Genotoxicity and mitochondrial toxicity of antiretroviral NRTI and PI drugs

Poirier, Miriam C.

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.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIABC010770-10
• Application #: 9343693
• Support Year: 10
• Fiscal Year: 2016

Institution

• Name: Basic Sciences

Publications

Liu, Yongmin; Shim Park, Eunwoo; Gibbons, Alexander T et al. (2016) Mitochondrial compromise in 3-year old patas monkeys exposed in utero to human-equivalent antiretroviral therapies. Environ Mol Mutagen 57:526-34

Poirier, Miriam C; Gibbons, Alexander T; Rugeles, Maria T et al. (2015) Fetal consequences of maternal antiretroviral nucleoside reverse transcriptase inhibitor use in human and nonhuman primate pregnancy. Curr Opin Pediatr 27:233-9

Liu, Yongmin; Shim, Eunwoo; Crespo-Mejias, Yasmin et al. (2015) Cardiomyocytes are Protected from Antiretroviral Nucleoside Analog-Induced Mitochondrial Toxicity by Overexpression of PGC-1?. Cardiovasc Toxicol 15:224-31

Olivero, Ofelia A; Ongele, Michael O; Braun, Hannan M et al. (2014) Selective protection of zidovudine-induced DNA-damage by the antioxidants WR-1065 and tempol. Environ Mol Mutagen 55:566-72

Herman, Eugene H; Knapton, Alan; Liu, Yongmin et al. (2014) The influence of age on serum concentrations of cardiac troponin I: results in rats, monkeys, and commercial sera. Toxicol Pathol 42:888-96

Onwuamah, Chika K; Ekama, Sabdat O; Audu, Rosemary A et al. (2014) Exposure of Allium cepa root cells to zidovudine or nevirapine induces cytogenotoxic changes. PLoS One 9:e90296

Liu, Yongmin; Shim, Eunwoo; Nguyen, Phuonggiang et al. (2014) Tempol protects cardiomyocytes from nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity. Toxicol Sci 139:133-41

Olivero, Ofelia A; Torres, Lorangelly Rivera; Gorjifard, Sayeh et al. (2013) Perinatal exposure of patas monkeys to antiretroviral nucleoside reverse-transcriptase inhibitors induces genotoxicity persistent for up to 3 years of age. J Infect Dis 208:244-8

Liu, Yongmin; Nguyen, Phuonggiang; Baris, Tara Z et al. (2012) Molecular analysis of mitochondrial compromise in rodent cardiomyocytes exposed long term to nucleoside reverse transcriptase inhibitors (NRTIs). Cardiovasc Toxicol 12:123-34

Torres, Salina M; March, Thomas H; Carter, Meghan M et al. (2010) In utero exposure of female CD-1 Mice to AZT and/or 3TC: I. Persistence of microscopic lesions in cardiac tissue. Cardiovasc Toxicol 10:37-50