Chlorothalonil causes intestinal injury by disrupting gut microbiota and decreasing sphinganine, which inactivates Nrf2 signaling and results in ferroptosis.
Chlorothalonil exposure induced histological intestinal damage including epithelial damage and goblet cell depletion in mice.
Chlorothalonil disrupted gut microbiota composition, specifically depleting Lactobacillus and enriching Enterococcus.
Untargeted metabolomics revealed that chlorothalonil exposure reduced intestinal sphinganine levels, linking microbiota disruption to oxidative stress and ferroptosis.
Chlorothalonil activated ferroptosis via the Keap1/Nrf2 pathway, evidenced by decreased GPX4 and SLC7A11 expression.
Iron deposition and mitochondrial injury, hallmark features of ferroptosis, were confirmed in chlorothalonil-exposed intestinal tissue.
Treatment with ferrostatin-1, a ferroptosis inhibitor, partially rescued the pathological phenotype induced by chlorothalonil.
The overall mechanistic pathway identified was that chlorothalonil causes microbiota dysbiosis leading to decreased sphinganine, which inactivates Nrf2 signaling and results in ferroptosis-mediated intestinal injury.
This research investigated how chlorothalonil, a widely used fungicide, damages the intestines. Scientists exposed mice to chlorothalonil and found that it caused visible damage to the intestinal lining, including loss of the mucus-producing cells that protect the gut. The fungicide also disrupted the balance of bacteria living in the gut, reducing beneficial Lactobacillus bacteria while allowing Enterococcus bacteria to overgrow. When the researchers transferred gut bacteria from chlorothalonil-exposed mice into healthy mice, the healthy mice also developed intestinal damage, confirming that the bacterial imbalance itself was causing harm. The study also found that chlorothalonil reduced levels of a molecule called sphinganine in the gut, which appears to be produced or regulated by gut bacteria. Low sphinganine levels led to a chain reaction that shut down a key cellular defense pathway (Nrf2 signaling), ultimately triggering a form of cell death called ferroptosis — a process involving iron accumulation and damage to cell energy structures (mitochondria). When the researchers gave mice a drug that blocks ferroptosis (ferrostatin-1), it partially protected the animals from the intestinal damage, providing further evidence that this cell death pathway is central to the harm caused by the fungicide. This research suggests that chlorothalonil may pose a risk to gut health through a previously unknown mechanism: by disrupting gut bacteria, depleting a protective molecule (sphinganine), and triggering a damaging form of cell death in intestinal cells. Since chlorothalonil is commonly used in agriculture and people may be exposed through food residues, these findings highlight the importance of understanding how pesticides and fungicides may affect the gut microbiome and intestinal health beyond their direct toxic effects.
Li Z, Hu Y, Chen L, Cheng J, Huang Y, Huang W, et al.. (2026). Fungicide Chlorothalonil Exposure Induced Intestinal Impairment via the Microbiota/Sphinganine/Ferroptosis Axis.. Journal of agricultural and food chemistry. https://doi.org/10.1021/acs.jafc.6c01962