Mutation Research/Genetic Toxicology and Environmental Mutagenesis
Cigarette smoking during pregnancy: Chromosome translocations and phenotypic susceptibility in mothers and newborns
Introduction
The first report of cancer caused by tobacco was made in 1761 when Hill reported a correlation between the use of snuff and oral cancer [1]. The same report stated that cancer could be prevented by avoiding the use of tobacco products. Two hundred thirty-nine years later, tobacco smoking, environmental tobacco smoke and smokeless tobacco were for the first time included in the Ninth Report on Carcinogens (RoC) as known human carcinogens [2]. The RoC listings are based on observed causal relationships between tobacco exposure and cancer or other illnesses. The International Agency for Research on Cancer (IARC) has linked active tobacco smoking with cancer causation at more than a dozen organ sites [3]. Approximately 4000 chemicals have been identified in tobacco smoke, many of which are classified as known or suspected human carcinogens [3].
Babies born to women who smoke during pregnancy are at increased risk for poor lung development, sudden infant death syndrome, and low birth weight. Whereas some studies report an association between tobacco exposure and childhood cancer, others do not [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Epidemiologic studies provide evidence that environmental tobacco exposure is harmful to children, but few reports address the health effects of maternal tobacco exposures upon children during gestation. Analyses are challenging because the gestational exposures in epidemiologic studies typically cannot be separated from pre- and post-gestational maternal and paternal exposures.
Several molecular epidemiologic studies have sought to correlate maternal smoking with biomarkers associated with tobacco exposure as measured in fetal cord blood or amniocytes [16]. Maternal smoking before and during pregnancy has been associated with increased chromosomal instability in amniocytes [17]. Cotinine, DNA adducts, gene mutations, chromosome aberrations, and micronuclei have all been examined [18], [19], [20], [21], [22], [23] to evaluate the effects of transplacental exposures in fetal cells and to determine whether tobacco exposure during embryological and fetal development can increase the risks of disease later in life.
Exposures during fetal development may influence cancer risks. There is a potentially increased incidence of cancer among children whose mothers were exposed during pregnancy. Compounds in passive and active tobacco smoke and their metabolites have been known for many years to be capable of crossing the placenta [24], [25]. Diethylstilbestrol is a powerful transplacental carcinogen, increasing the risk of vaginal clear cell carcinoma and testicular cancer in the children of exposed mothers [26], [27], [28]. Gestational exposure to alcohol is associated with childhood leukemia [11]. A recent pair of review articles [29], [30] summarize the literature on environmental exposures in children, including newborns. The results suggest that children are more susceptible than adults to the effects of exposure.
Cancer is influenced by interactions among frequency and timing of exposures and genetic susceptibility [31], [32]. Rare genetic variants with high penetrance contribute to approximately 5% of all cancers, whereas the remaining cases are largely attributed to gene–gene and gene–environment interactions. Genetic polymorphisms that increase the risk for cancer among smokers have been identified [33], [34], [35], [36]. Inherent genetic susceptibility to the effects of genotoxic exposures can be assessed by evaluating the sensitivity of peripheral blood lymphocytes to bleomycin in vitro [37], [38], [39]. Cells from susceptible individuals are compromised in their ability to repair chromosomal damage compared to non-susceptible people. Cloos et al. [40] compared gene expression patterns between mutagen-susceptible and mutagen-resistant cells. They describe expression differences in a spectrum of genes involved in response to bleomycin with potential for involvement in cancer.
Structural chromosome aberrations have long been known to be widely present in tumor cells, e.g. [41], and chromosome aberrations in peripheral lymphocytes of healthy individuals are significantly associated with increased cancer risks [42], [43]. Chromosome translocations are of particular interest in assessing chronic exposure because most translocations are stable through cell division and have been shown to accumulate under conditions of protracted or highly fractionated exposure [44], [45]. Translocation frequencies have been shown to be elevated in smokers compared to non-smokers, e.g. [46], [47], although other studies have not observed such an association, e.g. [48]. Recently, an international effort to collect information on translocation frequencies in normal, healthy subjects showed a statistically significant increase in translocations among cigarette smokers compared to non-smokers [49].
