Feiby L Nassan1, Joshua A Gunn2, Melissa M Hill2, Brent A Coull3, Russ Hauser4. 1. Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA. Electronic address: fen769@mail.harvard.edu. 2. Ethos Research & Development, Newport, KY, USA. 3. Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA. 4. Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology Harvard T. H. Chan School of Public Health, Boston, MA, USA; Vincent Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Abstract
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.
BACKGROUND:Quinolinic acid (QA), a neuroactive metabolite of the KynureninePathway (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-DBPmesalamine (background) at baseline crossed-over for 4 months to high-DBPmesalamine (high) (B1H-Arm) and vice versa for 15 men who were on high-DBPmesalamine 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-DBPmesalamine (H1B-Arm) had 72%, (95% confidence interval (CI): 18, 151) higher normalized-QA than men who were on background exposure and when high-DBPmesalamine 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-DBPmesalamine, 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.
Authors: Jonathan Savitz; Wayne C Drevets; Brent E Wurfel; Bart N Ford; Patrick S F Bellgowan; Teresa A Victor; Jerzy Bodurka; T Kent Teague; Robert Dantzer Journal: Brain Behav Immun Date: 2015-02-14 Impact factor: 7.217
Authors: Feiby L Nassan; Brent A Coull; Niels E Skakkebaek; Michelle A Williams; Ramace Dadd; Lidia Mínguez-Alarcón; Stephen A Krawetz; Elizabeth J Hait; Joshua R Korzenik; Alan C Moss; Jennifer B Ford; Russ Hauser Journal: Environ Int Date: 2016-08-26 Impact factor: 9.621
Authors: Feiby L Nassan; Brent A Coull; Niels E Skakkebaek; Anna-Maria Andersson; Michelle A Williams; Lidia Mínguez-Alarcón; Stephen A Krawetz; Janet E Hall; Elizabeth J Hait; Joshua R Korzenik; Jennifer B Ford; Alan C Moss; Russ Hauser Journal: Environ Res Date: 2017-10-01 Impact factor: 6.498
Authors: Katherine E Kelley; Sonia Hernández-Díaz; Erica L Chaplin; Russ Hauser; Allen A Mitchell Journal: Environ Health Perspect Date: 2011-12-15 Impact factor: 9.031