Prenatal Nicotine Exposure Research Articles

Association of Nicotine with Osteochondrogenesis and Osteoarthritis Development: The State of the Art of Preclinical Research.

The deleterious effects of nicotine on various health conditions have been well documented. Although many orthopedic diseases are adversely affected by nicotine, little is known about its preclinical effects on chondrogenesis or osteogenesis, cartilage formation, osteoarthritis (OA), and osteochondral repair. A systematic review was conducted examining the current scientific evidence on the effects of nicotine on chondrogenesis or osteogenesis in vitro, possible consequences of prenatal nicotine exposure (PNE) on cartilage and OA susceptibility in the offspring, and whether nicotine affects OA development and osteochondral repair in vivo, always focusing on their underlying mechanisms. The data reveal dose-dependent effects on articular chondrocytes and on the chondrogenesis and osteogenesis of medicinal signaling cells in vitro, with lower doses often resulting in positive effects and higher doses causing negative effects. PNE negatively affects articular cartilage development and induces OA in the offspring without or with nicotine exposure. In contrast, protective effects on OA development were only reported in monosodium iodoacetate-induced small animal models. Finally, nicotine repressed MSC-based osteochondral repair in vivo. Future studies need to investigate dose-dependent clinical effects of smoking on cartilage quality in offspring, OA susceptibility and progression, and osteochondral repair more in detail, thus identifying possible thresholds for its pathological effects.

Prenatal Nicotine Exposure in Rodents: Why Are There So Many Variations in Behavioral Outcomes?

The World Health Organization (WHO) reported that smoking cessation rates among women have stagnated in the past decade and estimates that hundreds of millions of women will be smokers in the next decade. Social, environmental, and biological conditions render women more susceptible to nicotine addiction, imposing additional challenges to quit smoking during gestation, which is likely why more than 8% of pregnancies in Europe are associated with smoking. In epidemiological investigations, individuals born from gestational exposure to smoking exhibit a higher risk of development of attention-deficit/hyperactive disorder (ADHD) and liability to drug dependence. Among other teratogenic compounds present in tobacco smoke, nicotine actions during neuronal development could contribute to the observed outcomes as nicotine misleads signaling among progenitor cells during brain development. Several experimental approaches have been developed to address the consequences of prenatal nicotine exposure (PNE) to the brain and behavior but, after four decades of studies, inconsistent data have been reported and the lack of consensus in the field has compromised the hypothesis that gestational nicotine exposure participates in cognitive and emotional behavioral deficits. In this review, we discuss the most commonly used PNE models with focus on their advantages and disadvantages, their relative validity, and how the different technical approaches could play a role in the disparate outcomes. We propose methodological considerations, which could improve the translational significance of the PNE models. Such alterations might be helpful in reconciling experimental findings, as well as leading to development of treatment targets for maladaptive behaviors in those prenatally exposed. In this article, we have reviewed the advantages and disadvantages of different variables of the commonly used experimental models of PNE. We discuss how variations in the nicotine administration methods, the timing of nicotine exposure, nicotine doses, and species employed could contribute to the disparate findings in outcomes for PNE offspring, both in behavior and neuronal changes. In addition, recent findings suggest consideration of epigenetic effects extending across generations. Finally, we have suggested improvements in the available PNE models that could contribute to the enhancement of their validity, which could assist in the reconciliation of experimental findings.

Nicotine exposure during pregnancy programs osteopenia in male offspring rats via α4β2-nAChR-p300-ACE pathway.

