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bioRxiv · 10.1101/2025.06.27.661925

Alpha-2-Macroglobulin mitigates mitochondrial dysfunction and neuronal apoptotic responses in pesticide-induced neurotoxicity

Dixit, S.
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Abstract

Persistent and repetitive application of pesticides has been linked to adverse effects on human metabolism and the onset of various disorders. Commonly used pesticides, such as carbamates (e.g., Aldicarb, ALD) and organophosphates (e.g., Chlorpyrifos, CPF), are widely applied in potato cultivation and household pest control. Chronic exposure to these substances has been implicated in the early onset of neurodegenerative disorders. Alpha-2-macroglobulin (A2M), a protein known for its regulatory role in oxidative stress, participates in multiple biological processes. Despite its significance, the role of A2M in mitigating mitochondrial-induced neuronal apoptosis triggered by pesticide interference remains poorly understood. This study explores the involvement of A2M in SH-SY5Y neuroblastoma cells exposed to pesticides, focusing on its impact on mitochondrial enzyme expression, inflammatory cytokines, neuronal apoptotic and anti-apoptotic proteins, and the activation of the Nrf2 signaling pathway. Comparative analyses of control and pesticide-exposed SH-SY5Y cells revealed that A2M positively modulates neuronal stress responses. Western blot profiling demonstrated that A2M upregulates anti-apoptotic proteins such as Bcl-2 and Nrf2, while downregulating pro-apoptotic markers, including Bax, Caspase-3, and Caspase-9. Biochemical assays showed that A2M enhances mitochondrial enzyme activity, particularly complexes I and III, while mitigating the reactive oxygen species (ROS) generated by ALD and CPF exposure. Furthermore, A2M was found to reduce DNA damage caused by pro-inflammatory cytokines, which are exacerbated by mitochondrial oxidative stress. These findings highlight the pivotal role of A2M in attenuating pesticide-induced neuronal toxicity through the regulation of mitochondrial function and inhibition of neuronal apoptosis. Research HighlightsO_LIThis study is the first to report the interaction between human alpha-2-macroglobulin and neuronal apoptotic markers in pesticides mediated neurotoxicity. C_LIO_LIThe study found that treatment of alpha-2-macroglobulin promotes the proliferation of Nrf2 pathway during oxidative stress in neuronal cells. C_LIO_LIThis research reveals that alpha-2-macroglobulin modulates oxidative stress in mitochondrial enzyme complexes and during mitochondrial dysfunction. C_LIO_LIThe study confirms that treatment of alpha-2-macroglobulin significantly alleviates pro inflammatory cytokines during pesticides mediated neurotoxicity. C_LIO_LIThis research provides new theoretical basis and molecular targets for the treatment of neurodegenerative diseases during early preclinical stages, offering broad application prospects. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/661925v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1acb2baorg.highwire.dtl.DTLVardef@109ead0org.highwire.dtl.DTLVardef@171f0borg.highwire.dtl.DTLVardef@1f745b1_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Dixit, S.. 2025-06-27. Alpha-2-Macroglobulin mitigates mitochondrial dysfunction and neuronal apoptotic responses in pesticide-induced neurotoxicity. https://doi.org/10.1101/2025.06.27.661925

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