Synergistic effects of arsenic and dibutyl phthalate on renal autophagy inhibition and fibrosis based on transcriptomic and computational toxicology

As an endocrine-disrupting chemical, dibutyl phthalate (DBP) is extensively utilized in industry, and it poses substantial hazards to both ecological and human health. Arsenic (As) is prevalent in everyday life and frequently encountered as environmental contaminants. The widespread contamination of As in the environment has elevated the associated health risks to a global public health challenge. This common As pollution not only severely undermines environmental quality but also endangers ecological security and the stability of ecosystems. The potential detrimental impacts of As or DBP on kidney injury have been extensively explored. Nevertheless, the mechanism of their combined toxicity as co-existing pollutants in the environment is not well understood. This research established an animal model of Hy-Line Brown laying hens exposed to As (55 mg/L), DBP (500 mg/kg), and combined As + DBP for 12 weeks, and then analyzed the toxicity mechanism of As and DBP in chicken kidneys by computational toxicology, transcriptomic analysis, immunofluorescence, and molecular docking. Our results showed that co-exposure to As and DBP induced overt renal dysfunction, accompanied by aberrant upregulation of cytochrome P450 enzyme superfamily members, which triggered antioxidant system impairment and marked downregulation of antioxidant-related gene expression. Ultimately, DBP exacerbated As-induced renal autophagy inhibition and fibrosis. Mechanistic analysis showed that activation of the signaling pathway involving AKT serine/threonine kinase 1 (AKT1) and mammalian target of rapamycin (mTOR) is the core link of As-induced kidney injury, and DBP may participate in the toxic interaction by regulating oxidative stress. Together, DBP exacerbates the As-induced renal autophagy inhibition and fibrosis via activating the AKT1/mTOR signaling pathway. This study offers a novel insight into elucidating the health hazards and pathogenic mechanism associated with co-exposure to As and DBP.