Prenatal nicotine exposure (PNE) induces developmental toxicity in offspring. However, the long-term harmful effects on bone development and the intrauterine programming mechanism attributed to PNE remain unclear. In the present research, pregnant Wistar rats were injected subcutaneously with nicotine (2 mg/kg/d) to obtain and analyze bone samples from the fetal and adult offspring. Bone marrow mesenchymal stem cells (BMSCs) were treated with nicotine during osteogenic differentiation to clarify the related molecular mechanisms. The results indicated that PNE led to bone dysplasia in the fetuses and reduced bone mass in the adult offspring, which was mediated by the sustained activation of the local bone renin angiotensin system (RAS) and suppressed osteogenic differentiation before and after birth. In vitro, nicotine suppressed BMSCs' osteogenic function through promoting angiotensin-converting enzyme (ACE) expression and activating RAS. Furthermore, nicotine induced histone acetylase p300 into the nuclei of the BMSCs by acting on the α4β2-nicotinic acetylcholine receptor (α4β2-nAChR), leading to the increased histone 3 lysine 9 acetylation level of ACE and RAS activation. Taken together, the sustained activation of local bone RAS mediated prenatal nicotine-induced osteopenia in adult offspring via the α4β2-nAChR-p300-ACE pathway.-Xiao, H., Wen, Y., Pan, Z., Shangguan, Y., Magdalou, J., Wang, H., Chen, L. Nicotine exposure during pregnancy programs osteopenia in male offspring rats via α4β2-nAChR-p300-ACE pathway.

Attenuated Tregs increase susceptibility to type 1 diabetes in prenatal nicotine exposed female offspring mice

The recession of regulatory T cells (Tregs) is pivotal for type 1 diabetes (T1D) progressing. Our previous study observed the decreased Tregs in prenatal nicotine exposure (PNE) offspring, but whether this led to the onset of T1D remains uncertain. Thus, this study aimed to investigate the effects of PNE on T1D susceptibility and the role of PNE-suppressed Tregs in T1D of female offspring. The decreased body weights and elevated blood glucose levels from postnatal day (PND) 21 to PND 42 indicated that PNE caused persistent impaired glucose homeostasis in offspring. The elevated serum glutamic acid decarboxylase autoantibody, the “Gold Standard” for the detection of T1D, was observed on PND 42, suggesting the early stage of T1D in PNE offspring during adolescence. The reduced pancreatic islet areas and beta cells number in PNE offspring were observed at neonatal period and became more severe during adolescence. In addition, PNE caused immune dysfunction in offspring, manifested as suppressed thymic Tregs percentage from PND 4 to PND 42 and splenic Tregs/Th17 ratio on PND 42. In conclusion, PNE resulted in metabolic changes of offspring that were consistent with T1D characteristics, which could be the consequence of Tregs recession from early life to adolescence.

Alterations in NMDAR-mediated signaling within the laterodorsal tegmental nucleus are associated with prenatal nicotine exposure

Cigarette smoking during pregnancy has been clinically associated with a variety of poorbehavioral outcomes for the exposed individuals, including higher risks for drug abuse and development of attention/deficit-hyperactive disorder (ADHD). Experimental studies support the hypothesis that nicotine might contribute to these risks, since prenatal nicotine exposure (PNE) in rodents was associated with greater addiction liability, hyperactivity, social impairments and a wide range of emotional and cognitive deficits. Alterations of glutamate signaling within brain regions involved in behavioral circuits could contribute to these outcomes. The pontine laterodorsal tegmental nucleus (LDT) exerts cholinergic modulation within the ventral tegmental area, nucleus accumbens, and cortical-projecting thalamic centers and PNE-associated alterations in LDT glutamate signaling could impact cholinergic output to these LDT targets. We have previously demonstrated that PNE alters AMPA-mediated signaling within LDT neurons, and in the present investigation, we focused on changes of NMDA receptors (NMDARs) and presence of silent synapses as an indicator of metaplastic processes in LDT cells associated with PNE treatment. PNE was associated with a decreased functional presence of GluN2B NMDAR subunits in synapses of large, putatively cholinergic neurons, whereas an increased function of this subunit was detected in small, likely GABAergic cells. In addition, PNE was associated with functional alterations of extrasynaptic NMDARs in putative cholinergic neurons, suggestive of an increased presence of GluN3A-containing NMDARs. An increased number of silent synapses was exclusively seen in the small cells. When taken together, we hypothesize that NMDA-mediated signaling changes within LDT neurons following PNE treatment would result in reductions of excitatory cholinergic modulatory tone in target brain regions, which would be expected to contribute to the behavioral deficits found among these individuals.

