Exploiting gene-environment interaction to detect adverse health effects of environmental chemicals on the next generation

There is increasing evidence from epidemiological studies that genetic susceptibilities may modify the teratogenic effects of toxic chemicals. However, in contrast to tobacco smoke, few epidemiological studies have addressed environmental chemicals, such as polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls in regard to genetic susceptibility. Recent studies, including the Hokkaido Study of Environments and Children's Health, have investigated the impacts of both environmental and genetic factors on children's development. Several xenobiotic-metabolizing genes have been reported to confer genetic susceptibility to low birth weight. These genes seem to be influenced functionally by maternal smoking during pregnancy, itself a significant risk factor. In our study, we found that birth weight was significantly lower among infants born to smoking women having the specific AHR, CYP1A1, GSTM1, CYP2E1 and NQO1 genotypes. When combinations of these genotypes were considered, birth weight was even lower. On the other hand, congenital anomalies such as hypospadias seemed to be caused by environmental factors in conjunction with genetic predisposition as suggested by linkage in several case-control studies reported to low birth weight. We have found an association between maternal CYP1A1 genotype or low birth weight and the risk of hypospadias irrespective of smoking. At the same time, birth weight was negatively correlated with maternal blood concentrations of polychlorinated dibenzofurans. Further studies should elucidate the impact of genetic factors on adverse effects of exposures to dioxin-related chemicals.