title: Short-term atrazine exposure causes behavioral deficits and disrupts monoaminergic systems in male C57BL/6 mice.
abstract: Excessive exposure to the widely used herbicide atrazine (ATR) affects several organ systems, including the brain, where neurochemical alterations reflective of dopamine (DA) circuitry perturbation have been reported. The present study aimed to investigate effects of short-term oral exposure to a dose-range (0, 5, 25, 125, or 250 mg/kg) of ATR on behavioral, neurochemical, and molecular indices of toxicity in adult male C57BL/6 mice. The experimental paradigm included open field, pole and grip tests (day 4), novel object recognition (NOR) and forced swim test (FST; day 9), followed by tissue collection 4h post dosing on day 10. After 4 days of exposure, ATR decreased locomotor activity (≥125 mg/kg). On day 9, ATR-exposed mice exhibited dose-dependent decreased performance in the NOR test (≥25 mg/kg) and spent more time swimming and less time immobile during the FST (≥125 mg/kg). Neurochemically, short-term ATR exposure increased striatal DA and DA turnover (its metabolite homovanillic acid [HVA] and the HVA/DA ratio; ≥125 mg/kg). In addition, ATR exposure increased the levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum (≥125 mg/kg) and it also increased DA turnover (≥125 mg/kg), 5-HIAA (125 mg/kg), and norepinephrine (≥125 mg/kg) levels in the prefrontal cortex. In the hippocampus, the only effect of ATR was to increase the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG; 250 mg/kg). At the molecular level, the expression of key striatal (protein) or nigral (mRNA) markers associated with nigrostriatal DA function, such as tyrosine hydroxylase, DA transporter, vesicular monoamine transporter 2, and DA receptors, was not affected by ATR. These results indicate that short-term ATR exposure targets multiple monoamine pathways at the neurochemical level, including in the striatum, and induces behavioral abnormalities suggestive of impaired motor and cognitive functions and increased anxiety. Impaired performance in the NOR behavioral test was the most sensitive endpoint affected by ATR; this should be taken into consideration for future low-dose ATR studies and for the assessment of risk associated with overexposure to this herbicide.
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.
authors.forename: Zhoumeng
authors.initials: Z
authors.lastname: Lin
authors.forename: Celia A
authors.initials: CA
authors.lastname: Dodd
authors.forename: Nikolay M
authors.initials: NM
authors.lastname: Filipov
mesh_terms: D000818:Animals; D001280:Atrazine / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D006540:Herbicides; D011954:Receptors, Dopamine; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; D001280:Atrazine; D004298:Dopamine; D009638:Norepinephrine
keywords: 3,4-dihydroxyphenylacetic acid; 3-MT; 3-methoxy-4-hydroxyphenylglycol; 3-methoxytyramine; 5-HIAA; 5-HT; 5-hydroxyindoleacetic acid; AChE; ANOVA; ATR; Atrazine; DA; DACT; DAT; DOPAC; Dopamine; Drd1; Drd2; Drd4; FST; Forced swim test; HRP; HVA; LOAEL; MHPG; N; NE; NOR; Newton; Novel object recognition test; Nurr1; PD; Parkinson's disease; Pesticides; TH; VMAT-2; VTA; acetylcholine esterase; analysis of variance; atrazine, 2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine; didealkylatrazine, 2-chloro-4,6-diamino-1,3,5-triazine; dopamine; dopamine receptor D1; dopamine receptor D2; dopamine receptor D4; dopamine transporter; forced swim test; homovanillic acid; horseradish peroxidase; intraperitoneal; ip; lowest observed adverse effect level; norepinephrine; novel object recognition test; nuclear receptor related 1; serotonin; tyrosine hydroxylase; ventral tegmental area; vesicular monoamine transporter 2