantly greater at all RPMs tested, with an approximate 15% enhancement in motor coordination overall compared to control and MD. Analyses of depressive symptomatology with the forced swim test (FST) yielded 2- and 3-fold higher immobility times in MD and MD + PNE respectively. When tested in an operant drinking paradigm to quantify the effect of treatment on 10%v/v ethanol drinking, the MD and MD + PNE groups showed heightened ethanol consumption by ∼3- and 2-fold respectively. However, the experience of PNE reduced ethanol consumption in adults relative to MD alone. To test the stressors’ impact on neurons in the amygdala and ventral tegmental area (VTA), mesolimbic anatomical regions associated with mood and reward, unbiased stereological measurements were performed and revealed ∼15% increase in number and density of neurons in the amygdala for both MD and MD + PNE, and ∼13% reduction in dopaminergic-like neurons in the VTA compared to control. We report here that multiple early stressors including prenatal nicotine and MD can modulate the neuroanatomy of the amygdala and VTA. These early life stressors can interact to influence the development of depressive-like and addictive behaviors.

Placental mechanism of prenatal nicotine exposure-reduced blood cholesterol levels in female fetal rats

Clinical studies showed that intrauterine growth retardation (IUGR) neonatus had lower cholesterol concentrations in cord blood, which might be associated with increased risk of metabolic syndrome and cardiovascular diseases in adulthood. We previously observed lower blood cholesterol levels in prenatal nicotine exposure (PNE)-induced IUGR fetal rats, and this study aimed to elucidate the placental mechanism. Pregnant Wistar rats were subcutaneously injected with nicotine (2.0 mg/kg⋅d) on gestational day 9–20. In vivo, PNE increased levels of total cholesterol (TCH), high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) in maternal serum, while decreased levels of TCH and LDL-C in female fetal serum. Meanwhile, the expression of scavenger receptor class B type 1 (SR-B1), ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) were decreased, and the expression of liver X receptor (LXR) α and β were also decreased in female placentas. In vitro, nicotine (0.1–10 μM) reduced the expression of LXRα, LXRβ, SR-B1, ABCA1 and ABCG1 in a concentration dependent manner, which could be annulled by nAChR antagonist and LXR agonist. Taken together, nicotine could inhibit the expression of SR-B1, ABCA1 and ABCG1 via nAChR and LXR α/β in female placentas, finally leading to reduced blood cholesterol levels in fetal rats.

Prenatal nicotine exposure retards osteoclastogenesis and endochondral ossification in fetal long bones in rats

This study investigated the mechanisms underlying the retarded development of long bone in fetus by prenatal nicotine exposure (PNE) which had been demonstrated by our previous work. Nicotine (2.0 mg/kg.d) or saline was injected subcutaneously into pregnant rats every morning from gestational day (GD) 9 to 20. Fetal femurs or tibias were harvested for analysis on GD 20. We found massive accumulation of hypertrophic chondrocytes and a delayed formation of primary ossification center (POC) in the fetal femur or tibia of rat fetus after PNE, which was accompanied by a decreased amount of osteoclasts in the POC and up-regulated expression of osteoprotegerin (OPG) but by no obvious change in the expression of receptor activator of NF-κB ligand (RANKL). In primary osteoblastic cells, both nicotine (0, 162, 1620, 16,200 ng/ml) and corticosterone (0, 50, 250, 1250 nM) promoted the mRNA expression of OPG but concentration-dependently suppressed that of RANKL. Furthermore, blocking α4β2-nicotinic acetylcholine receptor (α4β2-nAChR) or glucocorticoid receptor rescued the above effects of nicotine and corticosterone, respectively. In conclusion, retarded osteoclastogenesis may contribute to delayed endochondral ossification in long bone in fetal rats with PNE. The adverse effects of PNE may be mediated via the direct effect of nicotine and indirect effect of maternal corticosterone on osteoblastic cells.

