651: Maternal smoking during pregnancy and the risk of pediatric cardiovascular diseases of the offspring: A population-based cohort study with up to 18-years follow up

Maternal Cigarette Smoking and Congenital Heart Defects

Environmental Tobacco Smoke and Asthma

Maternal prenatal smoking and long-term gastrointestinal morbidity of the offspring: A population-based cohort analysis

Maternal smoking during pregnancy and the risk of pediatric cardiovascular diseases of the offspring: A population-based cohort study with up to 18-years of follow up

Maternal cigarette smoking during pregnancy is associated with increased risk of perinatal morbidity and mortality. However, the mechanisms underlying adverse birth outcomes following prenatal exposure to cigarette smoke remain unknown due, in part, to the absence or unreliability of information regarding maternal cigarette smoke exposure during pregnancy. Our goal was to determine if placental cotinine could be a reliable biomarker of fetal cigarette smoke exposure during pregnancy. Cotinine levels were determined in placentas from 47 women who reported smoking during pregnancy and from 10 women who denied cigarette smoke exposure. Cotinine levels were significantly higher in placentas from women reporting cigarette smoking (median = 27.2 ng/g) versus women who reported no smoke exposure (2.3 ng/g, <i>P</i> &lt; 0.001). Receiver operating characteristic curve analysis identified an optimal cut point of 7.5 ng/g (sensitivity = 78.7%, specificity = 100%) to classify placenta samples from mothers who smoked versus those from mothers who did not. Among 415 placentas for which maternal cigarette smoking status was unavailable, 167 had cotinine levels &gt; 7.5 ng/g and would be considered positive for cigarette smoke exposure. Data from quantitative reverse-transcription polymerase chain reaction analyses demonstrated that in utero cigarette smoke exposure predicted by cotinine in placenta is associated with changes in the expression of xenobiotic-metabolizing enzymes in fetal tissues. <i>CYP1A1</i> mRNA in fetal lung and liver tissue and <i>CYP1B1</i> mRNA in fetal lung tissue were significantly induced when cotinine was detected in placenta. These findings indicate that cotinine in placenta is a reliable biomarker for fetal exposure and response to maternal cigarette smoking during pregnancy.

Maternal cigarette smoking during pregnancy is associated with increased risk of perinatal morbidity and mortality. However, the mechanisms underlying adverse birth outcomes following prenatal exposure to cigarette smoke remain unknown due, in part, to the absence or unreliability of information regarding maternal cigarette smoke exposure during pregnancy. Our goal was to determine if placental cotinine could be a reliable biomarker of fetal cigarette smoke exposure during pregnancy. Cotinine levels were determined in placentas from 47 women who reported smoking during pregnancy and from 10 women who denied cigarette smoke exposure. Cotinine levels were significantly higher in placentas from women reporting cigarette smoking (median = 27.2 ng/g) versus women who reported no smoke exposure (2.3 ng/g, P < 0.001). Receiver operating characteristic curve analysis identified an optimal cut point of 7.5 ng/g (sensitivity = 78.7%, specificity = 100%) to classify placenta samples from mothers who smoked versus those from mothers who did not. Among 415 placentas for which maternal cigarette smoking status was unavailable, 167 had cotinine levels > 7.5 ng/g and would be considered positive for cigarette smoke exposure. Data from quantitative reverse-transcription polymerase chain reaction analyses demonstrated that in utero cigarette smoke exposure predicted by cotinine in placenta is associated with changes in the expression of xenobiotic-metabolizing enzymes in fetal tissues. CYP1A1 mRNA in fetal lung and liver tissue and CYP1B1 mRNA in fetal lung tissue were significantly induced when cotinine was detected in placenta. These findings indicate that cotinine in placenta is a reliable biomarker for fetal exposure and response to maternal cigarette smoking during pregnancy.

More Rigor Needed in Systematic Reviews on “Waterpipe” (Hookah, Narghile, Shisha) Smoking

Collection of RNA for analysis of noncoding RNA, protein for histone modifications and plasma for exosomes/ extracellular vesicles is the next frontier of understanding how the environment affects gene regulation.

