LIFESTYLE FACTORS AFFECTING FETAL SOMATIC MUTATION

Summary

Principal Investigator: William Bigbee
Abstract: DESCRIPTION: (Adapted from Investigator's Abstract) Somatic mutations during embryonic/fetal life have prospective health implications. Early cancer-predisposing mutations in oncogenes, tumor suppressor genes, or genes involved in DNA repair may result in significant numbers of initiated mutant cells at birth due to clonal expansion during growth and development of the fetus. Clonal expansion of mutant cells during development can also result in mosaic expression of genes presenting as birth defects. Mutations occurring early in development can also be fixed in differentiating germ cells leading to gonadal mosaicism and the emergence of new Mendelian disorders. This study of 300 maternal/newborn pairs is designed to assess the impact of maternal environments on embryonic/fetal somatic mutation at two independent loci (HPRT and GPA) in placental blood cells. This proposed investigation follows the investigators' initial survey of somatic mutation in newborns in which they found that maternal exposure to tobacco smoke and lower socioeconomic status, perhaps because of its association with maternal lifestyle factors, appears to increase the frequency and alter the spectrum of the molecular mechanisms of somatic mutation in utero. Subjects will be recruited from an ethnically and socioeconomically diverse population of women at their first prenatal visit, typically at 10-14 weeks gestation. They will be interviewed and administered a comprehensive questionnaire to characterize their exposure to tobacco smoke and determine other demographic variables. Maternal blood samples will be obtained at initial interview, at 28-32 weeks of gestation, and at delivery. The blood samples from these mothers, together with placental blood samples from their newborns, will be assayed for 4-amino biphenyl hemoglobin (4-ABP-Hb) adducts to quantitate the biologically effective dose of tobacco smoke mutagens to the mother and fetus throughout gestation. HPRT and GPA mutant frequencies measured in placental blood samples will be tested for association with 4-ABP-Hb adduct levels, and other lifestyle/exposure variables. The molecular spectrum of HPRT mutations in the newborns will be analyzed for evidence of environmental exposures. Finally, GPA mutation frequencies in maternal/newborn pairs will be tested for association suggestive of shared gene/environment factors. The investigators state that this focused study will seek to confirm their preliminary findings in an independent population of mothers and newborns and to specifically ascertain whether the previously observed associations reflect the direct mutagenic effect of specific and identifiable maternal exposures.
Funding Period: 1996-08-10 - 2001-07-31
more information: NIH RePORT

Top Publications

  1. pmc Cigarette smoking during pregnancy: chromosome translocations and phenotypic susceptibility in mothers and newborns
    L Michelle Bennett
    Physical and Life Sciences Directorate, L 452, Lawrence Livermore National Laboratory, Livermore, CA 94550, United States
    Mutat Res 696:81-8. 2010
  2. ncbi HPRT gene alterations in umbilical cord blood T-lymphocytes in newborns of mothers exposed to tobacco smoke during pregnancy
    Phouthone Keohavong
    Department of Environmental and Occupational Health, University of Pittsburgh, 3343 Forbes Avenue, Pittsburgh, PA 15260, USA
    Mutat Res 572:156-66. 2005
  3. ncbi Use of the glycophorin A somatic mutation assay for rapid, unambiguous identification of Fanconi anemia homozygotes regardless of GPA genotype
    Viktoria N Evdokimova
    Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, 3343 Forbes Avenue, Pittsburgh, PA 15213, USA
    Am J Med Genet A 135:59-65. 2005
  4. pmc Qualitatively and quantitatively similar effects of active and passive maternal tobacco smoke exposure on in utero mutagenesis at the HPRT locus
    Stephen G Grant
    Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    BMC Pediatr 5:20. 2005
  5. ncbi The absence of interaction between drug metabolizing enzyme genotypes and maternal lifestyle factors on glycophorin A somatic mutation frequency levels in newborns
    Tomoko Nukui
    Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
    Pharmacogenet Genomics 16:129-38. 2006
  6. ncbi Genotoxicity assessed by the comet and GPA assays following in vitro exposure of human lymphoblastoid cells (H9) or perinatal exposure of mother-child pairs to AZT or AZT-3TC
    Patricia A Escobar
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Environ Mol Mutagen 48:330-43. 2007

Scientific Experts

  • Phouthone Keohavong
  • Stephen G Grant
  • William L Bigbee
  • L Michelle Bennett
  • Patricia A Escobar
  • Roberta B Ness
  • Richard D Day
  • Tomoko Nukui
  • Viktoria N Evdokimova
  • James D Tucker
  • Yun Wang
  • Gail F Harger
  • Marilyn J Ramsey
  • Dale M Walker
  • Carol J Nesel
  • Miriam C Poirier
  • Billy W Day
  • Ofelia A Olivero
  • Nancy A Wade
  • Elaine J Abrams
  • Quanxin Meng
  • Vernon E Walker
  • Gail Harger
  • Heather A Gordish-Dressman
  • Marjorie Romkes
  • Sharon L Wenger
  • Reagan K McLoughlin

Detail Information

Publications6

  1. pmc Cigarette smoking during pregnancy: chromosome translocations and phenotypic susceptibility in mothers and newborns
    L Michelle Bennett
    Physical and Life Sciences Directorate, L 452, Lawrence Livermore National Laboratory, Livermore, CA 94550, United States
    Mutat Res 696:81-8. 2010
    ..However, peripheral lymphocytes in pregnant women are more susceptible to genetic damage than peripheral lymphocytes in newborns...
  2. ncbi HPRT gene alterations in umbilical cord blood T-lymphocytes in newborns of mothers exposed to tobacco smoke during pregnancy
    Phouthone Keohavong
    Department of Environmental and Occupational Health, University of Pittsburgh, 3343 Forbes Avenue, Pittsburgh, PA 15260, USA
    Mutat Res 572:156-66. 2005
    ....
  3. ncbi Use of the glycophorin A somatic mutation assay for rapid, unambiguous identification of Fanconi anemia homozygotes regardless of GPA genotype
    Viktoria N Evdokimova
    Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, 3343 Forbes Avenue, Pittsburgh, PA 15213, USA
    Am J Med Genet A 135:59-65. 2005
    ..The quantitative and qualitative aspects of the GPA assay relevant for applying this test for FA diagnosis, and perhaps for carrier detection, are discussed...
  4. pmc Qualitatively and quantitatively similar effects of active and passive maternal tobacco smoke exposure on in utero mutagenesis at the HPRT locus
    Stephen G Grant
    Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    BMC Pediatr 5:20. 2005
    ..Previous studies attempting to establish a direct link between active smoking and levels of somatic mutation have largely discounted the effects of passive or secondary exposure, and have produced contradictory results...
  5. ncbi The absence of interaction between drug metabolizing enzyme genotypes and maternal lifestyle factors on glycophorin A somatic mutation frequency levels in newborns
    Tomoko Nukui
    Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
    Pharmacogenet Genomics 16:129-38. 2006
    ..The observed variation in newborn GPA frequency might be due to either environmental factors not assessed in this study or inter-individual differences in alternative metabolic or DNA repair pathways...
  6. ncbi Genotoxicity assessed by the comet and GPA assays following in vitro exposure of human lymphoblastoid cells (H9) or perinatal exposure of mother-child pairs to AZT or AZT-3TC
    Patricia A Escobar
    Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Environ Mol Mutagen 48:330-43. 2007
    ..Overall, the mutagenic effects found in mother-child pairs receiving AZT-based treatments justify their surveillance for long-term genotoxic consequences...