Male Subfertility By Ni2+ Poisoning of Ca2+ Channels ?

Ca2 通道 Ni2 中毒导致男性生育力低下？

• 批准号: 6314846
• 负责人: SUSAN H BENOFF
• 金额: $ 12.3万
• 依托单位: NORTH SHORE UNIVERSITY HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6314846
• 关键词: biomarker; biopsy; blood chemistry; calcium channel; cytotoxicity; environmental toxicology; fertility; human tissue; male; metal poisoning; nickel; occupational health /safety; protein isoforms; seminal vesicles; sperm; sperm motility

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+.

镍被广泛用于钢合金和金属板中。镍 盐被广泛认可为过敏原和致癌物。它们的潜在影响 在人类的男性生育方面尚未得到彻底探索，但是啮齿动物的研究 显示Ni2+诱导可逆的睾丸萎缩和精子造成。在 初步研究，即使纳摩尔Ni2+浓度无效 在人类的精子运动中，补充体外孵育培养基 纳摩尔ni2+显着降低了人类精子对角色反应的反应 诱导剂，一种生物测定，是人类精子受精的极好预测指标 潜在的。当前的目标是确定人类是否存在相关性 在体外结果的种群，如果是的话，开始剖析 Ni2+直接靶向的分子。人血和精液中的Ni2+水平 血浆将与体外受精相关，人为 使用标本的授精速率以及具有精子功能的生物标志物 在先前研究金属离子有毒物质的过程中收集。 Ni2+的水平 也将与不育的人类睾丸活检和 肥沃的男人。效应大小（平均值的方差除以组内部 差异为0.1，使用当前手头的样品可检测到。 辅助因子的混杂作用（包括激素和其他金属水平 有毒物质，常规精液分析参数和生活方式因素）将 还可以评估由于Ni2+引起的效果。扰动的后果 钙水平（睾丸中凋亡细胞的可能增加并减少 在生发性上皮中的聚合作用将确定评估 Ni2+有毒作用与CD2+证明的机制相似的可能性 和PB2+。作为躯体细胞文献和初步实验 离子通道阻滞剂表明T型电压门控Ca2+离子通道提供 Ni2+进入生殖细胞的两种方法和有毒物质的早期靶标 人类睾丸mRNA中T型Ca2+离子同工型的作用，T型Ca2+离子通道的表达 将与生育状况相关，以确定同工型表达是否为 在A 与L型Ca2+离子通道同工型的表达相似的方式是生物标志物 用于CD2+的睾丸毒性。