Cardiac Mitochondrial Compromise in 1-Yr-Old <I>Erythrocebus patas</I> Monkeys Perinatally- Exposed to Nucleoside Reverse Transcriptase Inhibitors

Abstract

Hearts from 1-yr-old Erythrocebus patas monkeys were examined after in utero and 6-wk-postbirth exposure to antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs). Protocols were modeled on those given to human immunodeficiency virus (HIV)-1-infected pregnant women. NRTIs were administered daily to the dams for the last 20% or 50% of gestation, and to the infants for 6 wk after birth. Exposures included: no drug (n = 4); Zidovudine, 3'-azido-3'-deoxythymidine (AZT; n = 4); AZT/Lamivudine, (-)-beta-L-2', 3'-Dideoxy-3'-thiacytidine (Epivir, 3TC) (n = 4); AZT/Didanosine (Videx, ddI) (n = 4); and Stavudine (Zerit, d4T)/3TC (n = 4). Echocardiograms and clinical chemistry showed no drug-related changes, but the d4T/3TC-exposed fetuses at 6 and 12 mo had increased white cell counts (p < 0.05). At 1 yr of age, oxidative phosphorylation (OXPHOS) enzyme activities were similar in heart mitochondria from all groups. Mitochondrial pathology, that included clones of damaged mitochondria (p < 0.05), was found in hearts of all 1-yr drug-exposed infants. Levels of mtDNA were elevated (p < 0.05) in hearts of all NRTI-exposed monkeys in the following order: control < d4T/3TC < AZT < AZT/3TC < AZT/ddI. The clinical status of NRTI-exposed infants, as evidenced by behavior, clinical chemistry, OXPHOS activity and echocardiogram, was normal. However, extensive mitochondrial damage with clusters of similar-appearing damaged heart mitochondria observed by electron microscopy, and an increase in mtDNA quantity, that persisted at 1 yr of age, suggest the potential for cardiotoxicity later in life.

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

“…Subsequently, the tissue pieces were processed for EM as described previously [Divi et al, 2005]. Thin sections were stained with uranyl acetate and lead citrate (EM Stain, Leica, Bannockburn, IL), and observed and photographed at 10,0003 magnification with an electron microscope (H7000; Hitachi, Tokyo, Japan) operated at 75 kV.…”

“…The procedure for HC-CIA was essentially the same as that described previously [Divi et al, 2005]. Briefly, sample DNA was coupled to Digoxigenin (DIG)-Chem-Link (Roche, Indianapolis, IN) at 858C for 30 min, and the resulting DIG-DNA was collected by centrifugation and sonicated (15 sec at 20% amplitude; Ultrasonic Processor, Sonics and Materials, Thomas Scientific, Swedesboro, NJ) before denaturation at 958C for 3 min.…”

“…Pregnant women and monkey dams were either unexposed or given NRTIs during a substantial fraction of the infants' development. The drug-exposed monkeys were born to immunodeficiency retrovirus-free dams [Divi et al, 2005], while the drugexposed human infants were born to HIV-1-infected mothers . In this report, an interspecies comparison of mitochondrial integrity was possible because umbilical cords and cord blood leukocytes were available from both species.…”

Neurologic Outcomes in HIV-Exposed/Uninfected Infants Exposed to Antiretroviral Drugs During Pregnancy in Latin America and the Caribbean

“…Of particular interest is the impact of ARV exposure on neurologic outcomes in HEU infants. Concerns about toxicity related to zidovudine (ZDV) from in vitro animal 1,2 and adult human studies predated the landmark Pediatric AIDS Clinical Trials Group (PACTG) 076 trial. 3 These concerns became more prominent with the results from the French Perinatal Cohort Study (FPCS) that reported eight (0.3%) cases of established or possible mitochondrial dysfunction (MD) among nearly 1,800 ARV-exposed HEU infants in contrast to zero cases among an approximately equal number of ARV-unexposed HEU infants.…”

Tolérance pour l’enfant des antirétroviraux durant la grossesse

“…On sait maintenant que l'inhibition de la gamma polymérase mitochondriale n'est pas le seul mécanisme en cause et que la zidovudine induit aussi des altérations qualitatives de l'ADN mitochondrial [15]. Chez le singe nouveau-né exposé in utero, des différences quantitatives et qualitatives sont constatées dans différents tissus, en comparaison avec des singes témoins [16]. Les données humaines sont plus difficiles à interpréter et encore discordantes.…”