Progressive Mitochondrial Compromise in Brains and Livers of Primates Exposed In Utero to Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• DOI: 10.1093/toxsci/kfq235
• Publication Date: 2010-08-12T02:14:14Z
• Authors: Rao L. Divi; Tracey L. Einem; Sarah L. Leonard ...; Marie E. Shockley; Maryanne M. Kuo; Marisa C. St Claire; Anthony Cook; Kunio Nagashima; Steven W. Harbaugh; Jeffrey W. Harbaugh; Miriam C. Poirier
• Keywords: Mitochondrial toxicity; Reverse-transcriptase inhibitor

Mitochondrial compromise has been documented in infants born to women infected with the human immunodeficiency virus (HIV-1) who received nucleoside reverse transcriptase inhibitor (NRTI) therapy during pregnancy. To model these exposures, we examined mitochondrial integrity at birth and 1 year brain cortex liver from offspring of retroviral-free Erythrocebus patas dams-administered human-equivalent NRTI doses for last half (10 weeks) gestation. Additional infants, followed year, were given same drugs as their mothers first 6 weeks life. Exposures included: no drug, Zidovudine (AZT), Lamivudine (3TC), AZT/3TC, AZT/Didanosine (ddI), Stavudine (d4T)/3TC. In liver, oxidative phosphorylation (OXPHOS) enzyme activities (complexes I, II, IV) showed minimal differences between unexposed NRTI-exposed both times. Brain mitochondria most patas, age, contained significant (p< 0.05) morphological damage observed by electron microscopy (EM), based on scoring coded photomicrographs. DNA (mtDNA) levels depleted significantly 3TC d4T/3TC groups all groups. 1-year-old exposed utero NRTIs, mtDNA depletion was 28.8–51.8% 37.4–56.5% liver. These investigations suggest that some may sustain similar should be long term cognitive function.