Genotoxic and Functional Consequences of Transplacental Zidovudine Exposure in Fetal Monkey Brain Mitochondria

Abstract

Mitochondrial toxicity was assessed in the brains of developing Erythrocebus patas monkey fetuses exposed in utero to the nucleoside analogue drug zidovudine (3'-azido-3'deoxythymidine or AZT). Pregnant E. patas monkeys were given 0 (n = 5), 10 (n = 3), and 40 (n = 3) mg of AZT/day, equivalent to 21 and 86% of the human daily dose, for the last half (about 10 weeks) of gestation. Mitochondria were isolated from fetal cerebrum and cerebellum at birth and mitochondrial morphology was examined in these tissues by transmission electron microscopy (TEM). Oxidative phosphorylation (OXPHOS) enzyme specific activities were measured spectrophotometrically. Mitochondrial DNA (mtDNA) integrity and quantity were determined by Southern blot and slot blot analysis. In the cerebral mitochondria, reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase (complex I) specific activity decreased by 25% in monkeys treated with 40 mg of AZT/day compared with unexposed monkeys (p > or = .05). At the same AZT dose in the cerebral mitochondria, succinate dehydrogenase (complex II) and cytochrome c reductase (complex IV)-specific activities showed dose-dependent increases (p > or = .05), compared with those in controls. In the cerebellum, no difference was seen in mitochondrial OXPHOS enzyme activities between unexposed and exposed fetuses. Furthermore, TEM demonstrated no difference in mitochondrial morphology in frontal cerebrum or cerebellum from unexposed and exposed fetuses, and all fetuses had similar amounts of mtDNA in both tissues. Cerebral mtDNA degradation was noted in the highest AZT dosage group, whereas mtDNA from cerebellum was uneffected. Thus, in fetal patas monkeys given a human equivalent daily dose of AZT during the last half of pregnancy, mitochondria in the fetal cerebrum appear to sustain moderate damage, while the fetal cerebellum mitochondria were not effected.

Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage

“…Furthermore, similar to HIV-1 gp120, the earliest antiretroviral drug, AZT, has been shown to impair neurogenesis (79-81), besides affecting cerebrocortical mitochondria (82). Efavirenz (EFV) and NVP, which are currently FDA approved and used in NNRTI regimens (http://aidsinfo.nih.gov/guidelines), have been suggested to exert neurotoxicity (14,62,83).…”

Increased mtDNA Levels Without Change in Mitochondrial Enzymes in Peripheral Blood Mononuclear Cells of Infants Born to HIV-Infected Mothers on Antiretroviral Therapy

“…2 A similar potential for mitochondrial toxicity from in utero exposure to ARV therapy has been suggested by primate studies, in which dose-related fetal abnormalities in mitochondrial structure and function have been reported in skeletal muscle, cardiac muscle, and brain. 3,4 Although transient hyperlactatemia is common in infants perinatally exposed to ARV therapy, 5,6 only rare cases of symptomatic hyperlactatemia have been reported. In these cases of lactic acidosis, the central nervous system was involved frequently and seems to be particularly vulnerable to mitochondrial insults.…”

Histochemical Changes in the Cerebellum of Wistar Rats Administered with Oral Doses of Zidovudine

“…In another study, mitochondrial DNA was observed to be damaged in liver tissues [27]. In yet another study of prenatal exposure of 40 mg/day of ZDV in inpatas monkeys showed damage of cerebral mitochondria [28]. Neurobehavioural changes reported by different authors, revealed the cerebral effect of ZDV [29][30][31].…”