title: Interaction between cadmium and aromatic DNA adducts in hprt mutagenesis during foetal development.
abstract: 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/10(8) 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.
authors.affiliation: Department of Health Risk Analysis and Toxicology, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. R.Godschalk@GRAT.unimaas.nl
authors.forename: Roger
authors.initials: R
authors.lastname: Godschalk
authors.forename: Janneke
authors.initials: J
authors.lastname: Hogervorst
authors.forename: Harma
authors.initials: H
authors.lastname: Albering
authors.forename: Patricia
authors.initials: P
authors.lastname: Mercelina-Roumans
authors.forename: Frederik-Jan
authors.initials: FJ
authors.lastname: van Schooten
authors.forename: Jelte
authors.initials: J
authors.lastname: de Haan
authors.forename: Jos
authors.initials: J
authors.lastname: Kleinjans
mesh_terms: D002104:Cadmium / Q000097:blood / Q000633:toxicity*; D018736:DNA Adducts / Q000097:blood*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D047109:Fetal Development / Q000187:drug effects* / Q000235:genetics; D017930:Genes, Reporter; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D007231:Infant, Newborn; D008214:Lymphocytes / Q000737:chemistry / Q000201:enzymology; D008431:Maternal-Fetal Exchange / Q000187:drug effects / Q000502:physiology; D019216:Metals, Heavy / Q000097:blood / Q000633:toxicity*; D016296:Mutagenesis; D009154:Mutation; D011247:Pregnancy; D012907:Smoking / Q000378:metabolism
chemical_list: D018736:DNA Adducts; D019216:Metals, Heavy; D002104:Cadmium; D007041:Hypoxanthine Phosphoribosyltransferase