Comparison of the Effects of Three Dual-Nucleos(t)ide Reverse Transcriptase Inhibitor Backbones on Placenta Mitochondria Toxicity and Oxidative Stress Using a Mouse Pregnancy Model

Abstract

Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are the backbone of HIV antiretroviral therapy (ART). ART use in pregnancy has been associated with adverse birth outcomes, in part due to NRTI-induced mitochondrial toxicity. Direct comparison on the effects of commonly used dual-NRTI regimens on placental mitochondria toxicity in pregnancy is lacking. We compared zidovudine/lamivudine, abacavir/lamivudine, and tenofovir/emtricitabine using a mouse model and examined markers of placental mitochondrial function and oxidative stress. Zidovudine/lamivudine and abacavir/lamivudine were associated with lower fetal and placental weights compared to controls, whereas tenofovir/emtricitabine was associated with the least fetal and placental weight reduction, as well as lower resorption rates. Placental mitochondrial DNA content, as well as placental expression of cytochrome c-oxidase subunit-II, DNA polymerase gamma, and citrate synthase, was higher in tenofovir/emtricitabine-treated mice compared to other groups. Zidovudine/lamivudine-treated mice had elevated malondialdehyde levels (oxidative stress marker) compared to other groups and lower mRNA levels of manganese superoxide dismutase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in the placenta compared to tenofovir/emtricitabine-treated mice. We observed differences in effects between NRTI regimens on placental mitochondrial function and birth outcomes. Tenofovir/emtricitabine was associated with larger fetuses, increased mtDNA content, and higher expression of mitochondrial-specific antioxidant enzymes and mitochondrial biogenesis enzymes, whereas zidovudine/lamivudine was associated with markers of placental oxidative stress.