Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 279, Issue 3, Pages 331-337Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2014.06.023
Keywords
Anandamide; Fatty acid amide hydrolase; Fenitrothion; Sperm toxicity; Organophosphate insecticide; Endocannabinoid system
Categories
Funding
- Japan Ministry of Education, Culture, Sports, Science, and Technology [20310035, B19790404]
- [24659303]
- Grants-in-Aid for Scientific Research [20310035] Funding Source: KAKEN
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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 10 mg/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 over-stimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement. (C) 2014 Elsevier Inc. All rights reserved.
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