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This study demonstrates that mancozeb, a common fungicide, causes astrocyte atrophy and disrupts calcium signaling in the brain by specifically inhibiting the Orai1/STIM1-mediated store-operated calcium entry (SOCE) pathway. Experiments in mice showed that chronic mancozeb exposure reduced astrocyte markers in the hippocampus and corpus callosum, altered inhibitory neurotransmission, and caused hyperlocomotor behavior. Notably, these neurotoxic effects occurred at doses at or below the current acceptable daily intake for humans, suggesting that existing safety standards may be inadequate.
Why it matters
These findings raise significant concerns about the safety of mancozeb, a widely used agricultural fungicide, as the observed neurotoxic effects occurred at exposure levels currently considered safe for human consumption. The identification of a specific molecular mechanism (Orai1/STIM1 inhibition) provides a scientific basis for re-evaluating regulatory exposure limits and highlights potential risks to brain health from environmental pesticide exposure.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Mancozeb, a widely used fungicide composed of manganese ethylene-bis-dithiocarbamate with zinc salts, has raised concerns due to its potential neurotoxic effects. In this study, we investigated how chronic oral administration of mancozeb affects astrocyte function and neurobehavior in mice, focusing on store-operated calcium entry (SOCE), mediated by Orai1 and STIM1. Mancozeb treatment at 0.5 ug/kg/day for 4 weeks reduced glial fibrillary acidic protein (GFAP) expression in the hippocampus and corpus callosum of mice, indicating astrocyte atrophy. Further, administration at the human acceptable daily intake (30 ug/kg/day) for 1 week induced hippocampal astrocyte atrophy and hyperlocomotor activity in open field tests. In vitro experiments revealed that mancozeb specifically inhibited SOCE in astrocytes by targeting the Orai1/STIM1 complex, as its inhibitory effect was abolished by short hairpin RNA (shRNA)-mediated knockdown of Orai1 or STIM1, but not by knockdown of TRPA1 or scramble shRNA. This demonstrates that mancozeb-mediated SOCE inhibition critically depends on the presence of Orai1 and STIM1, highlighting the molecular specificity of its action. Furthermore, mancozeb diminished endoplasmic reticulum (ER) calcium stores and P2Y1 receptor agonist-induced calcium transients. Electrophysiological analyses revealed that mancozeb selectively decreased the inhibitory postsynaptic current frequency without affecting excitatory currents, suggesting reduced astrocyte-mediated GABA release. Collectively, these findings demonstrate that mancozeb disrupts astrocytic calcium homeostasis through Orai1/STIM1-dependent SOCE inhibition, leading to astrocyte atrophy and altered inhibitory neurotransmission, which may underlie the observed behavioral changes. These results highlight the potential neurotoxic risk posed by mancozeb via the impairment of astrocyte function and intracellular calcium regulation. Importantly, these neurotoxic effects occurred at concentrations below current regulatory safety limits (ADI), indicating that mancozeb-induced disruption of astrocytic calcium signaling provides a mechanistic basis for re-evaluating established human safety exposure standards.