Transplacentally exposed human and monkey newborn infants show similar evidence of nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity.

Effective reduction in maternal-fetal human immunodeficiency virus-1 (HIV-1) transmission has been achieved by administration of nucleoside reverse transcriptase inhibitors (NRTIs) during pregnancy, and although most exposed children are clinically normal at birth, mitochondrial dysfunction has been reported. To examine mitochondrial integrity on a molecular level, we evaluated mitochondrial morphology by electron microscopy (EM) and mitochondrial DNA (mtDNA) quantity in umbilical cords and cord blood from NRTI-exposed and unexposed human and monkey newborns. Human subjects included infants born to HIV-1-infected mothers who received Combivir (Zidovudine [AZT] plus Lamivudine [3TC]) (n = 9) or AZT plus Didanosine [ddI] (n = 2) during pregnancy, and infants born to HIV-1-uninfected mothers (n = 7). NRTI-exposed Erythrocebus patas monkey dams (n = 3 per treatment group) were given human-equivalent dosing regimens containing 3TC, AZT/3TC, AZT/ddI, or Stavudine (d4T)/3TC during gestation. Four infants born to unexposed patas dams served as controls. Mitochondria in umbilical cord endothelial cells from NRTI-exposed monkey and human infants showed substantial abnormal pathology by EM, the extent of which was quantified from coded photomicrographs and shown to be different (P < 0.05) from the unexposed monkey and human newborns. Significant (P < 0.05) mtDNA depletion was found in umbilical cords from both human and monkey NRTI-exposed infants and in human, but not in monkey, cord blood leukocytes. For umbilical cords, an increase in mitochondrial morphological damage correlated with reduction in mtDNA quantity in fetal monkeys (r = 0.94). The treatment-induced mitochondrial compromise in infant monkeys ranked as follows: d4T/3TC > AZT/ddI > AZT/3TC > 3TC. The study demonstrates that transplacental NRTI exposures induce similar mitochondrial damage in cord blood and umbilical cords taken from retroviral-uninfected monkey infants and from human infants born to HIV-1-infected women.

Divi RL ，Leonard SL ，Kuo MM ，Nagashima K ，Thamire C ，St Claire MC ，Wade NA ，Walker VE ，Poirier MC ... -  《ENVIRONMENTAL AND MOLECULAR MUTAGENESIS》

Erythrocebus patas monkey offspring exposed perinatally to NRTIs sustain skeletal muscle mitochondrial compromise at birth and at 1 year of age.

Divi RL ，Leonard SL ，Walker BL ，Kuo MM ，Shockley ME ，St Claire MC ，Nagashima K ，Harbaugh SW ，Harbaugh JW ，Poirier MC ... -  《-》

Progressive mitochondrial compromise in brains and livers of primates exposed in utero to nucleoside reverse transcriptase inhibitors (NRTIs).

Divi RL ，Einem TL ，Fletcher SL ，Shockley ME ，Kuo MM ，St Claire MC ，Cook A ，Nagashima K ，Harbaugh SW ，Harbaugh JW ，Poirier MC ... -  《-》

Mitochondrial damage and DNA depletion in cord blood and umbilical cord from infants exposed in utero to Combivir.

Divi RL ，Walker VE ，Wade NA ，Nagashima K ，Seilkop SK ，Adams ME ，Nesel CJ ，O'Neill JP ，Abrams EJ ，Poirier MC ... -  《AIDS》

Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine.

Gerschenson M ，Nguyen V ，Ewings EL ，Ceresa A ，Shaw JA ，St Claire MC ，Nagashima K ，Harbaugh SW ，Harbaugh JW ，Olivero OA ，Divi RL ，Albert PS ，Poirier MC ... -  《AIDS RESEARCH AND HUMAN RETROVIRUSES》