title: Mitochondrial compromise in 3-year old patas monkeys exposed in utero to human-equivalent antiretroviral therapies.
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. Here we have 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 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 < 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 < 0.01), but not in AZT/3TC/NVP-exposed patas. Overall the data show that 3-year-old patas sustain persistent mitochondrial dysfunction as a result of perinatal ARV drug exposure. Environ. Mol. Mutagen. 57:526-534, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, Bethesda, Madison.
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, Bethesda, Madison.
authors.forename: Eunwoo
authors.initials: E
authors.lastname: Shim Park
authors.affiliation: Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, Bethesda, Madison.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Gibbons
authors.affiliation: Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, Bethesda, Madison.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Shide
authors.affiliation: Methods and Technologies Branch, DCCPS, National Cancer Institute, NIH, Bethesda, Madison.
authors.forename: Rao L
authors.initials: RL
authors.lastname: Divi
authors.affiliation: Shared Animal Facility, NIH Animal Center, Dickerson, Madison.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Woodward
authors.affiliation: Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, Bethesda, Madison.
authors.forename: Miriam C
authors.initials: MC
authors.lastname: Poirier
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D004272:DNA, Mitochondrial / Q000032:analysis* / Q000235:genetics; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000633:toxicity; D004359:Drug Therapy, Combination; D004901:Erythrocebus patas; D005260:Female; D005865:Gestational Age; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D019259:Lamivudine / Q000008:administration & dosage / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D008929:Mitochondria, Heart / Q000187:drug effects / Q000235:genetics / Q000648:ultrastructure; D010101:Oxygen Consumption / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D015215:Zidovudine / Q000008:administration & dosage / Q000633:toxicity; D000099227:Abacavir
chemical_list: D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D015224:Dideoxynucleosides; D019259:Lamivudine; D015215:Zidovudine; D000099227:Abacavir
keywords: Seahorse analyzer; abacavir; lamivudine; mitochondrial DNA; nevirapine; zidovudine