The role of maternal emotional states during pregnancy and early infancy on infant cortisol levels: A prospective study

AbstractCortisol plays an important role in human body functioning, stress response, and reactivity, and altered cortisol levels have been related to psychopathology throughout life. This study investigates several types of clinical and psychosocial prenatal, perinatal, and postnatal factors related to morning cortisol levels in 71 12‐month‐old infants. Several sociodemographic, obstetrical, environmental, and psychological predictors were taken into account. Regression models show that prenatal anxiety, type of birth, depressive symptoms at 6 months, and the mothers' feelings about the relationship with their child explain 32.9% of the variance in morning cortisol levels in 12‐month old infants. When sociodemographic, obstetrical, environmental, and psychological variables are taken into account, maternal emotional status and feelings about the mother–infant bonding are the most important factors that explain infant cortisol levels, which suggests that they should be included in obstetric and paediatric care routines to improve infant health.Highlights Cortisol has an important effect on human homeostasis, growth, neurodevelopment, stress response and reactivity; however, altered cortisol levels have been related to psychopathology throughout life. This study aims to investigate, prospectively from pregnancy, several types of clinical and psychosocial prenatal, perinatal and postnatal factors related to infant morning cortisol levels at 12 months. When several kind of factors are taken into account (prenatal life events, prenatal and postnatal nicotine exposure, gender, gestational age at birth, infant birth weight, parity, socioeconomic status, maternal psychopathology, breastfeeding status and anthropometry), prenatal anxiety, type of birth, postnatal depression and mothers' feelings about the relationship with their infant are the are the variables that better predict infant morning cortisol levels. Maternal emotional characteristics are the central axis for influencing the development of HPA axis. Healthcare professionals may pay more attention to the mother feelings and emotions along prenatal and postnatal infant development to promote infant mental health.

Distribution of α7 Nicotinic Acetylcholine Receptor Subunit mRNA in the Developing Mouse.

Homomeric α7 nicotinic acetylcholine receptors (nAChRs) are abundantly expressed in the central and peripheral nervous system (CNS and PNS, respectively), and spinal cord. In addition, expression and functional responses have been reported in non-neuronal tissue. In the nervous system, α7 nAChR subunit expression appears early during embryonic development and is often transiently upregulated, but little is known about their prenatal expression outside of the nervous system. For understanding potential short-term and long-term effects of gestational nicotine exposure, it is important to know the temporal and spatial expression of α7 nAChRs throughout the body. To that end, we studied the expression of α7 nAChR subunit mRNA using highly sensitive isotopic in situ hybridization in embryonic and neonatal whole-body mouse sections starting at gestational day 13. The results revealed expression of α7 mRNA as early as embryonic day 13 in the PNS, including dorsal root ganglia, parasympathetic and sympathetic ganglia, with the strongest expression in the superior cervical ganglion, and low to moderate levels were detected in brain and spinal cord, respectively, which rapidly increased in intensity with embryonic age. In addition, robust α7 mRNA expression was detected in the adrenal medulla, and low to moderate expression in selected peripheral tissues during embryonic development, potentially related to cells derived from the neural crest. Little or no mRNA expression was detected in thymus or spleen, sites of immune cell maturation. The results suggest that prenatal nicotine exposure could potentially affect the nervous system with limited effects in non-neural tissues.

Prenatal nicotine exposure increases osteoarthritis susceptibility in male elderly offspring rats via low-function programming of the TGFβ signaling pathway

Epidemiological investigations indicate that effects related to prenatal adverse environments on the organs of the offspring could continue to adulthood. This study intends to confirm that prenatal nicotine exposure (PNE) increases the susceptibility of osteoarthritis (OA) in the male offspring, and to explore the potential intrauterine programming mechanism. During pregnancy, rats were divided into a PNE group and a control group. After birth, rats were given a high-fat diet for 6 months and long-distance running for 6 weeks. The rats were euthanized at 18 months after birth (PM18) and on gestational day 20 (GD20), respectively. Knee joints were collected for histochemistry, immunohistochemistry, and quantitative polymerase chain reaction (qPCR) assays. Histological analyses and the Mankin’s score showed increased cartilage destruction and accelerated OA progression in adult offspring from the PNE group. Immunohistochemistry results showed decreased expression of transforming growth factor beta (TGFβ) signaling pathway. Furthermore, the expression of apoptosis factors (caspase-3 and caspase-8), inflammatory factors [interleukin (IL)-1, IL-6] and matrix degradation enzymes [matrix metalloproteinase (MMP)-3, MMP-13] were also significantly increased. Traced back to the intrauterine period, it was found that the number of chondrocytes and the contents of Col2A1 and aggrecan in the matrix in the PNE group were decreased. And, the expression of the TGFβ signaling pathway was inhibited. These results suggested that PNE enhanced the susceptibility of OA in male elderly offspring rats by down-regulating TGFβ signaling, which increased articular cartilage local inflammation, matrix degradation, and cell apoptosis. This study confirmed the developmental origin of OA, and clarified the congenital and the living environment impact on the occurrence and development of OA. Our findings provide a theoretical and experimental basis for OA early prevention.

