Prenatal Exposure to Polycyclic Aromatic Hydrocarbons, Benzo[a]pyrene–DNA Adducts, and Genomic DNA Methylation in Cord Blood

Background: Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic environmental pollutants generated during incomplete combustion. After exposure and during metabolism, PAHs can form reactive epoxides that can covalently bind to DNA. These PAH–DNA adducts are established markers of cancer risk. PAH exposure has been associated with epigenetic alterations, including genomic cytosine methylation. Both global hypomethylation and hypermethylation of specific genes have been associated with cancer and other diseases in humans. Experimental evidence suggests that PAH–DNA adduct formation may preferentially target methylated genomic regions. Early embryonic development may be a particularly susceptible period for PAH exposure, resulting in both increased PAH–DNA adducts and altered DNA methylation. Objective: We explored whether prenatal exposure to PAHs is associated with genomic DNA methylation in cord blood and whether methylation levels are associated with the presence of detectable PAH–DNA adducts. Methods: In a longitudinal cohort study of nonsmoking women in New York City, we measured PAH exposure during pregnancy using personal air monitors, assessed PAH internal dose using prenatal urinary metabolites (in a subset), and quantified benzo[a]pyrene–DNA adducts and genomic DNA methylation in cord blood DNA among 164 participants. Results: Prenatal PAH exposure was associated with lower global methylation in umbilical cord white blood cells (p = 0.05), but global methylation levels were positively associated with the presence of detectable adducts in cord blood (p = 0.01). Conclusions: These observations suggest that PAH exposure was adequate to alter global methylation in our study population. Additional epidemiologic studies that can measure site-specific cytosine methylation and adduct formation will improve our ability to understand this complex molecular pathway in vivo.

[1]  N. Tretyakova,et al.  Endogenous cytosine methylation and the formation of carcinogen carcinogen-DNA adducts. , 2008, Nucleic acids symposium series.

[2]  F. Perera,et al.  Polycyclic aromatic hydrocarbon metabolite levels and pediatric allergy and asthma in an inner‐city cohort , 2010, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[3]  F P Perera,et al.  Polycyclic aromatic hydrocarbon-DNA adducts in human placenta and modulation by CYP1A1 induction and genotype. , 1998, Carcinogenesis.

[4]  N. Tretyakova,et al.  Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers , 2002, Oncogene.

[5]  G. Pfeifer.  Mutagenesis at methylated CpG sequences. , 2006, Current topics in microbiology and immunology.

[6]  A. Baccarelli,et al.  Global and gene‐specific promoter methylation changes are related to anti‐B[a]PDE‐DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon‐exposed individuals , 2009, International journal of cancer.

[7]  Zheng Li,et al.  Measurement of urinary monohydroxy polycyclic aromatic hydrocarbons using automated liquid-liquid extraction and gas chromatography/isotope dilution high-resolution mass spectrometry. , 2006, Analytical chemistry.

[8]  Robin M Whyatt,et al.  Effects of transplacental exposure to environmental pollutants on birth outcomes in a multiethnic population. , 2003, Environmental health perspectives.

[9]  M. Tang,et al.  Preferential Formation of Benzo[a]pyrene Adducts at Lung Cancer Mutational Hotspots in P53 , 1996, Science.

[10]  B. Sadikovic,et al.  DNA methylation analysis using CpG microarrays is impaired in benzopyrene exposed cells. , 2007, Toxicology and applied pharmacology.

[11]  M. Tang,et al.  Carcinogens preferentially bind at methylated CpG in the p53 mutational hot spots. , 1998, Cancer research.

[12]  R. Jirtle,et al.  Epigenetic Gene Regulation: Linking Early Developmental Environment to Adult Disease , 2006 .

[13]  D. A. Kenny,et al.  The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. , 1986, Journal of personality and social psychology.

[14]  D. Maltseva,et al.  Impact of benzo[a]pyrene-2'-deoxyguanosine lesions on methylation of DNA by SssI and HhaI DNA methyltransferases. , 2006, Biochemistry.

[15]  E. Susser,et al.  Genomic DNA Methylation among Women in a Multiethnic New York City Birth Cohort , 2008, Cancer Epidemiology Biomarkers & Prevention.

