High phthalate exposure increased urinary concentrations of quinolinic acid, implicated in the pathogenesis of neurological disorders: Is this a potential missing link?

Background: Quinolinic acid (QA), a neuroactive metabolite of the Kynurenine Pathway (KP), is an excitotoxin that is implicated in the pathogenesis of many neurological disorders. KP is the main tryptophan degradation pathway. Phthalates can structurally mimic tryptophan metabolites and diets containing phthalates in rats enhanced the production and excretion of QA. However, there are no human studies that have examined the association between phthalates and QA. Objectives: Taking advantage of different mesalamine formulations with/without dibutyl phthalate (DBP), we assessed whether DBP from mesalamine (> 1000x background) altered the urinary concentrations of QA. Methods: Men with inflammatory bowel disease participated in a prospective crossover pilot study. 15 Men were on non-DBP mesalamine (background) at baseline crossed-over for 4 months to high-DBP mesalamine (high) (B1H-Arm) and vice versa for 15 men who were on high-DBP mesalamine at baseline (H1B-Arm). Men provided 60 urine samples (2/man). We estimated crossover and cross-sectional changes in the creatinine normalized-QA using multivariable linear mixed effect models with random intercepts. Results: At baseline, men who were on high-DBP mesalamine (H1B-Arm) had 72%, (95% confidence interval (CI): 18, 151) higher normalized-QA than men who were on background exposure and when high-DBP mesalamine was removed for four months, normalized-QA decreased with 32%, (95% CI: -45.0, -15.1). Consistently, when men in B1H-Arm were newly-exposed to high-DBP mesalamine, normalized-QA increased with 11%, (95% CI: -11, 38). Conclusions: High-DBP exposure from mesalamine increased the urinary concentrations of QA, which was largely reversed after removal of the high-DBP exposure for four months. This novel hypothesis should warrant new promising research considering the KP and QA concentrations as a plausible mediator for the neurotoxicity possibly linked with phthalate exposures.