Paraquat Exposure Increases Oxidative Stress Within the Dorsal Striatum of Male Mice With a Genetic Deficiency in One-carbon Metabolism

Toxicol Sci. 2019 May 1;169(1):25-33. doi: 10.1093/toxsci/kfz034.

Abstract

Paraquat is an herbicide that is commonly used worldwide. Exposure to paraquat results in Parkinson's disease (PD)-like symptoms including dopaminergic cell loss. Nutrition has also been linked in the pathogenesis of PD, such as reduced levels of folic acid, a B-vitamin, and component of one-carbon metabolism. Within one-carbon metabolism, methylenetetrahydrofolate reductase (MTHFR) catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. A polymorphism in MTHFR (677 C&→T) has been reported in 5%-15% of North American and European human populations. The MTHFR polymorphism is also prevalent in PD patients. The goal of this study was to investigate the impact of paraquat-induced PD-like pathology in the context of reduced levels of MTHFR. Three-month-old male Mthfr+/- mice, which model the MTHFR polymorphism observed in humans, were administered intraperitoneal injections of paraquat (10 mg/kg) or saline 6 times over 3 weeks. At the end of paraquat treatment, motor and memory function were assessed followed by collection of brain tissue for biochemical analysis. Mthfr+/- mice treated with paraquat showed impaired motor function. There was increased microglial activation within the substantia nigra (SN) of Mthfr+/- mice treated with paraquat. Additionally, all Mthfr+/- mice that were treated with paraquat showed increased oxidative stress within the dorsal striatum, but not the SN. The present results show that paraquat exposure increases PD-like pathology in mice deficient in one-carbon metabolism.

Keywords: Parkinson’s disease; methyltetrahydrofolate reductase; one-carbon metabolism; oxidative stress; paraquat; striatum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Corpus Striatum / physiopathology
  • Herbicides / toxicity*
  • Male
  • Maze Learning / drug effects
  • Methylenetetrahydrofolate Reductase (NADPH2) / deficiency*
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Oxidative Stress / drug effects*
  • Paraquat / toxicity*
  • Parkinson Disease, Secondary / chemically induced*
  • Parkinson Disease, Secondary / genetics
  • Parkinson Disease, Secondary / metabolism
  • Parkinson Disease, Secondary / physiopathology

Substances

  • Herbicides
  • MTHFR protein, mouse
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Paraquat

Grant support