Decreased levels of H3K9ac and H3K27ac in the promotor region of ovarian P450 aromatase mediated low estradiol synthesis in female offspring rats induced by prenatal nicotine exposure as well as in human granulosa cells after nicotine treatment

Prenatal nicotine exposure (PNE) could induce ovarian dysplasia in offspring. This study aimed to confirm its intrauterine origin and explore a programming mechanism of ovarian dysplasia caused by PNE. Pregnant Wistar rats were injected subcutaneously with nicotine (2 mg/kg.d) from gestation day (GD) 9 to GD20. Serum of female offspring was obtained for hormone assays and ovarian tissues were collected. The results showed that PNE impaired ovarian development, and inhibited estradiol production and cytochrome P450 aromatase (P450arom) expression before and after birth. Moreover, the nicotinic acetylcholine receptors (nAChRs) expression was increased in utero, while histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac levels in the P450arom promoter region were decreased persistently in PNE group before and after birth. In vitro, nicotine decreased P450arom expression and estradiol production in human granulosa cell line KGN. Furthermore, nicotine treatment up-regulated nAChRα6 and α9 expression and down-regulated the H3K9ac and H3K27ac levels of the P450arom promoter region. Non-specific nAChRs inhibitor vecuronium bromide reversed these effects. These results suggest that PNE could induce ovarian dysplasia and inhibit estradiol synthesis in the female offspring rats, which was related to the decreased H3K9ac and H3K27ac levels in the promotor region of the P450arom via the nAChRs.

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.

Prenatal nicotine exposure induces depression‑like behavior in adolescent female rats via modulating neurosteroid in the hippocampus.

Prenatal nicotine exposure (PNE) is closely related to depression in offspring. However, the underlying mechanism is still unclear. We hypothesized that neurosteroid in the hippocampus may mediate PNE-induced depression-like behaviors. Nicotine was subcutaneously administered (1.0 mg/kg) to pregnant rats twice daily from gestational day (GD) 9 to 20. In adolescent offspring, PNE significantly increased immobility time and decreased the sucrose preference in female rats. The numbers of hippocampal neurons declined in the CA3 and DG regions. Steroidogenic acute regulatory protein (StAR) expression was suppressed in female rats. In fetal offspring, the neuronal numbers of CA3 regions in PNE female fetal hippocampal were significantly decreased, accompanied by the enhanced content of corticosterone and StAR expression. These data indicated that PNE induced depression-like behavior in adolescent female rats via the regulation of neurosteroid levels in the hippocampus.

Direct Effects of Nicotine Exposure on Murine Calvaria and Calvarial Cells

Despite the link between adverse birth outcomes due to pre- and peri-natal nicotine exposure, research suggests 11% of US women continue to smoke or use alternative nicotine products throughout pregnancy. Maternal smoking has been linked to incidence of craniofacial anomalies. We hypothesized that pre-natal nicotine exposure may directly alter craniofacial development independent of the other effects of cigarette smoking. To test this hypothesis, we administered pregnant C57BL6 mice drinking water supplemented with 0, 50, 100 or 200 μg/ml nicotine throughout pregnancy. On postnatal day 15 pups were sacrificed and skulls underwent micro-computed tomography (µCT) and histological analyses. Specific nicotinic acetylcholine receptors, α3, α7, β2, β4 were identified within the calvarial growth sites (sutures) and centers (synchondroses). Exposing murine calvarial suture derived cells and isotype cells to relevant circulating nicotine levels alone and in combination with nicotinic receptor agonist and antagonists resulted in cell specific effects. Most notably, nicotine exposure increased proliferation in calvarial cells, an effect that was modified by receptor agonist and antagonist treatment. Currently it is unclear what component(s) of cigarette smoke is causative in birth defects, however these data indicate that nicotine alone is capable of disrupting growth and development of murine calvaria.

