title: Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α-linolenate, tryptophan, tyrosine and other major metabolic pathways.
abstract: Overexposure to the commonly used herbicide atrazine (ATR) affects several organ systems, including the brain. Previously, we demonstrated that short-term oral ATR exposure causes behavioral deficits and dopaminergic and serotonergic dysfunction in the brains of mice. Using adult male C57BL/6 mice, the present study aimed to investigate effects of a 10-day oral ATR exposure (0, 5, 25, 125, or 250mg/kg) on the mouse plasma metabolome and to determine metabolic pathways affected by ATR that may be reflective of ATR's effects on the brain and useful to identify peripheral biomarkers of neurotoxicity. Four hours after the last dosing on day 10, plasma was collected and analyzed with high-performance, dual chromatography-Fourier-transform mass spectrometry that was followed by biostatistical and bioinformatic analyses. ATR exposure (≥5mg/kg) significantly altered plasma metabolite profile and resulted in a dose-dependent increase in the number of metabolites with ion intensities significantly different from the control group. Pathway analyses revealed that ATR exposure strongly correlated with and disrupted multiple metabolic pathways. Tyrosine, tryptophan, linoleic acid and α-linolenic acid metabolic pathways were among the affected pathways, with α-linolenic acid metabolism being affected to the greatest extent. Observed effects of ATR on plasma tyrosine and tryptophan metabolism may be reflective of the previously reported perturbations of brain dopamine and serotonin homeostasis, respectively. ATR-caused alterations in the plasma profile of α-linolenic acid metabolism are a potential novel and sensitive plasma biomarker of ATR effect and plasma metabolomics could be used to better assess the risks, including to the brain, associated with ATR overexposure.
authors.affiliation: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA; Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA. Electronic address: zhoumeng@ksu.edu.
authors.forename: Zhoumeng
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: James.Roede@ucdenver.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Roede
authors.affiliation: Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, GA 30602, USA. Electronic address: willahe@uga.edu.
authors.forename: Chunla
authors.initials: C
authors.lastname: He
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: dpjones@emory.edu.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
authors.affiliation: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA; Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA. Electronic address: filipov@uga.edu.
authors.forename: Nikolay M
authors.initials: NM
authors.lastname: Filipov
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001280:Atrazine / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods; D008810:Mice, Inbred C57BL; D017550:Spectroscopy, Fourier Transform Infrared; D013997:Time Factors; D023382:Toxicity Tests, Acute; D014364:Tryptophan / Q000097:blood*; D014443:Tyrosine / Q000097:blood*; D017962:alpha-Linolenic Acid / Q000097:blood*
chemical_list: D015415:Biomarkers; D006540:Herbicides; D017962:alpha-Linolenic Acid; D014443:Tyrosine; D014364:Tryptophan; D001280:Atrazine
keywords: Atrazine; Biomarker; Dual chromatography-Fourier-transform mass spectrometry (DC-FTMS); Metabolic pathway analysis; Metabolomics; Pesticide