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 single injection of cisplatin 15 mg/kg body weight (bw) to the pregnant rat on day 18 of gestation. The consequences of such DNA damage may be clinically relevant as cisplatin is given to pregnant women discovered to have ovarian cancer during pregnancy. In this study, kidneys, livers, and brains of exposed pregnant rats and their offspring were examined for mitochondrial functional integrity. Consistent with previous literature, the most severe toxicity occurred in maternal kidney, where oxidative phosphorylation (OXPHOS) enzyme activities were significantly (approximately 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, cisplatin exposure did not alter mitochondrial morphology or mtDNA quantity, but specific activities of OXPHOS Complexes II and IV were significantly decreased. Fetal brain sustained no discernible mitochondrial toxicity. Therefore, cisplatin-induced mitochondrial toxicity in maternal rat kidney is severe, while damage to mitochondria in fetal kidney and liver, occurring as a result of the transplacental drug exposure, appears to be mild.
Gerschenson
M
M
Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
Paik
C Y
CY
Gaukler
E L
EL
Diwan
B A
BA
Poirier
M C
MC
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000201:enzymology / Q000648:ultrastructure; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004272:DNA, Mitochondrial / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000196:embryology / Q000201:enzymology / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000201:enzymology / Q000648:ultrastructure; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D002945:Cisplatin