Developmental nicotine exposure affects larval brain size and the adult dopaminergic system of Drosophila melanogaster

BackgroundPregnant women may be exposed to nicotine if they smoke or use tobacco products, nicotine replacement therapy, or via e-cigarettes. Prenatal nicotine exposure has been shown to have deleterious effects on the nervous system in mammals including changes in brain size and in the dopaminergic system. The genetic and molecular mechanisms for these changes are not well understood. A Drosophila melanogaster model for these effects of nicotine exposure could contribute to faster identification of genes and molecular pathways underlying these effects. The purpose of this study was to determine if developmental nicotine exposure affects the nervous system of Drosophila melanogaster, focusing on changes to brain size and the dopaminergic system at two developmental stages.ResultsWe reared flies on control or nicotine food from egg to 3rd instar larvae or from egg to adult and determined effectiveness of the nicotine treatment. We used immunohistochemistry to visualize the whole brain and dopaminergic neurons, using tyrosine hydroxylase as the marker. We measured brain area, tyrosine hydroxylase fluorescence, and counted the number of dopaminergic neurons in brain clusters.We detected an increase in larval brain hemisphere area, a decrease in tyrosine hydroxylase fluorescence in adult central brains, and a decrease in the number of neurons in the PPM3 adult dopaminergic cluster. We tested involvement of Dα7, one of the nicotinic acetylcholine receptor subunits, and found it was involved in eclosion, as previously described, but not involved in brain size.ConclusionsWe conclude that developmental nicotine exposure in Drosophila melanogaster affects brain size and the dopaminergic system. Prenatal nicotine exposure in mammals has also been shown to have effects on brain size and in the dopaminergic system. This study further establishes Drosophila melanogaster as model organism to study the effects of developmental nicotine exposure. The genetic and molecular tools available for Drosophila research will allow elucidation of the mechanisms underlying the effects of nicotine exposure during development.

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.

Prenatal nicotine exposure intergenerationally programs imperfect articular cartilage via histone deacetylation through maternal lineage

Accumulating evidence has shown that the impact of prenatal environmental factors on the organs of the offspring could last until the adulthood. Here, we aimed to investigate these effects and the potential mechanism of prenatal nicotine exposure (PNE) on the female adult cartilage of the first generation (PNE-F1) and the second generation (PNE-F2). Pregnant Wistar rats were injected with 2.0 mg/kg.d nicotine from gestational day (GD) 9 to 20. Then their F1 generation at GD20 and postnatal week (PW) 12, and F2 generation at PW12 were harvested. The expression of extracellular matrix (ECM) and transforming growth factor β (TGFβ) signaling genes were analyzed by real-time quantitative PCR, and the histone acetylation was examined by chromatin immunoprecipitation assay. The results showed that PNE reduced the ECM and TGFβ signaling gene expressions in both PNE-F1 and PNE-F2 female adult articular cartilage. In the F1 generation, PNE inhibited the acetylation at H3K9 of TGFβ, TGFβ receptor 1 (TGFβR1), SRY-type high mobility group box 9 (SOX9), a1 chain of type II collagen (COL2A1) and aggrecan (ACAN) gene promoters at both GD20 and PW12. In PNE-F2 at PW12, the obvious deacetylation at H3K9 of the TGFβR1 and COL2A1 promoters still existed. Moreover, in rat fetal chondrocytes, corticosterone rather than nicotine directly induced the hypoacetylation of H3K9 of TGFβR1 and COL2A1 genes, which might be the main cause of imperfect cartilage for PNE-F2. This study may be helpful to elucidate the developmental variability of articular cartilage quality and useful for the early prevention of articular damage.