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.

Influences of prenatal nicotine exposure on behavioral functions of the offspring: Involvement of chemokine levels in the brain.

Influences of prenatal nicotine exposure on behavioral functions of the offspring: Involvement of chemokine levels in the brain.

胎生期ニコチン曝露は、仔の行動変化を引き起こす：脳内サイトカインの関与

胎生期ニコチン曝露は、仔の行動変化を引き起こす：脳内サイトカインの関与

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.

Excitotoxicity and compensatory upregulation of GAD67 in fetal rat hippocampus caused by prenatal nicotine exposure are associated with inhibition of the BDNF pathway

Prenatal nicotine exposure (PNE) can cause hypersensitivity of hypothalamic-pituitary-adrenal (HPA) axis in offspring with intrauterine growth retardation. The purpose of this study was to explore the original mechanism of intrauterine development that mediates hypersensitivity of the HPA axis in offspring due to PNE. Pregnant Wistar rats were injected subcutaneously with 2 mg/kg·d of nicotine on the 9th to the 20th gestational day (GD9-GD20) and the fetuses were extracted at GD20. Compared with the control group, fetal rats by PNE showed increased hippocampal apoptosis, reduced synaptic plasticity and downregulation of the brain-derived neurotrophic factor (BDNF) pathway, whereas glutamic acid decarboxylase 67 (GAD67) expression was upregulated. Rat fetal hippocampal H19-7/IGF1R cell lines were treated with different concentrations of nicotine (1, 10 and 100 μM) for 3 days, the extracellular fluid glutamate (Glu) level increased and similar effects were observed as in vivo. Intervention treatments caused the opposite results. These results indicated that PNE downregulates the BDNF pathway and mediates the hippocampal excitotoxicity; then, the compensatory upregulation of GAD67 causes the imbalance of signal output in the fetal hippocampus. The negative feedback regulation of the paraventricular hypothalamic nucleus by the hippocampus is unbalanced, eventually causing hypersensitivity of the HPA axis of the offspring.

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

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

RVis: a freely available modelling platform

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.

Two intrauterine programming mechanisms of adult hypercholesterolemia induced by prenatal nicotine exposure in male offspring rats

Epidemiologic studies showed that low birth weight is associated with high cholesterol and an increased risk of cardiovascular diseases in adulthood. This study aimed to elucidate the intrauterine programming mechanisms of adult hypercholesterolemia. The results showed that prenatal nicotine exposure (PNE) caused intrauterine growth retardation and hypercholesterolemia in male adult offspring rats. Hepatic cholesterol synthesis and output were deceased in utero but increased in adults; hepatic reverse cholesterol transport (RCT) persistently deceased before and after birth. Meanwhile, PNE elevated serum corticosterone level and decreased hepatic IGF1 pathway activity in male fetuses, whereas converse changes were observed in male adults. The chronic stress model and cortisol-treated HepG2 cells verified that excessive glucocorticoid (GC)-induced GC-IGF1 axis programming enhanced hepatic cholesterol synthesis and output. In addition, PNE decreased the expression of specific protein 1 and P300 enrichment and H3K27 acetylation at the promoter region of genes responsible for RCT both in fetal and adult, male livers and reduced expression of those genes, similar alterations were also confirmed in cortisol-treated HepG2 cells, suggesting that excessive GC-related programming induced continuous RCT reduction by epigenetic modification. Taken together, the "2-programming" approach discussed above may ultimately contribute to the development of hypercholesterolemia in male adult offspring.-Zhou, J., Zhu, C., Luo, H., Shen, L., Gong, J., Wu, Y., Magdalou, J., Chen, L., Guo, Y., Wang, H. Two intrauterine programming mechanisms of adult hypercholesterolemia induced by prenatal nicotine exposure in male offspring rats.