ZIA BC 010770 (ZIA) | |||
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Title | Genotoxicity and mitochondrial toxicity of antiretroviral NRTI and PI drugs | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Poirier, Miriam | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $353,872 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Biochemical Epidemiology (100.0%) Cancer (100.0%) Chemoprevention (40.0%) Chemotherapy (50.0%) Digestive Diseases (10.0%) |
Leukemia (20.0%) Liver Cancer (10.0%) Lung (20.0%) Uterine (30.0%) Vaginal (20.0%) |
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Research Type | |||
Exogenous Factors in the Origin and Cause of Cancer Chemoprevention |
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Abstract | |||
Antiretroviral (ARV) drug therapy, given during pregnancy for prevention of mother-to-child transmission of human immunodeficiency virus 1 (HIV-1), induces fetal mitochondrial dysfunction in some children. However the persistence/reversibility of that dysfunction is unclear. We followed Erythrocebus patas (patas) monkey offspring for up to 3 years of age (similar in development to a 15 year old human) after exposure of the dams to human-equivalent in utero ARV exposure protocols. Pregnant patas dams (3-5/exposure group) were given ARV drug combinations that included zidovudine (AZT) / lamivudine (3TC) / abacavir (ABC), or AZT / 3TC / nevirapine (NVP), for the last 10 weeks (50%) of gestation. Infants kept for 1 and 3 years also received drug for the first 6 weeks of life. In offpsring at birth, 1 year and 3 years of age mitochondrial morphology, examined by electron microscopy (EM), was compromised compared to the unexposed controls. Mitochondrial DNA (mtDNA), measured by Hybrid Capture Chemiluminescence Assay (HCCA) was depleted in hearts of patas exposed to AZT/3TC/NVP at all ages (p less than 0.05), but not in those exposed to AZT/3TC/ABC at any age. Compared to unexposed controls, mitochondrial reserve capacity oxygen consumption rate (OCR by Seahorse) in cultured bone marrow mesenchymal fibroblasts from 3 year old patas offspring was ~50% reduced in AZT/3TC/ABC-exposed patas (p less than 0.01), but not in AZT/3TC/NVP-exposed patas. Overall the data show that three year old patas sustain persistent mitochondrial dysfunction as a result of perinatal ARV drug exposure. |