In utero exposure of female CD-1 mice to AZT and/or 3TC: II. Persistence of functional alterations in cardiac tissue.
To delineate temporal changes in the integrity and function of mitochondria/cardiomyocytes in hearts from mice exposed in utero to commonly used nucleoside analogs (NRTIs), CD-1 mice were exposed in utero to 80 mg AZT/kg, 40 mg 3TC/kg, 80 mg AZT/kg plus 40 mg 3TC/kg, or vehicle alone during days 12-18 of gestation and hearts from female mouse offspring were examined at 13 and 26 weeks postpartum. Alterations in cardiac mitochondrial DNA (mtDNA) content, oxidative phosphorylation (OXPHOS) enzyme activities, mtDNA mutations, and echocardiography of NRTI-exposed mice were assessed and compared with findings in vehicle-exposed control mice. A hybrid capture-chemiluminescence assay showed significant twofold increases in mtDNA levels in hearts from AZT- and AZT/3TC-exposed mice at 13 and 26 weeks postpartum, consistent with near doubling in mitochondrial numbers over time compared with vehicle-exposed mice. Echocardiographic measurements at 13 and 26 weeks postpartum indicated progressive thinning of the left ventricular posterior wall in NRTI-exposed mice, relative to controls, with differences becoming statistically significant by 26 weeks. Overall, progressive functional changes occurred in mouse mitochondria and cardiac tissue several months after in utero NRTI exposures; AZT and 3TC acted in concert to cause additive cardiotoxic effects of AZT/3TC compared with either drug alone.
Torres
Salina M
SM
College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA.
Divi
Rao L
RL
Walker
Dale M
DM
McCash
Consuelo L
CL
Carter
Meghan M
MM
Campen
Matthew J
MJ
Einem
Tracey L
TL
Chu
Yvonne
Y
Seilkop
Steven K
SK
Kang
Huining
H
Poirier
Miriam C
MC
Walker
Vernon E
VE
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D004272:DNA, Mitochondrial / Q000032:analysis / Q000187:drug effects; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004452:Echocardiography; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000254:growth & development / Q000503:physiopathology; D019259:Lamivudine / Q000633:toxicity*; D008163:Luminescent Measurements / Q000379:methods; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D051379:Mice; D008815:Mice, Inbred Strains; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D010085:Oxidative Phosphorylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology; D013997:Time Factors; D015215:Zidovudine / Q000633:toxicity*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D045222:Electron Transport Chain Complex Proteins; D019259:Lamivudine; D015215:Zidovudine