Exploratory studies revealed that AZT exposure down-regulated the microRNA hsa-miR-770-5p in the mammary epithelial cell line MCF10A. We therefore chose to study the hsa-miR-770-5p target gene Stathmin1 (STMN1), because the concomitant upregulation of this gene would cause microtubule erosion and mitotic spindle destabilization. Our previous studies showed that, after exposure to AZT, about 25% of normal human mammary epithelial cells (NHMECs) lacked the ability to polymerize microtubules. We performed reverse transfections to introduce overexpression of hsa-miR-770-5p (defined as mimic) and inhibition of hsa-miR-770 (defined as inhibitor) in MCF10A cells. We found that STMN1 RNA expression increased when hsa-miR-770-5p levels were very low, and confirmed this finding by Western blot. Therefore, down-regulation of hsa-miR-770-5p caused an increase in STMN1 expression, suggesting that AZT-induced genomic instability may occur through dysregulation of STMN1 and tubulin erosion. The manuscript is in progress. Monkey studies Truvada, the combination of a protease inhibitor tenofovir, and an NRTI emtricitabine, is used increasingly in human pregnancy and also for pre-exposure prophylaxis in non-HIV-1-infected adults. We currently have 3-4 monkeys taken at birth after in utero exposure to truvada, and are analyzing these for genotoxicity and mitochondrial toxicity. We are interested in examining agents that might protect heart and brain from toxicities induced by NRTI therapy. Previously we showed that Tempol and Tempol-H protect mitochondria of cultured cardiomyocytes from NRTI-induced damage. Currently we are analyzing at birth offspring of patas dams given no drugs, AZT/3TC alone, AZT/3TC/Tempol or Tempol alone. Analysis of heart tissue EMs has demonstrated that infants given AZT/3TC/Tempol are protected from mitochondrial damage seen with AZT/3TC. Examination of brain and bone marrow cells is in progress.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010770-12
Application #
9779702
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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

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