Genetic susceptibility of newborns for DNA damage

Despite many efforts made to improve human health, incidence in childhood cancer is increasing and relevant data regarding biomonitoring of newborns to unintended mutagen exposure are lacking. The overall goal of this thesis was to assess the susceptibility of newborns (preterm and full term) to mutagens by comparison with their mothers using biomarkers of exposure, effect and susceptibility in well characterized small Belgian and large European study populations of mother-newborn pairs.
In a first part, the repair capacity of 25 preterm newborns and their mothers was assessed to H2O2 in vitro induced oxidative DNA damage using a cellular repair assay previously developed in our laboratory. This resulted in lower repair capacity levels of preterm newborns in comparison with their mothers and term newborns. Multivariate linear regression analysis revealed higher background DNA damage levels in preterm infants from smoking fathers than those from non smoking fathers. In addition, preterm infants born by vaginal delivery seem to repair more slowly the in vitro induced oxidative DNA damage in comparison with preterm infants born by caesarean delivery.
Next, a cellular phenotype assay for nucleotide excision repair (NER) was developed, using benzo(a)pyrenediolepoxide (BPDE) as model mutagen and aphidicolin (APC) as DNA polymerase inhibitor. Repair capacity is defined as the amount of DNA damage induced by BPDE in presence of aphidicolin (APC), diminished with the damage induced by BPDE and APC alone. Overall, the newly developed assay demonstrated to be reliable, specific for NER and reproducible. Moreover, it showed low intra- and high inter-individual variation, indicating its applicability in biomonitoring studies.
Subsequently, the NER repair phenotype assay was used to assess the repair capacity of 25 term newborns and their mothers and taking into account demographic data. This resulted in a lower calculated repair capacity of term newborns in comparison with their mothers. Multiple regression analysis revealed more DNA damage after treatment with APC alone in newborns that were born by vaginal delivery compared to those delivered with a cesarean section.
The last chapter was conducted within EU-project NewGeneris and involved the scoring of micronuclei (MN) frequencies in cord blood and peripheral blood from newborns and mothers from Rhea cohort in Crete using a semi automated image analysis system. Micronuclei in mononucleated (MNMONO) and binucleated (MNBN) T-lymphocytes and the cytokinesis block proliferation index (CBPI) were calculated in 251 newborns (224 full term and 22 preterm) and 223 mothers including 182 pairs and were studied in relation to maternal and gestational factors. Statistically significant higher MNBN and CBPI levels were observed in mothers compared to newborns. Multiple linear regression analysis revealed an increase of MNMONO frequencies in newborns with mother's BMI and a decrease with gestational age.
In conclusion, our results indicate that special attention regarding preterm newborns and gestational age is needed since they might be more susceptible for both in utero and in vitro exposure. Moreover, we observed that the genotoxic response of term newborns might be depending on the origin of the mutagen and thereby induced DNA damage. These findings should be confirmed in a larger study population combining transgenerational genetic and/or epigenetic effects, antioxidant levels, genotypes, repair enzyme efficiency/levels.