Interaction between cadmium and aromatic DNA adducts in hprt mutagenesis during foetal development

• Published in: Mutagenesis Vol. 20; no. 3; pp. 181 - 185
• Main Authors: Godschalk, Roger, Hogervorst, Janneke, Albering, Harma, Mercelina-Roumans, Patricia, van Schooten, Frederik-Jan, de Haan, Jelte, Kleinjans, Jos
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2005; Oxford Publishing Limited (England)
• Subjects: Atomic absorption spectroscopy; Biological and medical sciences; Cadmium; Cadmium - blood; Cadmium - toxicity; Deoxyribonucleic acid; DNA; DNA Adducts - blood; DNA Repair - drug effects; DNA Repair - genetics; Female; Fetal Blood - chemistry; Fetal Development - drug effects; Fetal Development - genetics; Fundamental and applied biological sciences. Psychology; Genes, Reporter; Heavy metals; Humans; Hypoxanthine Phosphoribosyltransferase - genetics; Infant, Newborn; Lymphocytes; Lymphocytes - chemistry; Lymphocytes - enzymology; Maternal-Fetal Exchange - drug effects; Maternal-Fetal Exchange - physiology; Metals, Heavy - blood; Metals, Heavy - toxicity; Molecular and cellular biology; Molecular genetics; Mutagenesis; Mutagenesis. Repair; Mutation; Neonates; Pregnancy; Smoking; Smoking - metabolism; Spectral analysis; Spectrometry; Synergistic effect; Xenobiotics; Cadmium; Mutagenesis; Enzyme; Transferases; Glycosyltransferases; Development; Hypoxanthine phosphoribosyltransferase; Pentosyltransferases; Molecular adduct
• ISSN: 0267-8357; 1464-3804
• DOI: 10.1093/mutage/gei022

The foetus is exposed to multiple xenobiotics through the mother's circulation and this is possibly involved in the development of diseases in later life. Heavy metals and lipophilic genotoxins in umbilical cord blood of newborns may have synergistic effects on mutagenesis in the hypoxanthine-phosphoribosyltransferase (HPRT) reporter gene. Concentrations of zinc (Zn), lead (Pb) and cadmium (Cd) were determined in the peripheral and cord blood of 16 non-smoking and 9 smoking healthy mothers by atomic absorption spectrometry. Lipophilic DNA adducts in lymphocytes were determined in the same subjects by 32P-postlabelling and the HPRT-variant frequency was assessed by the evaluation of 6-thioguanine resistant cells. Although the Cd/Zn ratio was 2.5-fold higher in the blood of smoking women than in non-smoking women (1.0 ± 0.2 and 0.4 ± 0.1, respectively, P = 0.007), this difference could not be observed in umbilical cord blood (0.3 ± 0.1 and 0.3 ± 0.1, respectively, P = 0.66). Similarly, mean DNA adduct levels were increased in the lymphocytes of smoking women compared with non-smoking controls (0.99 ± 0.31 adducts/108 nt and 0.43 ± 0.12, respectively, P = 0.009), but were only marginally higher in the neonates of smokers than in their non-smoking counterparts (0.57 ± 0.29 and 0.24 ± 0.09, respectively, P = 0.38). Since Cd is known to effectively inhibit DNA repair, we hypothesized that concomitant exposure of neonates to Cd and genotoxic compounds may result in an increased fixation of DNA damage into somatic mutations. Indeed, the number of HPRT-variants per adduct (i.e. the mutagenic efficiency of adducts) correlated positively with the Cd concentrations in cord blood (r = 0.61, P = 0.001). These data suggest a molecular link between DNA damage, inhibition of DNA repair by Cd and in vivo mutagenesis during foetal development. Thus, exposure to heavy metals may enhance the mutagenic potential of DNA-damaging compounds and results in biologically relevant genotoxic effects in neonates.