Cisplatin exposure induces mitochondrial toxicity in pregnant rats and their fetuses

High levels of cis-diamminedicholorplatinum II (cisplatin)-DNA adducts have previously been observed at term in mitochondrial DNA (mtDNA) from organs of pregnant rats, and from their offspring, after administration of a singl e injection of cisplatin 15 mg/kg body weight (bw) to the pregnant rat on d ay 18 of gestation. The consequences of such DNA damage may be clinically r elevant as cisplatin is given to pregnant women discovered to have ovarian cancer during pregnancy. In this study, kidneys, livers, and brains of expo sed pregnant rats and their offspring were examined for mitochondrial funct ional integrity. Consistent with previous literature, the most severe toxic ity occurred in maternal kidney, where oxidative phosphorylation (OXPHOS) e nzyme activities were significantly (similar to 50%) impaired for Complexes II, III, and IV, mtDNA levels in drug-exposed animals were higher than in the unexposed controls, and abnormal mitochondrial morphology was observed by transmission electron microscopy (TEM). In fetal kidneys and livers, cis platin exposure did not alter mitochondrial morphology or mtDNA quantity, b ut specific activities of OXPHOS Complexes II and IV were significantly dec reased. Fetal brain sustained no discernible mitochondrial toxicity. Theref ore, cisplatin-induced mitochondrial toxicity in maternal rat kidney is sev ere, while damage to mitochondria in fetal kidney and liver, occurring as a result of the transplacental drug exposure, appears to be mild. (C) 2001 E lsevier Science Inc. All rights reserved.