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Progressive Mitochondrial Compromise in Brains and Livers of Primates Exposed In Utero to Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

  1. Author:
    Divi, R. L.
    Einem, T. L.
    Fletcher, S. L. L.
    Shockley, M. E.
    Kuo, M. M.
    St Claire, M. C.
    Cook, A.
    Nagashima, K.
    Harbaugh, S. W.
    Harbaugh, J. W.
    Poirier, M. C.

  2. Author Address

    [Divi, Rao L.; Einem, Tracey L.; Fletcher, Sarah L. Leonard; Shockley, Marie E.; Kuo, Maryanne M.; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [St Claire, Marisa C.] NIAID, Div Clin Res, NIH, Frederick, MD 21702 USA. [Cook, Anthony; Harbaugh, Steven W.; Harbaugh, Jeffrey W.] Bioqual Inc, Rockville, MD 20850 USA. [Nagashima, Kunio] Sci Applications Int Corp Frederick, Electron Microscope Lab, Natl Canc Inst Frederick, Adv Technol Program, Ft Detrick, MD 21702 USA.;Poirier, MC, NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bldg 37,Room 4032,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA.;divir@exchange.nih.gov
    1. Year: 2010
    2. Date: Nov
  2. Journal: Toxicological Sciences
    1. 118
    2. 1
    3. Pages: 191-201
  4. Type of Article: Article
  5. ISSN: 1096-6080
  1. Abstract:

    Mitochondrial compromise has been documented in infants born to women infected with the human immunodeficiency virus (HIV-1) who received nucleoside reverse transcriptase inhibitor (NRTI) therapy during pregnancy. To model these human exposures, we examined mitochondrial integrity at birth and 1 year in brain cortex and liver from offspring of retroviral-free Erythrocebus patas dams-administered human-equivalent NRTI doses for the last half (10 weeks) of gestation. Additional infants, followed for 1 year, were given the same drugs as their mothers for the first 6 weeks of life. Exposures included: no drug, Zidovudine (AZT), Lamivudine (3TC), AZT/3TC, AZT/Didanosine (ddI), and Stavudine (d4T)/3TC. In brain and liver, oxidative phosphorylation (OXPHOS) enzyme activities (complexes I, II, and IV) showed minimal differences between unexposed and NRTI-exposed offspring at both times. Brain and liver mitochondria from most NRTI-exposed patas, both at birth and 1 year of age, contained significant (p < 0.05) morphological damage observed by electron microscopy (EM), based on scoring of coded photomicrographs. Brain and liver mitochondrial DNA (mtDNA) levels in NRTI-exposed patas were depleted significantly in the 3TC and d4T/3TC groups at birth and were depleted significantly (p < 0.05) at 1 year in all NRTI-exposed groups. In 1-year-old infants exposed in utero to NRTIs, mtDNA depletion was 28.8-51.8% in brain and 37.4-56.5% in liver. These investigations suggest that some NRTI-exposed human infants may sustain similar mitochondrial compromise in brain and liver and should be followed long term for cognitive integrity and liver function.

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External Sources

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  2. DOI: 10.1093/toxsci/kfq235
  3. View record in Web of Science®
  4. WOS: 000283092200021

Library Notes

  1. Fiscal Year: FY2010-2011
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