Inhibition of human sperm motility and capacitation by ziram is mediated by decreasing tyrosine protein kinase

Abstract

Many endocrine disruptors may interfere with sperm motility, hyperactivation, and capacitation, thereby leading to male infertility. In the current study, we screened 14 endocrine disruptors, including plant ingredients, cigarette ingredients, minerals, insecticides and fungicides, plastics, and plasticizers, to inhibit human sperm motility and forward motility. Only ziram, a dithiocarbamate fungicide, can effectively inhibit sperm motility, forward motility, hyperactivation, capacitation, and spontaneous acrosome reaction of normal human spermatozoa. Its half maximum inhibitory concentration (IC50) values were less than 4 μM. Ziram also inhibited sperm motility and forward motility of asthenozoospermia spermatozoa and IC50 values were about 6–8 μM. In addition, ziram inhibited normal sperm motility, calcium influx, reactive oxygen species, and mitochondrial membrane potential at 2.5 and/or 5 μM, with IC50 values ​​exceeding 100 μM, although it did not affect sperm DNA fragmentation up to 5 μM. Ziram-mediated inhibition of sperm motility and forward motility was irreversible. Forskolin, 8Br-cAMP, pentoxifylline, progesterone, vitamin E, and A23187 cannot prevent ziram-mediated inhibition of sperm motility and forward motility. Further studies have shown that ziram inhibited the level of tyrosine protein kinase with an IC50 value of about 10 μM, without affecting p21-activated kinase 4, and it caused damage to the mitochondrial structure of normal spermatozoa at 2.5 and 5 μM. In conclusion, ziram irreversibly inhibits human sperm motility, forward motility, and capacitation by reducing the level of tyrosine protein kinase and damaging the ultrastructure of mitochondria.