Atrazine exposure induces TDP-43 protein translocation: A potential mechanism for prefrontal cortical neurodegeneration induced by environmental pollutants

Abstract

Atrazine (ATR) is a widely utilized herbicide that has been demonstrated to exert a multitude of deleterious effects on the environment, particularly with regard to water and soil contamination. Moreover, its disruption of endocrine function and implications for antibiotic resistance underscore the urgent need to prioritize alternative solutions for both ecosystems and human health. Therefore, the objective of this study was to investigate a range of neurotoxic effects associated with atrazine-induced damage in the prefrontal lobe of mice. The results of this study indicate that treatment with ATR in C57BL/6 J mice resulted in cognitive-related behavioral deficits, including anxiety and depression, as well as motor impairments. In vivo analyses demonstrated that ATR exposure resulted in a reduction in neuronal synapse density at the microstructural level, while also compromising prefrontal morphological integrity, nociceptor count, and overall neuronal health within the brain. These findings collectively suggest that synaptic deficits are implicated in ATR-induced behavioral abnormalities observed in these mice. Furthermore, our findings revealed that ATR exposure resulted in elevated TDP-43 expression levels that were ectopically localized within the cytoplasm. This alteration led to impaired functionality of mRNP granules and contributed to the development of abnormal synaptic defects. Conversely, TDP-43 has the potential to localize ectopically to mitochondria, where it activates the mitochondrial unfolded protein response (UPRmt), which ultimately results in mitochondrial dysfunction. These findings collectively indicate a strong correlation between TDP-43 dysregulation and the progression of neurodegenerative diseases. Further investigation into the potential neurotoxicity of atrazine may foster heightened awareness, leading to more stringent regulatory measures, research into safer alternatives, and the adoption of sustainable practices, which are essential for safeguarding environmental integrity alongside human health.