Transplacental cisplatin exposure induces persistent fetal mitochondrial and genomic DNA damage in patas monkeys.
A previous attempt to model transplacental cisplatin exposure and genotoxicity employed several pregnant Erythrocebus patas monkeys; most of the animals were exposed near the end of gestation and cisplatin-DNA adduct analyses included only genomic DNA. Here, both genomic and mitochondrial DNA adduct formation have been determined in fetuses from two pregnant monkeys exposed at the end of the second trimester of gestation. Multiple fetal tissues were obtained after doses of 0.315 mg cisplatin/kg body weight (5.3 mg/m2 total) on days 101 and 106 of gestation. Cesarean sections were performed 24 h after exposure and 27 d after exposure. Cisplatin genomic (g)-DNA adducts were observed in fetal adrenal, brain, heart, kidney, liver, skin, spleen, and thymus. When placentas from the two animals were divided into four concentric regions at increasing distances from the umbilical cord, and g-DNA was assayed, cisplatin DNA adduct levels were similar in all four regions. Mitochondrial (mt)-DNA adducts were higher than g-DNA adducts in maternal liver and fetal liver, brain and kidney, suggesting that the mitochondria may constitute a particular target for cisplatin genotoxicity. The study demonstrates significant fetal genotoxicity in g-DNA and mt-DNA of patas monkeys exposed to cisplatin in utero, suggesting that similarly exposed human fetuses may also sustain drug-induced DNA damage.
Giurgiovich
A J
AJ
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892-4255, USA.
Anderson
L M
LM
Jones
A B
AB
Dove
L F
LF
Moskal
T J
TJ
Rice
J M
JM
Olivero
O A
OA
Poirier
M C
MC
D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage* / Q000633:toxicity*; D018736:DNA Adducts / Q000187:drug effects; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000187:drug effects*; D005314:Embryonic and Fetal Development / Q000187:drug effects* / Q000235:genetics; D004901:Erythrocebus patas; D005260:Female; D008431:Maternal-Fetal Exchange / Q000187:drug effects*; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects
D018736:DNA Adducts; D004272:DNA, Mitochondrial; D002945:Cisplatin