Exposure to Methylmercury at Juvenile Stage Worsens Autism-like Symptoms in Adult BTBR T+tf/J Mice Due to Lack of Nuclear Factor Erythroid 2-Related Factor 2 Signaling Upregulation in Periphery and Brain

Abstract

Autism spectrum disorder (ASD) is a multifaceted developmental condition that first appears in infancy. The condition is characterized by recurrent patterns in behavior and impairments in social and vocalization abilities. Methylmercury is a toxic environmental pollutant, and its derivatives are the major source of organic mercury to human beings. Inorganic mercury, which is released from a variety of pollutants into oceans, rivers, and streams, is transformed into methylmercury by bacteria and plankton in the water, which later builds up in fish and shellfish, and then enters humans through the consumption of fish and shellfish and increases the risk of developing ASD by disturbing the oxidant–antioxidant balance. However, there has been no prior research to determine the effect of juvenile exposure of methylmercury chloride on adult BTBR mice. Therefore, the current study evaluated the effect of methylmercury chloride administered during the juvenile stage on autism-like behavior (three-chambered sociability, marble burying, self-grooming tests) and oxidant–antioxidant balance (specifically Nrf2, HO-1, SOD-1, NF-kB, iNOS, MPO, and 3-nitrotyrosine) in the peripheral neutrophils and cortex of adult BTBR and C57BL/6 (B6) mice. Our results show that exposure to methylmercury chloride at a juvenile stage results in autism-like symptoms in adult BTBR mice which are related to a lack of upregulation of the Nrf2 signaling pathway as demonstrated by no significant changes in the expression of Nrf2, HO-1, and SOD-1 in the periphery and cortex. On the other hand, methylmercury chloride administration at a juvenile stage increased oxidative inflammation as depicted by a significant increase in the levels of NF-kB, iNOS, MPO, and 3-nitrotyrosine in the periphery and cortex of adult BTBR mice. This study suggests that juvenile exposure to methylmercury chloride contributes to the worsening of autism-like behavior in adult BTBR mice through the disruption of the oxidant–antioxidant balance in the peripheral compartment and CNS. Strategies that elevate Nrf2 signaling may be useful to counteract toxicant-mediated worsening of ASD and may improve quality of life.

Potential Neuroprotective Effect of Melatonin in the Hippocampus of Male BTBR Mice

“…Collectively, these effects are consistent with a role for NFkB in enhancing excitatory synaptic function. In BTBR mice, peripheral inflammatory mediators activate transcription factors such as NFkB in peripheral immune cells [ 71 ], likely worsening systemic inflammation. Our data, besides characterizing the inflammatory status of CA3 hippocampal neurons, confirm the well-known anti-inflammatory properties of melatonin reported in previous studies on a plethora of diseases and models.…”

Methylmercury Induces Apoptosis in Mouse C17.2 Neural Stem Cells through the Induction of OSGIN1 Expression by NRF2

“…Until now, nuclear factor erythroid 2-related factor 2 (NRF2) has been reported as a transcription factor involved in the induction of OSGIN1 expression [26,27], and the partial binding sequence of NRF2 is located −69 to −58 bp from the transcription start site of the OSGIN1 gene (Figure 4A). It has also been reported that methylmercury activates NRF2 in various cell types and mice [28][29][30][31]. Therefore, to clarify the involvement of NRF2 in OSGIN1 induction by methylmercury, we transfected C17.2 cells with three types of siRNA against NRF2 mRNA and examined the effects of methylmercury exposure on OSGIN1 expression.…”

Central Causation of Autism/ASDs via Excessive [Ca2+]i Impacting Six Mechanisms Controlling Synaptogenesis during the Perinatal Period: The Role of Electromagnetic Fields and Chemicals and the NO/ONOO(-) Cycle, as Well as Specific Mutations

“…Peroxynitrite was shown to be elevated in autism based on a test using 3-nitrotyrosine as a specific marker for peroxynitrite (Sajdel-Sulkowska et al [213]; De Felice et al [214]; Nadeem et al [215,216]; Algahtani et al [217]; Carey et al [218]). Peroxynitrite elevation by the NO/ONOO(-) cycle, as discussed here and in thousands of other papers, produces oxidative stress.…”