title: Dithiocarbamate fungicides increase intracellular Zn(2+) levels by increasing influx of Zn(2+) in rat thymic lymphocytes.
abstract: Dithiocarbamate fungicides are used as alternative antifouling agents to highly toxic organotin antifouling agents, such as tri-n-butyltin and triphenyltin. There are some concerns regarding their environmental and health risks. It has been shown that tri-n-butyltin increases intracellular Zn(2+) levels of mammalian lymphocytes. Therefore, we examined the effects of dithiocarbamate fungicides (Ziram, Thiram, and Zineb) on rat thymic lymphocytes using a flow-cytometric technique to elucidate how these fungicides affect intracellular Zn(2+) levels. We further determined whether the agents increase intracellular Zn(2+) and/or Ca(2+), because both Zn(2+) and Ca(2+) are intracellular signals in lymphocytes, and excessive increases in their intracellular concentrations can have adverse effects. Dithiocarbamate fungicides increased intracellular Zn(2+) levels, without affecting intracellular Ca(2+) levels. Ziram was the most potent compound, increasing intracellular Zn(2+) levels via Zn(2+) influx. Ziram (1μM) greatly decreased the cellular nonprotein thiol content, and Zn(2+) chelators attenuated the Ziram-induced decrease. Ziram increased the population of annexin V-positive cells in a Zn(2+)-dependent manner. Therefore, we propose that dithiocarbamate fungicides induce Zn(2+) influx, resulting in an excessive elevation of intracellular Zn(2+) levels, leading to the induction of apoptosis. This study gives a basic insight into the mechanisms of dithiocarbamate fungicide-induced adverse events.
authors.affiliation: Laboratory of Cellular Signaling, Graduate School of Integrated Arts and Sciences, The University of Tokushima, Tokushima 770-8502, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kanemoto-Kataoka
authors.affiliation: Laboratory of Cellular Signaling, Graduate School of Integrated Arts and Sciences, The University of Tokushima, Tokushima 770-8502, Japan.
authors.forename: Tomohiro M
authors.initials: TM
authors.lastname: Oyama
authors.affiliation: Laboratory of Cellular Signaling, Graduate School of Integrated Arts and Sciences, The University of Tokushima, Tokushima 770-8502, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishibashi
authors.affiliation: Laboratory of Cellular Signaling, Graduate School of Integrated Arts and Sciences, The University of Tokushima, Tokushima 770-8502, Japan. Electronic address: oyamay@tokushima-u.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Oyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005453:Fluorescence; D005659:Fungicides, Industrial / Q000494:pharmacology*; D017136:Ion Transport; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*; D015039:Ziram / Q000494:pharmacology*
chemical_list: D005659:Fungicides, Industrial; D015039:Ziram; D015032:Zinc
keywords: Intracellular Zn(2+); Lymphocytes; Thiram; Zineb; Ziram