Gene mutations with characteristic deletions in cord blood T lymphocytes associated with passive maternal exposure to tobacco smoke

Abstract

We have investigated the molecular effects of passive maternal cigarette exposure in a newborn population and consider the possible implications of the observed genetic changes in the development of neoplastic diseases in children. We present a distribution analysis of somatic mutational events in a reporter gene, HPRT, in cord blood T lymphocytes from newborns after transplacental exposure to cigarette smoke. Analysis of 30 HPRT mutant isolates from 12 newborn infants born to mothers with no evidence of environmental exposure to cigarette smoke and 37 HPRT mutant isolates from 12 infants born to mothers exposed to passive cigarette smoke showed a significant difference in the HPRT mutational spectrum in those exposed in utero to cigarette smoke. The most notable change was an increase in 'illegitimate' genomic deletions mediated by V(D)J recombinase, a recombination event associated with hematopoietic malignancies in early childhood. Recent epidemiological studies of maternal and paternal cigarette smoke exposure and childhood cancers may need to be re-interpreted, given these results.

Risk of childhood germ cell tumors in association with parental smoking and drinking

“…Cases were recruited through COG. Eligible cases had to have newly diagnosed GCT between January 1, 1993 and December 31,2001, and be registered with the COG data and statistics center. There had to be a telephone in the patient's residence, and the patient's biologic mother had to speak English and be available for interview.…”

“…Otherwise, the mother provided a surrogate interview. Interviews were conducted between January 1, 1997 and December 31,2001.…”

Accumulation of somatic mutations in proliferating T cell clones from children treated for leukemia

“…Welldeveloped molecular techniques are available for analyses of mutant cells. 24,32,33 Previously observed HPRT mutations Leukemia include base substitutions at more that 270 sites in all nine exons, small deletions and insertions, large structural alterations, splice site changes in introns and specialized genetic events such as V(D)J recombinase-mediated deletions. 23,34 Since the HPRT gene is located on the X-chromosome, molecular analyses at the DNA/RNA level were performed in a different way for mutant isolates from males and females.…”

“…23,34 Since the HPRT gene is located on the X-chromosome, molecular analyses at the DNA/RNA level were performed in a different way for mutant isolates from males and females. 24 Mutant isolates from males were first analyzed by multiplex genomic HPRT PCR to determine the presence or absence of the nine HPRT exons. 33,35 Mutant isolates from males showing no genomic alterations were characterized by reverse transcriptase (RT) PCR and DNA sequencing of cDNA amplified products.…”

“…[20][21][22] Molecular analyses of HPRT mutations have revealed spectra that not only differ between children and adults but also show changes associated with exposures to specific mutagens. [23][24][25][26] As a result, the analysis of HPRT T cell Mfs and mutational spectra have been well-established quantitative and qualitative measures, respectively, of in vivo spontaneous mutational events and genotoxicity in humans.…”