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Rotenone-induced toxicity is mediated by Rho-GTPases in hippocampal neurons
Monica Sanchez1, Laura Gastaldi, Monica Remedi
1Unidad CEPROCOR, Agencia Cordoba Ciencia, Córdoba, Argentina.
Abstract:
In this study, we have examined the effects of rotenone in primary cultures of hippocampal and dopaminergic neurons in order to obtain insights into the possible mechanisms underlying the neurotoxic effects of this pesticide. The results obtained indicate that a 48-h exposure to rotenone (0.1 microM) produces a complete and selective suppression of axon formation. This effect was dose dependent, not accompanied by changes in microtubule organization, and reversible after washout of the agrochemical from the tissue culture medium. Interestingly, pull-down assays revealed that rotenone decreases Cdc42 and Rac activities, whereas increasing that of Rho. In accordance with this, treatment of neuronal cultures with cytochalasin D, an actin-depolymerizing drug, or with the Rho-kinase inhibitor Y27632, or overexpression of Tiam1, a guanosine nucleotide exchange factor for Rac, reverts the inhibitory effect of rotenone on axon formation. Taken together, our data suggest that at least some of the neurotoxic effects of rotenone are associated with an inhibition of actin dynamics through modifications of Rho-GTPase activity.
Insights
Rotenone pesticide exposure impairs axon formation in neurons by disrupting actin dynamics. This neurotoxic effect is linked to altered Rho-GTPase activity and can be reversed by specific treatments.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Rotenone is a pesticide with known neurotoxic effects.
- Understanding the precise mechanisms of rotenone's neurotoxicity is crucial for public health and safety.
Purpose of the Study:
- To investigate the molecular mechanisms behind rotenone's neurotoxic effects on hippocampal and dopaminergic neurons.
- To identify specific cellular pathways affected by rotenone exposure.
Main Methods:
- Primary neuronal cultures (hippocampal and dopaminergic) were exposed to rotenone.
- Axon formation, microtubule organization, and Rho-GTPase activity (Cdc42, Rac, Rho) were assessed.
- Effects of specific drugs (cytochalasin D, Y27632) and gene overexpression (Tiam1) were evaluated.
Main Results:
- Rotenone (0.1 microM) selectively suppressed axon formation in a dose-dependent and reversible manner.
- Microtubule organization remained unchanged, but rotenone altered Rho-GTPase activity (decreased Cdc42/Rac, increased Rho).
- Treatments targeting actin dynamics and Rho-GTPase signaling (cytochalasin D, Y27632, Tiam1) reversed rotenone's inhibitory effect on axon formation.
Conclusions:
- Rotenone's neurotoxicity involves the inhibition of actin dynamics.
- Alterations in Rho-GTPase signaling pathways are a key mechanism underlying rotenone-induced neurotoxicity.
- These findings provide insights into the cellular basis of pesticide neurotoxicity and potential therapeutic targets.
