Cisplatin-DNA adduct formation in maternal and fetal rat tissues after transplacental cisplatin exposure

Abstract

Cis-diamminedichloroplatinum (II) (cisplatin), given to pregnant rats at 5 mg/kg body weight (bw) is a trans placental carcinogen for fetal liver, kidney, nervous system and lung, resulting in tumor incidences of 22.5, 10.5, 6.1 and 7.5% respectively, in offspring grown to adulthood (B.A. Diwan et al., 1995, Toxicol. Appl. Pharm., 132, 115). In this study, the capacity of cisplatin to pass through the placental barrier and bind covalently to DNA in maternal and fetal tissues was evaluated. Pregnant F344/NCr rats were injected i.p. with single doses of 5, 10 or 15 mg cisplatin/kg bw at 18 days of gestation and sacrificed 24 h later. Cisplatin-DNA adducts were determined by dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA) using both High (90 pmol/micrograms DNA) and Low (0.50 pmol/ microgram DNA) Modified cisplatin-DNA standards and atomic absorbance spectrometry (AAS). The adduct quantities determined by the two DELFIAs varied in concert, but the DELFIA with Low Modified standard gave actual values similar to those observed with AAS. In maternal and fetal tissues, with the exception of placenta in one experiment and maternal kidney in another experiment, the extent of cisplatin-DNA adduct formation increased with dose. In maternal kidney, the low adduct levels observed at the 15 mg/kg dose may reflect kidney toxicity. Fetal kidney, liver and lung contained fewer cisplatin-DNA adducts than the corresponding maternal tissues. In contrast, at 5 and 15 mg/kg, fetal brain DNA contained higher adduct levels than maternal brain DNA. This study demonstrates the presence of DNA damage induced by cisplatin in multiple maternal and fetal rat tissues at tumorigenic doses of drug; the results are therefore consistent with the hypothesis that genotoxic mechanisms play an important role in the drug-induced tumor incidence.