Imidacloprid exposure at population-relevant doses induces hepatic lipid dysregulation: Exploring the role of cGAS-STING pathway-mediated hepatocyte senescence.

Imidacloprid (IMI) exposure at human-relevant doses led to liver function impairment and histopathological changes in mice over 24 weeks.

• A 24-week drinking water exposure experiment was conducted in mice using three human-relevant doses of IMI: 0.015 μg/mL, 0.52 μg/mL, and 0.033 mg/mL.
• Toxicological analyses confirmed liver function impairment across exposure groups.
• Histopathological changes in liver tissue were observed in IMI-exposed mice.
• The study design aimed to reflect long-term human-relevant exposure conditions.

IMI exposure induced abnormal hepatic lipid metabolism in mice at population-relevant doses.

• Hepatic lipid metabolism abnormalities were statistically significant (p < 0.05) across IMI-exposed groups.
• Three dose levels reflecting human-relevant exposures were tested over 24 weeks via drinking water.
• Lipid dysregulation was observed as part of a broader hepatotoxic profile induced by IMI.

IMI exposure upregulated the expression of senescence-associated proteins in mouse liver.

• Senescence-associated protein expression was significantly elevated in IMI-exposed mice (p < 0.05).
• Upregulation of senescence markers was observed across human-relevant dose groups.
• The induction of hepatocyte senescence was identified as a component of IMI's hepatotoxic mechanism.

The cGAS-STING pathway was identified as a mediator of IMI-induced hepatocyte senescence.

• Mechanistic investigations in HepG2 cells revealed that the cGAS-STING pathway may mediate hepatocyte senescence induced by IMI.
• Inhibition of the cGAS-STING pathway in HepG2 cells markedly alleviated cellular lipid metabolic disorders (p < 0.05).
• Inhibition of this pathway also significantly reduced cellular senescence in HepG2 cells (p < 0.05).
• The findings link cGAS-STING pathway activation to both hepatocyte senescence and lipid metabolism dysregulation.

Existing evidence has linked IMI exposure to lipid metabolism disorders, but the mechanisms at human-relevant doses were incompletely elucidated prior to this study.

• The long-term impact of IMI exposure at human-relevant doses was described as 'even less well characterized' prior to this study.
• The study was framed as filling a research gap regarding mechanisms mediating IMI-induced hepatic lipid metabolism aberrations and hepatocyte senescence.
• IMI is classified as a neonicotinoid pesticide, and the authors call for additional toxicological investigations based on human-relevant exposure levels to comprehensively evaluate neonicotinoid toxicity.