NAChRs-ERK1/2-Egr-1 signaling participates in the developmental toxicity of nicotine by epigenetically down-regulating placental 11β-HSD2

Impaired placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity which inactivates maternal glucocorticoids is associated with poor fetal growth and a higher risk of chronic diseases in adulthood. This study aimed to elucidate the epigenetically regulatory mechanism of nicotine on placental 11β-HSD2 expression. Pregnant Wistar rats were administered 1.0 mg/kg nicotine subcutaneously twice a day from gestational day 9 to 20. The results showed that prenatal nicotine exposure increased corticosterone levels in the placenta and fetal serum, disrupted placental morphology and endocrine function, and reduced fetal bodyweight. Meanwhile, histone modification abnormalities (decreased acetylation and increased di-methylation of histone 3 Lysine 9) on the HSD11B2 promoter and lower-expression of 11β-HSD2 were observed. Furthermore, the expression of nicotinic acetylcholine receptor (nAChR) α4/β2, the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and Ets-like protein-1 (Elk-1), and the expression of early growth response-1 (Egr-1) were increased in the nicotine groups. In human BeWo cells, nicotine decreased 11β-HSD2 expression, increased nAChRα9 expression, and activated ERK1/2/Elk-1/Egr-1 signaling in the concentration (0.1–10 μM)-dependent manner. Antagonism of nAChRs, inhibition of ERK1/2 and Egr-1 knockdown by siRNA were able to block/abrogate the effects of nicotine on histone modification and expression of 11β-HSD2. Taken together, nicotine can impair placental structure and function, and induce fetal developmental toxicity. The underlying mechanism involves histone modifications and down-regulation of 11β-HSD2 through nAChRs/ERK1/2/Elk-1/Egr-1 signaling, which increases active glucocorticoids levels in the placenta and fetus, and eventually inhibits the fetal development.

Adolescent mouse hippocampal function was impaired by prenatal nicotine exposure

Adolescent mouse hippocampal function was impaired by prenatal nicotine exposure

Combination in prenatal nicotine exposure with juvenile isolation rearing induces depressive behavior and change of tryptophan metabolism

Combination in prenatal nicotine exposure with juvenile isolation rearing induces depressive behavior and change of tryptophan metabolism

Human brain organoid-on-a-chip to model prenatal nicotine exposure

Nicotine has been recognized to trigger various neuronal disabilities in the fetal brain and long-lasting behavioral deficits in offspring. However, further understanding of fetal brain development under nicotine exposure is challenging due to the limitations of existing animal models. Here, we create a new brain organoid-on-a-chip system derived from human induced pluripotent stem cells (hiPSCs) that allows us to model neurodevelopmental disorders under prenatal nicotine exposure (PNE) at early stages. The brain organoid-on-a-chip system facilitates 3D culture, in situ neural differentiation, and self-organization of brain organoids under continuous perfused cultures in a controlled manner. The generated brain organoids displayed well-defined neural differentiation, regionalization, and cortical organization, which recapitulates the key features of the early stages of human brain development. The brain organoids exposed to nicotine exhibited premature neuronal differentiation with enhanced expression of the neuron marker TUJ1. Brain regionalization and cortical development were disrupted in the nicotine-treated organoids identified by the expressions of forebrain (PAX6 and FOXG1), hindbrain (PAX2 and KROX20) and cortical neural layer (preplate TBR1 and deep-layer CTIP2) markers. Moreover, the neurite outgrowth showed abnormal neuronal differentiation and migration in nicotine-treated brain organoids. These results suggest that nicotine exposure elicits impaired neurogenesis in early fetal brain development during gestation. The established brain organoid-on-a-chip system provides a promising platform to model neurodevelopmental disorders under environmental exposure, which can be extended for applications in brain disease studies and drug testing.

