Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine
Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine
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DOI：
10.1089/088922204322749530
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发表时间：
2004-01-01
影响因子：
1.5
通讯作者：
Poirier, MC
中科院分区：
文献类型：
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作者：
Gerschenson, M;Nguyen, V;Poirier, MC
本研究旨在探讨齐多夫定（AZT）和拉米夫定（3TC）宫内暴露对红头猴胎儿线粒体的毒性作用。在妊娠的最后10周（50%），对妊娠的patas猴每天给予40 mg AZT（人类每日剂量的86%，基于体重），在妊娠的最后4周，每天给予24 mg 3TC（人类每日剂量的84%，基于体重）。在足月时，发现AZT被掺入来自骨骼肌、肝脏、肾脏和胎盘的胎儿线粒体DNA中。通过透射电子显微镜（EM）的药物暴露的胎儿心脏和骨骼肌细胞表现出线粒体膜妥协，线粒体增殖，和受损的肌节，而在大脑和小脑的线粒体形态正常。与未暴露的胎儿相比，在暴露于药物的胎儿的心脏（平均降低87%，p = 0.02）和骨骼肌（平均降低98%，p = 0.002）中观察到氧化磷酸化（OXPHOS）复合物I比活性的大量耗竭。此外，药物暴露胎仔骨骼肌中复合物IV活性高度耗竭（平均值降低85%，p = 0.004）（p <0.004）。脑、大脑和小脑的OXPHOS变化无统计学意义。与未暴露的对照组相比，暴露于药物的胎仔的心脏、骨骼肌、小脑和大脑中的线粒体DNA量基本耗尽（>50%）。总体而言，数据表明，在人类等效给药方案中，在子宫内暴露于AZT +3TC的猴胎仔出生时观察到显著的线粒体损伤。
This study was designed to investigate fetal mitochondrial toxicity in Erythrocebus patas monkeys exposed in utero to zidovudine (AZT) and lamivudine (3TC), and taken at term. Pregnant patas monkeys were given a daily dose of 40 mg AZT (86% of the human daily dose, based on body weight), for the last 10 weeks (50%) of gestation, and a daily dose of 24 mg 3TC (84% of the human daily dose, based on body weight) for the last 4 weeks of gestation. At term, AZT was found to be incorporated into fetal mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy ( EM) drug-exposed fetal cardiac and skeletal muscle cells showed mitochondrial membrane compromise, mitochondrial proliferation, and damaged sarcomeres, while mitochondria in brain cerebrum and cerebellum were morphologically normal. Substantial depletion of oxidative phosphorylation (OXPHOS) Complex I specific activities was observed in heart (87% reduction in mean, p = 0.02) and skeletal muscle (98% reduction in mean, p = 0.002) from drug-exposed fetuses, compared to unexposed fetuses. In addition Complex IV activity was highly depleted (85% reduction in mean, p = 0.004) in skeletal muscle from the drug-exposed fetuses ( p 5 0.004). Brain cerebrum and cerebellum showed no statistically significant OXPHOS changes with drug exposure. Mitochondrial DNA quantity was substantially depleted (>50%) in heart, skeletal muscle, cerebellum, and cerebrum from drug-exposed fetuses compared to unexposed controls. Overall, the data indicate that significant mitochondrial damage was observed at birth in monkey fetuses exposed in utero to AZT plus 3TC in a human-equivalent dosing protocol.