Lead interaction with human protamine (HP2) as a mechanism of male reproductive toxicity.
Lead interaction with human protamine (HP2) as a mechanism of male reproductive toxicity.
复制标题
DOI：
10.1021/tx000017v
复制
发表时间：
2000-07
影响因子：
4.1
通讯作者：
B. Quintanilla-Vega;D. Hoover;W. Bal;E. Silbergeld;M. Waalkes;L. Anderson
中科院分区：
文献类型：
--
作者：
B. Quintanilla-Vega;D. Hoover;W. Bal;E. Silbergeld;M. Waalkes;L. Anderson
在精子发生过程中，组蛋白被蛋白蛋白取代，蛋白蛋白浓缩并保护精子DNA。在人类中，锌有助于精子染色质的稳定性，并与鱼精蛋白P2 （HP2）结合。与核蛋白的化学相互作用会阻止正常的精子染色质凝聚，可能会引起精子基因组的变化，从而影响生育能力和后代的发育。由于铅对含锌蛋白具有高亲和力，我们研究了铅与HP2的相互作用作为其对精子毒性的新机制。紫外/可见光谱和CD光谱结果表明，HP2在两个不同的位点与Pb（2+）结合，导致蛋白质构象发生变化。他们还提供了证据，表明硫醇基团主要参与Zn（2+）和Pb（2+）与HP2的结合，并且HP2可能有与Zn（2+）无关的Pb（2+）的附加结合位点。HP2对Pb（2+）和Zn（2+）的亲和力非常相似，表明Pb（2+）可以在体内与Zn（2+）竞争或取代HP2。铅与HP2的相互作用导致HP2-DNA结合程度的剂量依赖性降低，尽管铅与DNA的相互作用也有助于这种效应。因此，铅降低HP2-DNA相互作用水平的能力可能导致精子染色质凝聚的改变，从而降低生育能力。
During spermatogenesis, histones are replaced by protamines, which condense and protect sperm DNA. In humans, zinc contributes to sperm chromatin stability and binds to protamine P2 (HP2). Chemical interactions with nuclear protamines, which prevent normal sperm chromatin condensation, may induce changes in the sperm genome and thus affect fertility and offspring development. Since lead has a high affinity for zinc-containing proteins, we investigated lead interactions with HP2 as a novel mechanism of its toxicity to sperm. UV/vis and CD spectroscopy results indicated that HP2 binds Pb(2+) at two different sites, causing a conformational change in the protein. They also provided evidence that thiol groups are primarily involved in Zn(2+) and Pb(2+) binding to HP2 and that HP2 may have additional binding sites for Pb(2+) not related to Zn(2+). HP2 affinities for Pb(2+) and Zn(2+) were very similar, suggesting that Pb(2+) can compete with or replace Zn(2+) in HP2 in vivo. This interaction of lead with HP2 resulted in a dose-dependent decrease in the extent of HP2-DNA binding, although lead interaction with DNA also contributed to this effect. Therefore, the ability of lead to decrease the level of HP2-DNA interaction may result in alterations to sperm chromatin condensation, and thus in reduced fertility.