What are the effects on fertility of cigarette smoke-induced toxicity on male offspring exposed during the gestational/weaning period? Maternal cigarette smoke exposure during the gestational/weaning period causes long-term defects in male offspring fertility. Cigarette smoke is a well-known reproductive toxicant which is particularly harmful to both fetal and neonatal germ cells. However, recent studies suggest a significant portion of young mothers in the developed world still smoke during pregnancy. In the context of male reproductive health, our understanding of the effects of in utero exposure on offspring fertility is limited. In this study, 27 C57BL/6 5-week-old female mice were exposed via the nose-only to cigarette smoke (treatment) or 27 were exposed to room air (control) for 6 weeks before being housed with stud males to produce litters. In the treatment group, smoke exposure continued throughout mating, pregnancy and lactation until weaning of pups at 21 days post birth. Male offspring were examined at post-natal days 3, 6, 12, 21 and 98 (adult). Approximately 108 maternal smoke-exposed C57BL/6 offspring and controls were examined. Spermatogenesis was examined using testicular histology and apoptosis/DNA damage was assessed using caspase immunohistochemistry and TUNEL. Sertoli cell morphology and fluctuations in the spermatogonial stem cell population were also examined using immunohistochemistry. Microarray and QPCR analysis were performed on adult testes to examine specific long-term transcriptomic alteration as a consequence of maternal smoke exposure. Sperm counts and motility, zona/oolemma binding assays, COMET analysis and mitochondrial genomic sequencing were also performed on spermatozoa obtained from adult treated and control mice. Fertility trials using exposed adult male offspring were also performed. Maternal cigarette smoke exposure caused increased gonocyte and meiotic spermatocyte apoptosis (P < 0.01) as well as germ cell depletion in the seminiferous tubules of neonatal and juvenile offspring. Aberrant testicular development characterized by abnormal Sertoli and germ cell organization, a depleted spermatogonial stem cell population (P < 0.01), atrophic seminiferous tubules and increased germ cell DNA damage (P < 0.01) persisted in adult offspring 11 weeks after exposure. Microarray analysis of adult offspring testes associated these defects with meiotic germ cell development, sex hormone metabolism, oxidative stress and Sertoli cell signalling. Next generation sequencing also revealed a high mitochondrial DNA mutational load in the testes of adult offspring (P < 0.01). Adult maternal smoke-exposed offspring also had reduced sperm counts with spermatozoa exhibiting morphological abnormalities (P < 0.01), affecting motility and fertilization potential. Odf2, a spermatozoa flagellum component required for coordinated ciliary beating, was also significantly down-regulated (P < 0.01) in maternal smoke-exposed adult offspring, with aberrant localization along the spermatozoa flagellum. Adult maternal smoke-exposed offspring took significantly longer to impregnate control females and had a slight but significant (P < 0.01) reduction in litter size. This study examined only one species (mouse) using a smoking model which only simulates human cigarette smoke exposure. This study represents the first comprehensive animal model of maternal smoking on male offspring reproductive function, suggesting that exposure during the gestational/weaning period causes long-term defects in male offspring fertility. This is due to a compromised spermatogonial stem cell population resulting from gonocyte apoptosis and impaired spermatogenic development. This results in significant germ cell damage and Sertoli cell dysfunction, impacting germ cell number, tubule organization, DNA damage and spermatozoa in adult offspring. This study strengthens the current literature suggesting that maternal exposure impairs male offspring fertility, which is currently debated due to conflicting studies. This study was funded by the Australian Research Council, Hunter Medical Research Institute, National Health and Medical Research Council of Australia and the Newcastle Permanent Building Society Charitable Trust. The authors declare no conflict of interest.

Maternal cigarette smoke exposure disturbs glutamate/GABA balance in pFRG of neonatal rats

Maternal preeclampsia and the risk of pediatric gastrointestinal diseases of the offspring: A population-based cohort study.

Background/Objectives: Environmental pollutants can profoundly affect immune development, yet their impact on offspring vaccine responsiveness remains poorly understood. To address this, we investigated the impact of maternal cigarette smoke (CS) exposure, a major contributor to household air pollution, on influenza vaccine responsiveness in offspring. Methods: Pregnant dams were exposed to CS or air during gestation and lactation. Two weeks post-weaning, offspring received two influenza vaccinations. After the booster vaccination, vaccine-specific delayed-type hypersensitivity (DTH), serum immunoglobulins, and splenic T cells were analyzed. Results: Vaccinated offspring exhibited robust DTH responses and comparable levels of vaccine-specific IgG1 and IgG2a, regardless of maternal exposure. Importantly, maternal CS exposure did not affect splenic Th1 cell frequency in vaccinated offspring but increased the frequency of activated Th2 cells. Conclusions: In conclusion, immune development was affected by enhanced Th2 activation, but vaccine efficacy was not impaired. These findings suggest that, under the current conditions of CS exposure (duration, route, and timing) and influenza vaccine dose, vaccine-induced immunity may exhibit resilience even in the presence of environmental immune modulators such as maternal CS exposure. However, these unexpected results highlight the need for further investigation into the broader health implications of maternal pollutant exposure, particularly considering how exposure timing, type, and route, as well as vaccine characteristics, may influence immune development and responsiveness. A deeper understanding of these factors is essential to fully elucidating the clinical relevance of maternal pollutant exposure on childhood vaccine efficacy.