Assessment of the cerebellar neurotoxic effects of nicotine in prenatal alcohol exposure in rats

The adverse effects of prenatal nicotine and alcohol exposure on human reproductive outcomes are a major scientific and public health concern. In the United States, substantial percentage of women (20–25%) of childbearing age currently smoke cigarettes and consume alcohol, and only a small percentage of these individuals quit after learning of their pregnancy. However, there are very few scientific reports on the effect of nicotine in prenatal alcohol exposure on the cerebellum of the offspring. Therefore, this study was conducted to investigate the cerebellar neurotoxic effects of nicotine in a rodent model of Fetal Alcohol Spectrum Disorder (FASD). In this study, we evaluated the behavioral changes, biochemical markers of oxidative stress and apoptosis, mitochondrial functions and the molecular mechanisms associated with nicotine in prenatal alcohol exposure on the cerebellum. Prenatal nicotine and alcohol exposure induced oxidative stress, did not affect the mitochondrial functions, increased the monoamine oxidase activity, increased caspase expression and decreased ILK, PSD-95 and GLUR1 expression without affecting the GSK-3β. Thus, our current study of prenatal alcohol and nicotine exposure on cerebellar neurotoxicity may lead to new scientific perceptions and novel and suitable therapeutic actions in the future.

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.

Prenatal Nicotine Exposure Disrupts Infant Neural Markers of Orienting.

Prenatal nicotine exposure (PNE) from maternal cigarette smoking is linked to developmental deficits, including impaired auditory processing, language, generalized intelligence, attention, and sleep. Fetal brain undergoes massive growth, organization, and connectivity during gestation, making it particularly vulnerable to neurotoxic insult. Nicotine binds to nicotinic acetylcholine receptors, which are extensively involved in growth, connectivity, and function of developing neural circuitry and neurotransmitter systems. Thus, PNE may have long-term impact on neurobehavioral development. The purpose of this study was to compare the auditory K-complex, an event-related potential reflective of auditory gating, sleep preservation and memory consolidation during sleep, in infants with and without PNE and to relate these neural correlates to neurobehavioral development. We compared brain responses to an auditory paired-click paradigm in 3- to 5-month-old infants during Stage 2 sleep, when the K-complex is best observed. We measured component amplitude and delta activity during the K-complex. Infants with PNE demonstrated significantly smaller amplitude of the N550 component and reduced delta-band power within elicited K-complexes compared to nonexposed infants and also were less likely to orient with a head turn to a novel auditory stimulus (bell ring) when awake. PNE may impair auditory sensory gating, which may contribute to disrupted sleep and to reduced auditory discrimination and learning, attention re-orienting, and/or arousal during wakefulness reported in other studies. Links between PNE and reduced K-complex amplitude and delta power may represent altered cholinergic and GABAergic synaptic programming and possibly reflect early neural bases for PNE-linked disruptions in sleep quality and auditory processing. These may pose significant disadvantage for language acquisition, attention, and social interaction necessary for academic and social success.

Erratum to: Prenatal nicotine exposure induces HPA axis-hypersensitivity in offspring rats via the intrauterine programming of up-regulation of hippocampal GAD67.

Erratum to: Prenatal nicotine exposure induces HPA axis-hypersensitivity in offspring rats via the intrauterine programming of up-regulation of hippocampal GAD67.

Prenatal nicotine exposure induces HPA axis-hypersensitivity in offspring rats via the intrauterine programming of up-regulation of hippocampal GAD67.

The intrauterine programming of hypothalamic-pituitary-adrenal (HPA) axis hypersensitivity is associated with chronic adult diseases. Our previous studies demonstrated the HPA-axis hypersensitivity in offspring rats induced by prenatal nicotine exposure. The goal of the present study is to further investigate the intrauterine programming mechanism. Pregnant Wistar rats were subcutaneously administered with 2.0mg/kgday of nicotine from gestational day (GD) 9-20. A group of the pregnant rats was euthanized at GD20, and the fetal rats were extracted. The remaining rats were left to come to term, and the adult offspring were exposed to chronic stress. For adult offspring rats, prenatal nicotine exposure induced HPA-axis hypersensitivity after chronic stress, accompanied by imbalanced glutamatergic/GABAergic afferent inputs. Moreover, prenatal nicotine exposure enhanced the expression of hippocampal glutamic acid decarboxylase 67 (GAD67), accompanied by a decreased methylation ratio within nt -1019 to -689 of the GAD67 promoter, decreased expression of Dnmt1, and an increased GABA content and density of GABAergic neurons. The fetal rats exhibited changes consistent with the adult rats. Similar effects were also observed by treating the fetal hippocampal cell line H19-7 with 1-100μM nicotine, while dihydro-β-erythroidine hydrobromide (DHβE), the specific inhibitor of α4β2nAChR, can reverse the effects caused by nicotine. These results indicate that prenatal nicotine exposure can enhance the potential excitability of the hypothalamus via the intrauterine programming of up-regulation of hippocampal GAD67. All of these results contribute to the HPA-axis hypersensitivity in adult offspring.

