Cardiac mitochondrial compromise in 1-yr-old Erythrocebus patas monkeys perinatally-exposed to nucleoside reverse transcriptase inhibitors
| Autor: | Rao L, Divi, Sarah L, Leonard, Maryanne M, Kuo, Brettania L, Walker, Christine C, Orozco, Marisa C, St Claire, Kunio, Nagashima, Steven W, Harbaugh, Jeffrey W, Harbaugh, Chandrasekhar, Thamire, Craig A, Sable, Miriam C, Poirier |
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| Rok vydání: | 2005 |
| Předmět: |
DNA
DNA Mitochondrial Mitochondria Heart Ventricular Function Left Electrocardiography Leukocyte Count Animals Newborn Microscopy Electron Transmission Echocardiography Pregnancy Luminescent Measurements Image Processing Computer-Assisted Animals Reverse Transcriptase Inhibitors Female Lactic Acid Erythrocebus Creatine Kinase |
| Zdroj: | Cardiovascular toxicology. 5(3) |
| ISSN: | 1530-7905 |
| Popis: | 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 (p0.05). 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 (p0.05), was found in hearts of all 1-yr drug-exposed infants. Levels of mtDNA were elevated (p0.05) in hearts of all NRTI-exposed monkeys in the following order: controld4T/3TCAZTAZT/3TCAZT/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. |
| Databáze: | OpenAIRE |
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