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Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats

Yuki Ito1, Motohiro Tomizawa2, Himiko Suzuki1

  • 1Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.

Toxicology and Applied Pharmacology
|July 8, 2014
PubMed

Insights

Organophosphate pesticide fenitrothion causes male reproductive toxicity by inhibiting fatty acid amide hydrolase (FAAH). This disrupts the endocannabinoid system, impairing sperm motility and morphology in rats.

Area of Science:

  • Environmental toxicology
  • Reproductive toxicology
  • Endocrinology

Background:

  • Organophosphate (OP) compounds are known anticholinesterase agents with potential for off-target effects.
  • Male reproductive toxicity, including impaired sperm function, is a recognized adverse outcome of OP exposure.
  • The endocannabinoid system plays a role in male reproductive physiology.

Purpose of the Study:

  • To investigate the mechanism by which fenitrothion (FNT), an OP compound, induces male reproductive toxicity.
  • To determine if FNT affects the endocannabinoid signaling system in male reproductive organs.
  • To assess the impact of FNT on sperm parameters and identify the molecular targets involved.

Main Methods:

  • In vitro inhibition assays using rat testicular membrane preparations to assess FNT oxon's effect on fatty acid amide hydrolase (FAAH).
  • Subchronic oral administration of FNT (5 or 10mg/kg) to male Wistar rats for 9 weeks.
  • Activity-based protein profiling to identify inhibited proteins in testicular membranes.
  • Measurement of testicular anandamide (AEA) levels.
  • Analysis of sperm motility and morphology.
  • Linear regression analysis to correlate FAAH activity with toxicity parameters.

Main Results:

  • Fenitrothion oxon inhibited FAAH activity in rat testicular membranes in vitro.
  • Subchronic FNT exposure significantly reduced sperm motility and altered sperm morphology in rats.
  • Activity-based protein profiling confirmed selective inhibition of FAAH in the testes of FNT-treated rats.
  • Testicular AEA levels were elevated following FNT exposure, correlating with FAAH inhibition.
  • A significant correlation was observed between reduced testicular FAAH activity and impaired sperm morphology and motility.

Conclusions:

  • Fenitrothion-induced male reproductive toxicity is linked to the inhibition of FAAH.
  • Inhibition of FAAH leads to overstimulation of the endocannabinoid signaling system.
  • This disruption of the endocannabinoid system negatively impacts spermatogenesis and sperm motility.
Keywords:
AnandamideEndocannabinoid systemFatty acid amide hydrolaseFenitrothionOrganophosphate insecticideSperm toxicity

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