Abnormal Development - Smoking

Embryology - 2 Dec 2023        Expand to Translate
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Educational Use Only - Embryology is an educational resource for learning concepts in embryological development, no clinical information is provided and content should not be used for any other purpose.

Introduction

No smoking sign

There is an association between physical defects among newborns and maternal smoking tobacco during pregnancy.

Spontaneous abortion, ectopic implantation, pre-term births, low-weight full-term babies, and fetal and infant deaths all occur more frequently among mothers who smoke during pregnancy than among those who do not. These developmental abnormalities are therefore environmental (maternal) in origin and not congenital (though there are probably genetics involved with a tendency to smoke).

The possible relationship to preterm birth generates one major clinical problem, as preterm birth results in 47% of all neonatal deaths (UK data).

Also of great concern is that smoking is a suggested causative factor for low infant birth weight (LBW) (2.500kg and below). LBW is in turn related to future (postnatal) health by the fetal origins hypothesis.

Some Recent Findings

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." TGF-beta DOHAD Toxic Effect of Cigarette Smoke on Brainstem Nicotinic Receptor Expression: Primary Cause of Sudden Unexplained Perinatal Death "Among the neurotoxicants contained in tobacco smoke, if absorbed during pregnancy, nicotine significantly affects α7-nicotinic acetylcholine receptors, which play essential roles in the development of the brainstem regions receiving cholinergic projections in perinatal life. Immunohistochemical procedures for analysing formalin-fixed and paraffin-embedded brainstem samples from 68 fetuses and early newborns, with smoking and non-smoking mothers, who died of known and unknown causes, were carried out in order to determine if nicotine had activated the α7-nicotinic acetylcholine receptors. High α7-nicotinic acetylcholine receptor expression levels were only observed in the victims with smoking mothers. Frequently, these findings were associated with the hypoplasia of the brainstem structures controlling vital functions. The results of this study indicate that the exposition to nicotine in pregnancy exerts a strong direct effect on α7-nicotinic acetylcholine receptor activity especially in perinatal life and may be one of the primary risk factors leading to the sudden unexplained death of fetuses and newborns." Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 μg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father." mouse epigenetics Developmental effects of maternal smoking during pregnancy on the human frontal cortex transcriptome "Smoking exposure during the prenatal period was directly associated with differential expression of 14 genes; in contrast, during adulthood, despite a much larger sample size, only two genes showed significant differential expression (FDR < 10%). Moreover, 1,315 genes showed significantly different exposure effects between maternal smoking during pregnancy and direct exposure in adulthood (FDR < 10%)-these differences were largely driven by prenatal differences that were enriched for pathways previously implicated in addiction and synaptic function. Furthermore, prenatal and age-dependent differentially expressed genes were enriched for genes implicated in non-syndromic autism spectrum disorder (ASD) and were differentially expressed as a set between patients with ASD and controls in postmortem cortical regions. These results underscore the enhanced sensitivity to the biological effect of smoking exposure in the developing brain and offer insight into how maternal smoking during pregnancy affects gene expression in the prenatal human cortex." epigenetics Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation "Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns." epigenetics

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References | Discussion Page | Journal Searches | 2019 References | 2020 References Search term: Abnormal Development Smoking <pubmed limit=5>Abnormal Development Smoking</pubmed> Search term: Pregnancy Smoking <pubmed limit=5>Pregnancy Smoking</pubmed>

