Male Subfertility By Ni2+ Poisoning of Ca2+ Channels ?

镍被广泛用于合金钢和金属板材。镍 盐是公认的过敏原和致癌物。的潜在影响 对人类男性生育能力的影响还没有彻底研究，但啮齿动物的研究 结果表明，Ni ~（2+）可引起可逆性睾丸萎缩和生精障碍。在 初步研究，即使纳摩尔的Ni 2+浓度没有影响 对人精子活力的影响，在体外孵育培养基中补充 纳摩尔Ni ~（2+）可明显降低人精子顶体反应 诱导剂，一种生物测定，是人类精子增殖的一个很好的预测因子 潜力目前的目标是确定是否有一个相关的人类 如果是这样的话，开始解剖 Ni 2+直接靶向分子。人类血液和精液中Ni 2+的水平 血浆将与体外受精，人工授精， 授精率，并与精子功能的生物标志物，使用标本 在金属离子毒物的先前研究过程中收集的。Ni 2+水平 也将在储存的不育和不育的人类睾丸活检中进行对比， 有生育能力的男人效应量（均值方差除以组内 方差）为0.1将是可检测的使用目前手头上的标本。 辅因子的混杂效应（包括激素和其他金属 毒物、常规精液分析参数和生活方式因素）将 也可以评估由于Ni 2+引起的解剖效应。扰动的后果 钙水平（睾丸中凋亡细胞可能增加， 将确定在生殖上皮中的聚合作用），以评估 Ni 2+毒性作用与Cd 2+毒性作用机制相似的可能性 Pb2+。正如体细胞文献和用一种 离子通道阻滞剂提示T型电压门控性Ca 2+离子通道提供了 Ni 2+进入生殖细胞的途径和毒物的早期靶点 T型钙离子通道亚型在人睾丸mRNA中的表达 将与生育状态相关，以确定同种型表达是否是一种 作为一种生殖毒物， 与L型Ca 2+离子通道亚型的表达类似的方式是一种生物标志物 镉的睾丸毒性

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+.