Here we investigated potential interactions between maternal cigarette smoking during pregnancy, genetic susceptibility, and race, and evaluated the influence of smoking and susceptibility on translocations and other types of chromosome aberrations in mothers and their newborns. Chromosome aberrations were evaluated by simultaneously painting chromosomes 1, 2, and 4 in red and chromosomes 3, 5 and 6 in green. Genetic susceptibility was assessed using the in vitro bleomycin assay, and tobacco smoke exposure was assessed by several approaches including the use of a self-reported questionnaire, and the measure of serum cotinine levels in maternal blood samples.
Section snippets
Research subjects
Two hundred thirty-nine healthy pregnant female patients between the ages of 15 and 43 were recruited for the University of Pittsburgh Prenatal Exposures and Preeclampsia Prevention (PEPP) study [18]. Following informed consent, patients who volunteered for the study completed detailed questionnaires that were administered by trained interviewers. The questionnaires provided information about tobacco exposure, alcohol use, diet and nutrition, physical activity, race, and socio-demographics.
Demographics
The cohort from the larger PEPP study consisted of 239 mothers and their 241 newborns (including two sets of twins). A summary of the demographic data, both discrete and continuous, collected from the questionnaire is presented in Table 1. Specifically, the variables considered in this study included newborn gender, maternal race, smoking status, number of cigarettes smoked per day, socioeconomic status, education, and age. The study participants self-identified race and consisted of 49.4%
Discussion
This report demonstrates for the first time an association between genetic susceptibility, as measured by a bleomycin challenge assay, and the frequency of spontaneous chromosome aberrations including translocations measured by chromosome painting, in a cohort of human newborns. We also show that peripheral blood lymphocytes from newborns, as a group, are inherently more resistant to bleomycin-induced damage than peripheral blood lymphocytes from their mothers.
A positive association was
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
This work was performed in part under the auspices of the U.S. Department of Energy by the University of California, Lawrence Livermore National Laboratory under contract W-7405-ENG-48. Funding from the California Tobacco Related Disease Research Program Grant #8RT-0070 to JDT and NIH grant R01 HD33016 to WLB is gratefully acknowledged. We thank J. Montgomery for expert technical assistance with slide preparation and J. Williams, B. Cutter, F. Zamora, J. Coffey, S. Sun, J. Lamberton, B. Lear,
References (62)
- et al.
Impact of maternal lifestyle factors on newborn HPRT mutant frequencies and molecular spectrum—initial results from the Prenatal Exposures and Preeclampsia Prevention (PEPP) Study
Mutat. Res.
(1999) - et al.
HPRT gene alterations in umbilical cord blood T-lymphocytes in newborns of mothers exposed to tobacco smoke during pregnancy
Mutat. Res.
(2005) - et al.
Urine cotinine excretion in neonates exposed to tobacco smoke products in utero
J. Pediatr.
(1985) - et al.
Effects of smoking on fetoplacental-maternal system during pregnancy
Am. J. Obstet. Gynecol.
(1984) - et al.
Diethylstilboestrol. I. Pharmacology, toxicology and carcinogenicity in humans
Eur. J. Cancer
(1992) - et al.
Children's exposure to environmental pollutants and biomarkers of genetic damage. I. Overview and critical issues
Mutat. Res.
(2006) - et al.
Children's exposure to environmental pollutants and biomarkers of genetic damage. II. Results of a comprehensive literature search and meta-analysis
Mutat. Res.
(2006) - et al.
Molecular cytogenetic characterization of cancer cell alterations
Cancer Genet. Cytogenet.
(1997) - et al.
The accumulation of chromosome aberrations and Dlb-1 mutations in mice with highly fractionated exposure to gamma radiation
Mutat. Res.
(1998) - et al.
The effects of age and lifestyle factors on the accumulation of cytogenetic damage as measured by chromosome painting
Mutat. Res.
(1995)
International study of factors affecting human chromosome translocations
Mutat. Res.
Rapid method for the simultaneous measurement of nicotine and cotinine in urine and serum by gas chromatography–mass spectrometry
J. Chromatogr. B: Biomed. Sci. Appl.
Meconium analysis to assess fetal exposure to nicotine by active and passive maternal smoking
J. Pediatr.
Role of maternal exposures and newborn genotypes on newborn chromosome aberration frequencies
Mutat. Res.