Older papers

The effects of electronic cigarette emissions on systemic cotinine levels, weight and postnatal lung growth in neonatal mice "Electronic cigarette (E-cigarettes) emissions present a potentially new hazard to neonates through inhalation, dermal and oral contact. Exposure to nicotine containing E-cigarettes may cause significant systemic absorption in neonates due to the potential for multi-route exposure. Systemic absorption of nicotine and constituents of E-cigarette emissions may adversely impact weight and lung development in the neonate. ...These studies indicate that exposure to E-cigarette emissions during the neonatal period can adversely impact weight gain. In addition exposure to nicotine containing E-cigarettes can cause detectable levels of systemic cotinine, diminished alveolar cell proliferation and a modest impairment in postnatal lung growth." respiratory Helping pregnant smokers to quit "Although most smokers manage to quit during pregnancy, a proportion does not. In England, 26% of women smoke in the year before their pregnancy and 12% smoke through to delivery.1 The rate is similar in other high income countries, whereas in low and middle income countries, smoking rates are more variable and seem to be increasing among young women.2 In addition to the countless negative consequences for the smoker’s own mental and physical health, smoking in pregnancy is linked to a wide range of poor health outcomes for the child.3 Thus there is an urgent need to help pregnant smokers who find it difficult to quit." Smoking overrules many other risk factors for small for gestational age birth in less educated mothers. "In this study fully completed data were available for 3793 pregnant women of Dutch origin from a population-based cohort (ABCD study). Path-analysis was conducted to examine the role of explanatory factors in the relation of maternal education to SGA. ...Among a large array of potential factors, the elevated risk of SGA birth among low-educated women appeared largely attributable to maternal smoking and to a lesser extent to maternal height. To reduce educational inequalities more effort is required to include low-educated women especially in prenatal intervention programs such as smoking cessation programs instead of effort into reducing other SGA-risk factors, though these factors might still be relevant at the individual level." Influence of Smoking and Alcohol during Pregnancy on Outcome of VLBW Infants "Nicotine and alcohol consumption have been associated with premature delivery and adverse neonatal outcome. We wanted to analyze the influence of self-reported nicotine and alcohol consumption on outcome of VLBW infants.In an ongoing multicenter study 2 475 parents of former very low birth weight (VLBW) infants born between January 2009 and December 2011 answered questionnaires about maternal smoking habits and alcohol consumption during pregnancy. ...Smoking during pregnancy results in a high rate of growth restricted VLBW infants. Prenatal exposition to nicotine seems to increase postnatal complications such as BPD und ROP." Maternal smoking during pregnancy and kidney volume in the offspring: the Generation R Study "An adverse fetal environment leads to smaller kidneys, with fewer nephrons, which might predispose an individual to the development of kidney disease and hypertension in adult life. ... Among mothers who continued smoking, we observed dose-dependent associations between the number of cigarettes smoked during pregnancy and kidney volume in fetal life. Smoking less than five cigarettes per day was associated with larger fetal combined kidney volume, while smoking more than ten cigarettes per day tended to be associated with smaller fetal combined kidney volume (p for trend: 0.002). This pattern was not significant for kidney volume at the age of 2 years. Our results suggest that smoking during pregnancy might affect kidney development in fetal life with a dose-dependent relationship." Quantitative effects of tobacco smoking exposure on the maternal-fetal circulation "In pregnant women who smoke, higher arterial resistance indices and lower birth weights were observed, and these findings were associated with increasing levels of tobacco smoking exposure. The values were significantly different when compared to those found in non-smoking pregnant women. This study contributes to the findings that smoking damage during pregnancy is dose-dependent, as demonstrated by the objective methods for measuring tobacco smoking exposure."

Nicotine

Nicotine is a natural ingredient in tobacco leaves, where as an alkaloid it provides some protection for the plant being eaten by insects by acting as a botanical insecticide.

Tobacco also contains other minor alkaloids nornicotine, anatabine and anabasine.

There is a chemical datasheet for nicotine, the pure chemical, note that commercial tobacco products include many additional chemicals.

Neonates have a decreased ability to metabolise nicotine, with a 3-4 times longer half-life in newborns exposed to tobacco smoke compared with adults.

Cytochrome P450, Subfamily IIA, Polypeptide 6 (CYP2A6) is the main enzyme in the liver responsible for metabolism (oxidation) of nicotine. (More? OMIM Entry CYP2A6) and there are known mutations that occur in this gene which would also impact on nicotine metabolism.

See also the recent review paper Metabolism and disposition kinetics of nicotine. Hukkanen J, Jacob P 3rd, Benowitz NL. Pharmacol Rev. 2005 Mar;57(1):79-115. | Dempsey D, Jacob P 3rd, Benowitz NL. Nicotine metabolism and elimination kinetics in newborns. Clin Pharmacol Ther. 2000 May;67(5):458-65. | OMIM Entry CYP2A6

Carbon Monoxide

Mouse carbon monoxide exposure

Smoking tobacco is also a source of carbon monoxide (CO), a colourless and odorless gas formed mainly as a by-product of incomplete combustion of hydrocarbons and can cause cytotoxicity by tissue hypoxia.

