Impact of maternal lifestyle factors on newborn HPRT mutant frequencies and molecular spectrum - Initial results from the Prenatal Exposures and Preeclampsia Prevention (PEPP) Study

Epidemiological studies have demonstrated associations between maternal tob acco smoke exposure and consumption of alcohol during pregnancy and increas ed risk of pediatric malignancies, particularly infant leukemias. Molecular evidence also suggests that somatic mutational events occurring during fet al hematopoiesis in utero can contribute to this process. As part of an ong oing multi-endpoint biomarker study of 2000 mothers and newborns, the HPRT T-lymphocyte cloning assay was used to determine mutant frequencies (M-f) i n umbilical cord blood samples from an initial group of 60 neonates born to a sociodemographically diverse cohort of mothers characterized with respec t to age, ethnicity, socioeconomic status, and cigarette smoke and alcohol exposure. Non-zero M-f (N = 47) ranged from 0.19 to 5.62 X 10(-6), median 0 .70 x 10(-6), mean +/- SD 0.98 +/- 0.95 X 10(-6). No significant difference in M-f was observed between female and male newborns. Multivariable Poisso n regression analysis revealed that increased HPRT M-f were significantly a ssociated with maternal consumption of alcohol at the beginning [Relative R ate (RR)= 1.84, 95% CI = 0.99-3.40, P = 0.052) and during pregnancy (RR = 2 .99, 95% CI = 1.14-7.84, P = 0.026. No independent effect of self-reported active maternal cigarette smoking, either at the beginning or throughout pr egnancy, nor maternal passive exposure to cigarette smoke was observed. Alt hough based on limited initial data, this is the first report of a positive association between maternal alcohol consumption during pregnancy and HPRT M-f in human newborns. In addition, the spectrum of mutations at the HPRT locus was determined in 33 mutant clones derived from 19 newborns of mother s with no self-reported exposure to tobacco smoke and 14 newborns of mother s exposed passively or actively to cigarette smoke. In the unexposed group, alterations leading to specific exon 2-3 deletions, presumably as a result of illegitimate V(D)J recombinase activity, were found in five of the 19 m utants (26.3%); in the passively exposed group, two exon 2-3 deletions were present among the seven mutants (28.6%); and in the actively exposed group , six of the seven mutants (85.7%) were exon 2-3 deletions. Although no ove rall increase in HPRT Mi was observed and the number of mutant clones exami ned was small, these initial results point to an increase in V(D)J recombin ase-associated HPRT gene exon 2-3 deletions in cord blood T-lymphocytes in newborns of actively smoking mothers relative to unexposed mothers (P = 0.0 11). Together, these results add to growing molecular evidence that in uter o exposures to genotoxicants result in detectable transplacental mutagenic effects in human newborns. (C) 1999 Elsevier Science B.V. All rights reserv ed.