Impact of gestational nicotine exposure on intrauterine and fetal infection in a rodent model†

We investigated the interaction between prenatal nicotine exposure and intrauterine infection using established rat models. Beginning at gestation day (GD) 6, dams were continuously infused with either saline or 6 mg/kg/day nicotine (Nic). At GD 14, dams received either sterile broth or 105 colony-forming units Mycoplasma pulmonis (MP), resulting in four treatment groups: control (4 dams, 33 fetal units); MP only (5 dams, 55 fetal units); Nic only (5 dams, 61 fetal units), and Nic + MP (7 dams, 82 fetal units). At GD 18, nicotine exposure significantly increased (P ≤ 0.02) the percentage of amniotic fluids and fetuses infected by MP but did not impact colonization rates of maternal sites. Nicotine exposure significantly reduced the numbers of MP in the placenta required for high microbial loads (≥104 color-changing units) in the amniotic fluid (P < 0.01). Fetal inflammatory response lesions were most extensive in the Nic only and Nic + MP groups (P < 0.0001). Control and MP only placentas were interleukin (IL)10-dominant, consistent with an M2/Th2 environment. Placentas exposed to nicotine shifted to a neutral environment, with equivalent levels of interferon gamma (IFNG) and IL10. Both IL6 and tumor necrosis factor (TNF) levels in amniotic fluid were highly elevated when both nicotine and infection were present. Our study suggests that prenatal exposure to nicotine increases the risk for intrauterine infection, lowers the infectious dose required to breach the placental barrier and infect the amniotic fluid and fetus, and alters the pathology and inflammatory profile associated with maternal and fetal sites.

Developmental nicotine exposure increases the response to muscimol in hypoglossal motoneurons.

Prenatal nicotine exposure with continued exposure through breast milk over the first week of life (developmental nicotine exposure, DNE) is known to cause complex changes to the brainstem respiratory circuit including increased sensitivity to inhibitory neurotransmitters and increased staining of GABAAR‐1a subunit in the hypoglossal nucleus. Here we test the hypothesis that DNE alters the response of hypoglossal motoneurons (XII MNs) to the GABAA receptor agonist Muscimol. We obtainedwhole cell patch clamp recordings from XII MNs in medullary slices (700 micron thick) from DNE pups and control pups. Cells were voltage clamped at −75mV. Using a cesium based intracellular solution, and in the presence of the AMPA receptor antagonists 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX), the NMDA receptor antagonist D(‐)‐2‐Amino‐5‐phosphonopentanoic acid (AP‐5), the glycine receptor antagonist Strychnine, and the voltage gated sodium channel blocker Tetrodotoxin, bath application of 0.5 mM Muscimol produces an inward current in these cells. We measured peak inward current from 10 control cells and 10 DNE cells. Our results show that DNE causes in an increased GABAA receptor mediated inward current (Control {n=10} −239.3±30.75 pA, DNE {n=10} −364.4±38.7 pA, P=0.02). This result is consistent with DNE causing increased GABAA receptor expression in XII MNs.Support or Funding InformationNIH RO1H071302 AHA 12GRXIT120S0354

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&lt;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&lt;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&lt;0.006). Alternatively, in the amygdala a decrease in orexin‐type 2 receptors in PNE females compared to controls (P&lt;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.