Biomarkers of exposure to tobacco smoke and environmental pollutants in mothers and their transplacental transfer to the foetus. Part I. Bulky DNA adducts
Mutat. Res.
Tobacco Smoke and Involuntary Smoking. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
Greco risk of childhood cancer and adult lung cancer after childhood exposure to passive smoke: a meta-analysis
Environ. Health Perspect.
Prenatal exposure to parents’ smoking and childhood cancer
Am. J. Epidemiol.
Maternal smoking during pregnancy and childhood cancer
Am. J. Epidemiol.
Prenatal exposure to tobacco smoke and childhood brain tumors: results from the United States West Coast childhood brain tumor study
Cancer Epidemiol. Biomarkers Prev.
Childhood brain tumors and exposure to tobacco smoke
Cancer Epidemiol. Biomarkers Prev.
Maternal smoking in pregnancy: does it increase the risk of childhood cancer?
Int. J. Epidemiol.
From in utero and childhood exposure to parental smoking to childhood cancer: a possible link and the need for action
Hum. Exp. Toxicol.
Parental alcohol consumption, cigarette smoking, and risk of infant leukemia: a childrens cancer group study
J. Natl. Cancer Inst.
Childhood cancer and parental use of tobacco: deaths from 1953 to 1955
Br. J. Cancer
Childhood cancer and parental use of tobacco: findings from the inter-regional epidemiological study of childhood cancer (IRESCC)
Br. J. Cancer
Childhood cancer and parental use of tobacco: deaths from 1971 to 1976
Br. J. Cancer
Parental smoking and risk of childhood-cancer: a review of the evidence
Indoor Built Environ.
Smoking while pregnant: transplacental mutagenesis of the fetus by tobacco smoke
JAMA
Cited by (17)
DNA and chromosome damage induced by bleomycin in mammalian cells: An update
2018, Mutation Research - Reviews in Mutation ResearchCitation Excerpt :They also assessed genetic susceptibility by means of the BLM sensitivity test. They found that peripheral blood lymphocytes from pregnant woman were about three times more susceptible to BLM than newborns [93]. More recently, Buchynska et al. [94] analyzed the DNA repair deficiency in peripheral blood lymphocytes of endometrial cancer patients with a family history of cancer using the BLM sensitivity test (comet assay version).
Paternal Smoking as a Cause for Transgenerational Damage in the Offspring
2015, Handbook of Fertility: Nutrition, Diet, Lifestyle and Reproductive HealthRecreational drugs
2015, Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment: Third EditionNuclear abnormalities in cells from nasal epithelium: A promising assay to evaluate DNA damage related to air pollution in infants
2014, Jornal de PediatriaCitation Excerpt :Furthermore, early age genetic damage may affect the lifetime risk of adverse health outcomes. Because of that, the micronucleus assay method has been widely used to study genome damage in children after in utero and post-natal exposures in a variety of rural and urban environmental settings, resulting from maternal smoking as well as accidental industrial or technological overexposures.1–3 Through a survey of the current literature, it was observed that the frequency of nuclear abnormalities is very low at birth.
Prenatal PAH exposure is associated with chromosome-specific aberrations in cord blood
2010, Mutation Research - Genetic Toxicology and Environmental MutagenesisCitation Excerpt :A pooled analysis of age-related variations in chromosome frequency included results for translocation frequencies in newborns in which chromosomes 1–6 were examined with WCP [19]. In our data, the stable aberration rate in chromosomes 1–6 was 0.24 per 100 CE and our translocation rate was 0.12 per 100 CE, which is more than 2 times higher than that reported for newborns from California and Cumbria, UK by Sigurdson et al. [19] though only half as high as that recently reported among African-American newborns in Pittsburgh [16], suggesting that our population might be exposed to an intermediate level of PAH exposure. Our observed association between stable chromosomal aberrations and PAHs is consistent with other studies that have found that chromosomal aberrations are associated with exposures to PAH-containing mixtures.
Frequency of chromosomal aberrations in Prague mothers and their newborns
2010, Mutation Research - Genetic Toxicology and Environmental Mutagenesis
- 1
Current address: Center for Cancer Research, NCI, NIH, DHHS, Building 31, Room 3A11, 1 Center Drive, Bethesda, MD 20892-2440, United States. Tel.: +1 301 496 4345; fax: +1 301 496 0775.