A recent study has identified in a newborn mouse model, effects on neurodevelopment of even sub-clinical levels of carbon monoxide.

Carbon Monoxide:

• enters circulation though the respiratory system
• binding to haemoglobin to form carboxy-haemoglobin (COHb)
  • haemoglobin affinity is 240 times greater than for oxygen
  • fetal haemoglobin binds with even greater affinity
• tissue hypoxia occurs when COHb levels are greater than 70%

Epigenetics

A recent study has looked at the effect on birth weight of maternal smoking throughout pregnancy and associated epigenetic effects.

"Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns."

Links: epigenetics

Australian National Drug Strategy Household Survey 1995

Below are excerpted statistics from the 1995 household survey.

Smoking is higher among young women than young men, although males tend to smoke more heavily. Among 14-19 year olds: 13% are current regular smokers, 5% are occasional smokers, while 49% have never smoked.

For more information please email CEIDA Information Centre

Passive Smoking

Exposure of non-smokers to environmental tobacco smoke, "passive smoking", has been associated with a substantial increased disease risk (coronary heart disease, cancer) a recent study now adds diabetes to the possible deletirious effects. Houston TK, Kiefe CI, Person SD, Pletcher MJ, Liu K, Iribarren C. Active and passive smoking and development of glucose intolerance among young adults in a prospective cohort: CARDIA study. BMJ. 2006 May 6;332(7549):1064-9. "These findings support a role of both active and passive smoking in the development of glucose intolerance in young adulthood."

Smoking and Pregnancy

Smoking doubles the risk of having a low-birthweight baby and significantly increases the rate of perinatal mortality and several other adverse pregnancy outcomes. The mean reduction in birthweight for babies of smoking mothers is 200 g. High quality interventions to help pregnant women quit smoking produce an absolute difference of 8.1% in validated late-pregnancy quit rates. If abstinence is not achievable, it is likely that a 50% reduction in smoking would be the minimum necessary to benefit the health of mother and baby. Healthcare providers perform poorly in antenatal interventions to stop women smoking. Midwives deliver interventions at a higher rate than doctors. The efficacy of nicotine replacement therapy has not been established in pregnancy. Currently, its use should only be considered in women smoking more than 10 cigarettes per day who have made a recent, unsuccessful attempt to quit and who are motivated to quit. Relapse prevention programs have shown little success in the postpartum period. Data from: Quitting smoking in pregnancy Raoul A Walsh, John B Lowe, Peter J Hopkins (MJA 2001; 175: 320-323)

Placental Function

A review of three placental markers showed "maternal smoking impairs human placental development by changing the balance between cytotrophoblast (CTB) proliferation and differentiation"

Australia

Data in this graph from AIHW 2014 Report, Birthweight of babies born to Indigenous mothers.

Links: Birth Weight

References

Reviews

Jauniaux E & Burton GJ. (2007). Morphological and biological effects of maternal exposure to tobacco smoke on the feto-placental unit. Early Hum. Dev. , 83, 699-706. PMID: 17900829 DOI.

Articles

Venditti CC, Casselman R & Smith GN. (2011). Effects of chronic carbon monoxide exposure on fetal growth and development in mice. BMC Pregnancy Childbirth , 11, 101. PMID: 22168775 DOI.

Genbacev O, McMaster MT, Zdravkovic T & Fisher SJ. (2003). Disruption of oxygen-regulated responses underlies pathological changes in the placentas of women who smoke or who are passively exposed to smoke during pregnancy. Reprod. Toxicol. , 17, 509-18. PMID: 14555188

Search Pubmed

Search Pubmed: smoking and pregnancy

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Cite this page: Hill, M.A. (2023, December 2) Embryology Abnormal Development - Smoking. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Smoking

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© Dr Mark Hill 2023, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G