Low-dose oral pyrethroid exposure induces gastrointestinal dysfunction and alters nigrostriatal dopamine signaling pathways in mice

Abstract

BACKGROUND AND AIM: Insecticide exposure is associated with greater risk for developing Parkinson’s disease (PD). PD is characterized by motor impairments due to loss of nigrostriatal dopamine (DA) neurons in the midbrain, and patients commonly experience gastrointestinal (GI) dysfunction long before the onset of motor symptoms. Pyrethroids, synthetic insecticides commonly used around the world, disrupt DA signaling pathways. One of the most common routes of pyrethroid exposure is ingestion, so it is plausible that oral exposure acts locally within the GI tract and facilitates PD pathogenesis via the gut-brain axis. Here, we sought to determine the functional and molecular consequences of oral pyrethroid exposure in the adult mouse gut and brain in the context of idiopathic PD. METHODS: Adult mice were orally gavaged with 3 mg/kg deltamethrin weekly for 3 weeks. Intestinal behaviors were assessed to determine constipation phenotypes. Gut microbiome composition was determined by 16S rRNA sequencing. Intestinal and brain tissues were collected following the final dose to assess changes in gene expression and protein production pathways related to DA and other monoamine signaling, as determined by qPCR and western blot. RESULTS:Oral deltamethrin exposure significantly impaired GI function compared to vehicle controls. We observed reduced fecal output, changed gene and protein levels important for normal gut function, and altered gut microbial composition in deltamethrin-exposed mice, all of which are reflective of changes observed in PD patients. In the brain, oral deltamethrin exposure significantly altered production of proteins important for DA synthesis and reuptake compared to controls. CONCLUSIONS:Low-dose oral pyrethroid exposure induces GI dysfunction and alters DA pathways in the brain. These findings support the idea that pyrethroids induce functional and molecular changes relevant to PD pathology from within the gut, and further investigation is warranted to fully understand this phenomenon as a potential trigger in the etiology of PD. KEYWORDS: Pesticides, Chemical exposures, Neurodegenerative outcomes, Microbes/Microbiome