This study aimed to investigate whether maternal cigarette smoke exposure can disrupt fetal kidney development by changing the expression of growth and transcription factors essential for renal development, and thereafter predispose the offspring to chronic kidney disease later in life. Female Balb/c mice (6 weeks) were exposed either to cigarette smoke or air under identical conditions, 6 weeks prior to mating, during gestation and during lactation. Male offspring were sacrificed at three time points, postnatal day (P)1, P20 (weaning age), and 13 weeks (mature age). Blood, urine, and kidneys were collected for analysis. At P1, the developmental genes fibroblast growth factor 2, glial cell-line derived neurotrophic factor and paired box 2 were upregulated at mRNA and protein levels; whilst fibroblast growth factor (FGF) 7 and FGF10 were downregulated. At P20, mRNA expression of FGF2, FGF10 and Wingless-type 4 was upregulated by maternal smoke exposure. These changes were normalised in adulthood. Nephron development was delayed, with fewer nephron numbers from P1 persisted to adulthood; while glomerular volume was increased at P20 but reduced in adulthood. Pro-inflammatory marker monocyte chemoatractant protein 1 (MCP1) was increased in the kidney by maternal smoke exposure. These changes were accompanied by an increased albumin/creatinine ratio in adulthood, suggesting reduced renal dysfunction. In conclusion maternal cigarette smoke exposure prior to and during pregnancy, as well as lactation leads to significant renal underdevelopment and functional abnormalities in adulthood. This study confirms the hypothesis that maternal smoking predisposes offspring to chronic kidney disorders.

BackgroundMaternal smoking is a risk factor for pediatric lung disease, including asthma. Animal models suggest that maternal smoking causes defective alveolarization in the offspring. Retinoic acid signaling modulates both lung development and postnatal immune function. Thus, abnormalities in this pathway could mediate maternal smoking effects. We tested whether maternal smoking disrupts retinoic acid pathway expression and functioning in a murine model.MethodsFemale C57Bl/6 mice with/without mainstream cigarette smoke exposure (3 research cigarettes a day, 5 days a week) were mated to nonsmoking males. Cigarette smoke exposure continued throughout the pregnancy and after parturition. Lung tissue from the offspring was examined by mean linear intercept analysis and by quantitative PCR. Cell culture experiments using the type II cell-like cell line, A549, tested whether lipid-soluble cigarette smoke components affected binding and activation of retinoic acid response elements in vitro.ResultsCompared to tobacco-naïve mice, juvenile mice with tobacco toxin exposure had significantly (P < 0.05) increased mean linear intercepts, consistent with an alveolarization defect. Tobacco toxin exposure significantly (P < 0.05) decreased mRNA and protein expression of retinoic acid signaling pathway elements, including retinoic acid receptor alpha and retinoic acid receptor beta, with the greatest number of changes observed between postnatal days 3–5. Lipid-soluble cigarette smoke components significantly (P < 0.05) decreased retinoic acid-induced binding and activation of the retinoic acid receptor response element in A549 cells.ConclusionsA murine model of maternal cigarette smoking causes abnormal alveolarization in association with altered retinoic acid pathway element expression in the offspring. An in vitro cell culture model shows that lipid-soluble components of cigarette smoke decrease retinoic acid response element activation. It is feasible that disruption of retinoic acid signaling contributes to the pediatric lung dysfunction caused by maternal smoking.

Maternal cigarette smoke (CS) exposure exhibits a strong epidemiological association with Sudden Infant Death Syndrome, but other environmental stressors, including infection, hyperthermia, and hypoxia, have also been postulated as important risk factors. This study examines whether maternal CS exposure causes maladaptations within homeostatic control networks by influencing the response to lipopolysaccharide, heat stress, and/or hypoxia in neonatal rats. Pregnant dams were exposed to CS or parallel sham treatments daily for the length of gestation. Offspring were studied at postnatal days 6-8 at ambient temperatures (Ta) of 33°C or 38°C. Within each group, rats were allocated to control, saline, or LPS (200 µg/kg) treatments. Cardiorespiratory patterns were examined using head-out plethysmography and ECG surface electrodes during normoxia and hypoxia (10% O2). Serum cytokine concentrations were quantified from samples taken at the end of each experiment. Our results suggest maternal CS exposure does not alter minute ventilation (V̇e) or heart rate (HR) response to infection or high temperature, but independently increases apnea frequency. CS also primes the inflammatory system to elicit a stronger cytokine response to bacterial insult. High Ta independently depresses V̇e but augments the hypoxia-induced increase in V̇e Moreover, higher Ta increases HR during normoxia and hypoxia, and in the presence of an immune challenge, increases HR during normoxia, and reduces the increase normally associated with hypoxia. Thus, while most environmental risk factors increase the burden on the cardiorespiratory system in early life, hyperthermia and infection blunt the normal HR response to hypoxia, and gestational CS independently destabilizes breathing by increasing apneas.