title: Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats.
abstract: Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro. Subsequently, male Wistar rats were treated orally with 5 or 10mg/kg FNT for 9 weeks and the subchronic exposure unambiguously deteriorated sperm motility and morphology. The activity-based protein profiling analysis with a phosphonofluoridate fluorescent probe revealed that FAAH was selectively inhibited among the FNT-treated cellular membrane proteome in testis. Intriguingly, testicular AEA (endogenous substrate of FAAH) levels were elevated along with the FAAH inhibition caused by the subchronic exposure. More importantly, linear regression analyses for the FNT-elicited spermatotoxicity reveal a good correlation between the testicular FAAH activity and morphological indices or sperm motility. Accordingly, the present study proposes that the FNT-elicited spermatotoxicity appears to be related to inhibition of FAAH leading to overstimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement.
authors.affiliation: Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan. Electronic address: yukey@med.nagoya-cu.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tomizawa
authors.affiliation: Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Himiko
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Okamura
authors.affiliation: National Institute of Occupational Safety and Health, Kanagawa 214-8585, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Ohtani
authors.affiliation: Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Nunome
authors.affiliation: Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Noro
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan. Electronic address: kamijima@med.nagoya-cu.ac.jp.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kamijima
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D063388:Endocannabinoids / Q000502:physiology*; D004822:Epididymis / Q000166:cytology / Q000187:drug effects; D005278:Fenitrothion / Q000633:toxicity*; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D013058:Mass Spectrometry; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000523:psychology; D051381:Rats; D017208:Rats, Wistar; D013076:Sperm Count; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects* / Q000648:ultrastructure; D013737:Testis / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000255:Adenosine Triphosphate; D000581:Amidohydrolases; D063388:Endocannabinoids; D005278:Fenitrothion; D012739:Gonadal Steroid Hormones; D007306:Insecticides; D000099252:Fatty Acid Amide Hydrolases
keywords: Anandamide; Endocannabinoid system; Fatty acid amide hydrolase; Fenitrothion; Organophosphate insecticide; Sperm toxicity