Progressive Mitochondrial Compromise in Brains and Livers of Primates Exposed In Utero to Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Progressive Mitochondrial Compromise in Brains and Livers of Primates Exposed In Utero to Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
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DOI：
10.1093/toxsci/kfq235
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发表时间：
2010-11-01
影响因子：
3.8
通讯作者：
Poirier, Miriam C.
中科院分区：
文献类型：
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作者：
Divi, Rao L.;Einem, Tracey L.;Poirier, Miriam C.
线粒体损害已记录在婴儿出生的妇女感染人类免疫缺陷病毒（HIV-1）谁收到核苷逆转录酶抑制剂（NRTI）治疗在怀孕期间。为了模拟这些人类暴露，我们检查了出生时和1年的脑皮质和肝脏线粒体完整性，这些线粒体完整性来自无逆转录病毒的红猴母猴的后代，在妊娠的后半期（10周）给予相当于人类的NRTI剂量。另外的婴儿，随访1年，在出生后的前6周内给予与母亲相同的药物。暴露包括：无药物、齐多夫定（AZT）、拉米夫定（3 TC）、AZT/3 TC、AZT/去羟肌苷（ddI）和司他夫定（d4 T）/3 TC。在大脑和肝脏中，氧化磷酸化（OXPHOS）酶活性（复合物I，II和IV）显示未暴露和NRTI暴露的后代在两个时间之间的差异极小。根据编码显微照片的评分，通过电子显微镜（EM）观察到，出生时和1岁时大多数NRTI暴露大鼠的脑和肝线粒体均存在显著（p < 0.05）形态学损伤。在出生时，3 TC和d4 T/3 TC组暴露于NRTI的大鼠脑和肝脏线粒体DNA（mtDNA）水平显著降低，在所有NRTI暴露组中，1岁时mtDNA水平显著降低（p < 0.05）。在子宫内暴露于NRTI的1岁婴儿中，脑中mtDNA缺失率为28.8-51.8%，肝中为37.4-56.5%。这些研究表明，一些NRTI暴露的人类婴儿可能会在大脑和肝脏中维持类似的线粒体损害，应长期随访认知完整性和肝功能。
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.