Male Subfertility By Ni2+ Poisoning of Ca2+ Channels ?

镍被广泛用于制造钢、合金和金属板。镍 盐是公认的过敏原和致癌物。它们的潜在影响 对人类雄性生育能力的影响尚未被彻底探索，但啮齿类动物的研究 显示Ni2+可引起可逆性睾丸萎缩和生精停滞。在……里面 初步研究，即使纳米分子Ni2+浓度没有影响 对人精子活力的影响，在体外孵育液中添加 纳米Ni2+显著降低人类精子对顶体反应的反应 诱导剂，一种极好地预测人类精子受精的生物测试 潜力。目前的目标是确定人类体内是否存在关联 这一体外结果，如果是这样，开始解剖 直接被Ni2+靶向的分子。人体血液和精液中镍离子水平的研究 血浆将与体外受精、人工受精相关 受精率和精子功能的生物标志物，使用标本 在以前对金属离子毒物的研究过程中收集的。Ni2+离子水平 也将在不育和不育的人类睾丸活检组织中进行对比 有生育能力的男人。效应大小(平均值的方差除以组内 方差)为0.1将可以使用目前手头的样本检测到。 辅助因素(包括激素和其他金属水平)的混杂影响 毒物、常规精液分析参数和生活方式因素)将 也被评估为剖析由于Ni2+引起的影响。烦躁不安的后果 钙水平(可能是睾丸中凋亡细胞的增加和减少 生发上皮中的聚合作用)将被测定以评估 Ni2+的毒性作用可能与Cd+的毒性作用机制相似 和Pb2+。作为体细胞文献和初步实验 离子通道阻滞剂提示T型电压门控钙离子通道提供 Ni2+进入生殖细胞的途径和毒物的早期靶标 T型钙离子通道异构体在人睾丸mRNA中的作用和表达 将与生育状况相关联，以确定异构体表达是否为 提高对Ni2+作为生殖毒物的敏感性的生物标志物 与L型钙离子通道异构体的表达方式相似，是一个生物标志物 为镉对睾丸的毒性作用。

Nickel is widely used in steel alloys and as metal plate. Nickel salts are well-recognized as allergens and carcinogens. Their potential effects upon human male fertility have not been thoroughly explored, but rodent studies show Ni2+ induces reversible testicular atrophy and spermatogenic arrest. In preliminary studies, even though nanomolar Ni2+ concentrations have no effect upon human sperm motility, supplementing in vitro incubation media with nanomolar Ni2+ markedly decreased human sperms' response to acrosome reaction inducers, a bioassay that is an excellent predictor of human sperm fertilizing potential. The current goal is to determine if there is a correlate in human populations to this in vitro result, and, if so, to begin to dissect the molecules directly targeted by Ni2+. Levels of Ni2+ in human blood and seminal plasma will be correlated with in vitro fertilization, with artificial insemination rates, and with biomarkers of sperm function, using specimens collected in the course of prior studies of metal ion toxicants. Levels of Ni2+ will also be contrasted in stockpiled human testis biopsies of infertile and fertile men. An effect size (variance of the mean divided by the within-group variance) of 0.1 will be detectable using specimens currently on hand. Confounding effects of cofactors (including levels of hormones and other metal toxicants, conventional semen analysis parameters, and lifestyle factors) will also be assessed to dissect effects due to Ni2+. Consequences of perturbed calcium levels (possible increases in apoptotic cells in testes and decreased polymerized action in germinal epithelia) will be determined to assess the likelihood that Ni2+ toxicant action parallels mechanisms demonstrated for Cd2+ and Pb2+. As the somatic cell literature and preliminary experiments with an ion channel blocker suggest that T-type voltage-gated Ca2+ ion channels offer both means of Ni2+ entry into germ cells and an early target for toxicant action, expression of T-type Ca2+ ion channel isoforms in human testicular mRNA will correlated with fertility status to determine if isoform expression is a biomarker for increased sensitivity to Ni2+ as a reproductive toxicant, in a similar manner as expression of L-type Ca2+ ion channel isoforms is a biomarker for testicular toxicity of Cd2+.