Methylmercury chloride exposure exacerbates existing neurobehavioral and immune dysfunctions in the BTBR T+ Itpr3tf/J mouse model of autism

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by impaired communication, impaired reciprocal social interaction, restricted sociability deficits, and the presence of stereotyped patterns of behaviors. Immune dysregulation has been suggested to play a possible etiological role in ASD. Recent studies have demonstrated that exposure to methylmercury chloride (MeHgCl) leads to abnormal gait, motor deficits, impaired hearing, and memory deficits; however, its effects on behavioral and immunological responses have not been adequately investigated in ASD. In this study, we investigated the effects of MeHgCl exposure on marble burying, self-grooming behaviors, sociability tests, and locomotor activities in BTBR T⁺ Itpr3tf/J (BTBR) mice. We also explored the possible molecular mechanism underlying the effects of MeHgCl administration on IFN-γ-, T-bet-, IL-9-, and IL-17A-producing CD4⁺, CXCR5⁺, CXCR6⁺, and CCR9⁺ cells isolated from spleens. Furthermore, the effects of MeHgCl exposure on the mRNA expression and levels of pro-inflammatory cytokines in the brain tissue and serum samples were also assessed. Our results demonstrated that MeHgCl exposure caused a significant increase in marble burying, self-grooming behaviors and a decrease in social interactions and adverse effects on locomotor activity in BTBR mice. MeHgCl exposure also significantly increased the production of CD4⁺IFN-γ⁺, CD4⁺T-bet⁺, CCR9⁺T-bet⁺, CXCR5⁺IL-9⁺, CD4⁺IL-9⁺, CXCR6⁺IL-17A⁺, and CD4⁺IL-17A⁺ cells in the spleen. Furthermore, MeHgCl exposure increased mRNA and protein levels of pro-inflammatory cytokines in the brain and serum respectively in BTBR mice. In conclusion, MeHgCl administration aggravated existing behavioral and immune abnormalities in BTBR mice.

Keywords: Autism spectrum disorder; BTBR mice; Behavioral studies; Inflammatory mediators; Methylmercury chloride.