[16]  B. Sadikovic,et al.  Benzopyrene exposure disrupts DNA methylation and growth dynamics in breast cancer cells. , 2006, Toxicology and applied pharmacology.

[17]  Peggy Shepard,et al.  The challenge of preventing environmentally related disease in young children: community-based research in New York City. , 2002, Environmental health perspectives.

[18]  D. Weisenberger,et al.  Cytosine Methylation in a CpG Sequence Leads to Enhanced Reactivity with Benzo[a]pyrene Diol Epoxide That Correlates with a Conformational Change* , 1999, The Journal of Biological Chemistry.

[19]  F. Perera,et al.  DNA Damage from Polycyclic Aromatic Hydrocarbons Measured by Benzo[a]pyrene-DNA Adducts in Mothers and Newborns from Northern Manhattan, The World Trade Center Area, Poland, and China , 2005, Cancer Epidemiology Biomarkers & Prevention.

[20]  Robin M Whyatt,et al.  Predictors of personal polycyclic aromatic hydrocarbon exposures among pregnant minority women in New York City. , 2004, Environmental health perspectives.

[21]  Methylation of cytosine at C5 in a CpG sequence context causes a conformational switch of a benzo[a]pyrene diol epoxide-N2-guanine adduct in DNA from a minor groove alignment to intercalation with base displacement. , 2005, Journal of molecular biology.

[22]  Roger A. Jones,et al.  Formation of benzo[a]pyrene diol epoxide-DNA adducts at specific guanines within K-ras and p53 gene sequences: stable isotope-labeling mass spectrometry approach. , 2002, Biochemistry.

[23]  W. Schulz,et al.  Causes and consequences of DNA hypomethylation in human cancer. , 2005, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[24]  Hadley Wickham,et al.  ggplot2 - Elegant Graphics for Data Analysis (2nd Edition) , 2017 .

[25]  M. Tang,et al.  Cytosine methylation determines hot spots of DNA damage in the human P53 gene. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Frederica P. Perera,et al.  Effect of Prenatal Exposure to Airborne Polycyclic Aromatic Hydrocarbons on Neurodevelopment in the First 3 Years of Life among Inner-City Children , 2006, Environmental health perspectives.

[27]  F. Perera,et al.  DNA adducts and cancer risk in prospective studies: a pooled analysis and a meta-analysis. , 2008, Carcinogenesis.

[28]  Peter A. Jones,et al.  Inhibition of DNA methylation by chemical carcinogens in vitro , 1983, Cell.

[29]  B. Shaw,et al.  Base stacking and molecular polarizability: effect of a methyl group in the 5-position of pyrimidines. , 1987, Biochemical and biophysical research communications.

[30]  K. Willett,et al.  Benzo[a]pyrene effects on glycine N-methyltransferase mRNA expression and enzyme activity in Fundulus heteroclitus embryos. , 2010, Aquatic toxicology.

[31]  Jiantong Wang,et al.  Optimal serum cotinine levels for distinguishing cigarette smokers and nonsmokers within different racial/ethnic groups in the United States between 1999 and 2004. , 2009, American journal of epidemiology.

[32]  P. Molloy,et al.  DNA hypomethylation and human diseases. , 2007, Biochimica et biophysica acta.

[33]  H. Bartsch,et al.  An improved fluorometric assay for dosimetry of benzo(a)pyrene diol-epoxide-DNA adducts in smokers' lung: comparisons with total bulky adducts and aryl hydrocarbon hydroxylase activity. , 1992, Cancer research.

[34]  H. Bartsch,et al.  Polycyclic aromatic hydrocarbon-DNA adducts in humans: relevance as biomarkers for exposure and cancer risk. , 1998, Mutation research.

[35]  Frederica P. Perera,et al.  Biomarkers in Maternal and Newborn Blood Indicate Heightened Fetal Susceptibility to Procarcinogenic DNA Damage , 2004, Environmental health perspectives.

[36]  S. Amin,et al.  Role of hydrophobic effects in the reaction of a polynuclear aromatic diol epoxide with oligodeoxynucleotides in aqueous solutions. , 1998, Chemical research in toxicology.