An unintended consequence of sub-NOAEL triazole fungicides exposure: Bile acids disturbance mediated drug absorption perturbation

Triazole fungicides (TFs) are widely detected in food due to their extensive agricultural use. Current risk assessments of TFs, based on the no observed adverse effect level (NOAEL), mainly aim to prevent overt toxicities but overlook subtler physiological disruptions. TFs mainly accumulate in liver and non-specifically inhibit cytochrome P450 (CYP) enzymes, potentially disrupting CYP-related functions. Bile acids (BAs) are the key mediators for lipid absorption in intestine, and the rate-limiting enzymes for BAs synthesis, CYP7A1 and 27A1, are also members of the CYP family. With global population aging, more people are suffering from multiple chronic diseases and need long-term medication. In the present study, short-/long-term of one-twentieth/-fourth NOAEL oral tebuconazole (TEB) exposure animal models were established, and a series of beta blockers for cardiovascular diseases were selected to examine the effects of sub-NOAEL TEB-exposure on BAs pool and the related drug absorption behavior. It confirmed that the sub-NOAEL TEB exposure induced a hormesis in CYP7A1 and 27A1 activity in liver, led to significant BAs pool disturbance on capacity and composition, and increased the oral absorption rate of lipophilic propranolol hydrochloride. In vitro and in situ models suggested that the TEB-exposure-induced BAs-pool-disturbance led to a significant promotion on lipophilic beta-blocker permeation, through altering the structure and rheological properties of the mucus layer in intestine, and disrupting the tight junctions between intestinal epithelia. These changes are very likely to be dangerous to patients with cardiovascular diseases. This study calls for a critical re-evaluation of low-dose pesticide residues to public health, particularly vulnerable populations with multi-medication.