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Perinatal exposure of patas monkeys to antiretroviral nucleoside reverse transcriptase inhibitors induces genotoxicity persistent for up to 3 years of age
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"Taken together the patas and human studies provide a powerful statement for induction of fetal hematopoietic genotoxicity by in utero and perinatal ARV-drug exposures, especially since a 3 year old patas monkey is developmentally-similar to a 14 year old human. It may be important to follow HIV-1-uninfected children, born to HIV-1-infected mothers, long-term to evaluate the potential for persistent genotoxicity."
Perinatal genotoxicity and carcinogenicity of
anti-retroviral nucleoside analog drugs
http://www.natap.org/2012/HIV/081012_02.htm
Long-Term Mitochondrial Toxicity in HIV-Uninfected Infants Born to HIV-Infected Mothers
http://www.natap.org/2003/june/062303_4.htm
Mitochondrial damage and DNA depletion in cord blood and umbilical cord from infants exposed in utero to Combivir
http://www.natap.org/2004/HIV/050304_02.htm
Journal of Infectious Diseases Advance Access published April 6, 2013
Uncorrected Proof
Ofelia A. Olivero1, Lorangelly Rivera Torres1, Sayeh Gorjifard1, Dariya Momot1, Eryney
Marrogi1, Rao L. Divi1,2, Yongmin Liu1, Ruth A. Woodward3, Marsha J. Sowers3 and
Miriam C. Poirier1
1Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, CCR, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD 20892-4255
2Methods and Technologies Branch, Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, Executive Plaza North, Bethesda, MD, 20892-7324 3NIH Animal Center, Shared Animal Faclitiy,16701 Elmer School Rd., Dickerson, MD, 20837
Abstract
Background. Erythrocebus patas (patas) monkeys were used to model use of antiretroviral (ARV) drugs in HIV-1 infected pregnant women.
Methods. Pregnant patas dams were given human-equivalent daily ARV dosing for 50% of gestation. Mesenchymal cells, cultured from bone marrow of patas offspring obtained at birth, 1 and 3 yr of age, were examined for genotoxicity including: centrosomal amplification (CA); micronuclei (MN); and MN containing whole chromosomes (MN+C).
Results. Compared to controls, significant increases (p<0.05) in CA, MN and MN+C were found in most groups of offspring examined at birth, 1 and 3 yr.
Conclusions. Transplacental NRTI exposures induced fetal genotoxicity persistent for 3 yr.
INTRODUCTION
Antiretroviral (ARV) drug combinations provide a highly-successful approach for preventing the transmission of HIV-1/AIDS [1] in approximately 99% of the 10,000 HIV-1-infected women who become pregnant yearly in the United States. The nucleoside reverse transcriptase inhibitors (NRTIs) are major components of the ARV combinations in clinical use. In addition, they become incorporated into nuclear and mitochondrial DNA of the host, resulting in arrest of viral DNA replication [2], chromosome damage [3-5] and genomic instability [6].
Transplacental studies in mice showed incorporation of AZT into fetal organ DNA, mutagenesis, and tumor induction in the offspring [4, 7, 8]. Patas monkeys, born to pregnant dams receiving AZT, had AZT-DNA incorporation in nuclear and mitochondrial DNA of multiple organs [5] that was similar in magnitude to that observed in cord blood and umbilical cord DNA of human fetuses [2]. Furthermore, NRTI-induced mutagenicity was reported in human infants exposed in utero and during the perinatal period [2, 9], suggesting that these infants may be at risk for cancer induction [10].
To observe the fetal consequences of NRTI use in human pregnancy we employed pregnant patas dams exposed to clinically-relevant ARV drug combinations in human-equivalent protocols. Some of the offspring were taken at birth and others were given the same drugs for the first 6 weeks of life, and taken at 1 and 3 years of age. The patas placentation and NRTI pharmacokinetics are similar to those found in humans [11], and because the patas cannot be infected with simian immunodeficiency virus, drug effects can be examined in the absence of virus.
DISCUSSION
Here we have shown, using an ex vivo approach, that genomic instability and chromosome loss, induced in patas monkey bone marrow by in utero and perinatal exposure to human-equivalent protocols of ARV drugs, is persistent up to 3 years of age and can be revealed by measuring biomarkers of genotoxicity. The data showed significantly-increased levels of %CA, %MN and %MN+C in most ARV drug-exposed groups, compared to unexposed animals, at birth, 1 and 3 years of age. The damage in 1 and 3 year old patas, where the drug combinations were given in utero and for the first 6 weeks of life, revealed the persistence of this damage over time. Overall, these experiments reveal that, in addition to the direct mutagenic effects caused by NRTI-DNA incorporation, the NRTIs damage DNA indirectly by producing centrosomal and spindle abnormalities resulting in aneuploidy.
These patas transplacental studies have been designed to model human clinical protocols, and the daily doses given are close, although for 3TC and NVP the duration of exposure was shortened to 4 wk instead of 10 wk. Interestingly, the companion paper to this study, by Andre-Schmutz et al. [15] describes karyotyping of cord blood CD34- cells from ARV-exposed and unexposed infants, in which significantly more aneuploid cells were found in ARV-exposed infants born to HIV-1-infected mothers, than in unexposed infants from uninfected pregnancies. Taken together the patas and human studies provide a powerful statement for induction of fetal hematopoietic genotoxicity by in utero and perinatal ARV-drug exposures, especially since a 3 year old patas monkey is developmentally-similar to a 14 year old human. It may be important to follow HIV-1-uninfected children, born to HIV-1-infected mothers, long-term to evaluate the potential for persistent genotoxicity.
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