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Short-term atrazine exposure causes behavioral deficits and disrupts monoaminergic systems in male C57BL/6 mice.
Neurotoxicol Teratol 2013 Sep-Oct; 39:26-35NT

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+Show Affiliations

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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23770127

Citation

Lin, Zhoumeng, et al. "Short-term Atrazine Exposure Causes Behavioral Deficits and Disrupts Monoaminergic Systems in Male C57BL/6 Mice." Neurotoxicology and Teratology, vol. 39, 2013, pp. 26-35.
Lin Z, Dodd CA, Filipov NM. Short-term atrazine exposure causes behavioral deficits and disrupts monoaminergic systems in male C57BL/6 mice. Neurotoxicol Teratol. 2013;39:26-35.
Lin, Z., Dodd, C. A., & Filipov, N. M. (2013). Short-term atrazine exposure causes behavioral deficits and disrupts monoaminergic systems in male C57BL/6 mice. Neurotoxicology and Teratology, 39, pp. 26-35. doi:10.1016/j.ntt.2013.06.002.
Lin Z, Dodd CA, Filipov NM. Short-term Atrazine Exposure Causes Behavioral Deficits and Disrupts Monoaminergic Systems in Male C57BL/6 Mice. Neurotoxicol Teratol. 2013;39:26-35. PubMed PMID: 23770127.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Short-term atrazine exposure causes behavioral deficits and disrupts monoaminergic systems in male C57BL/6 mice. AU - Lin,Zhoumeng, AU - Dodd,Celia A, AU - Filipov,Nikolay M, Y1 - 2013/06/14/ PY - 2013/04/03/received PY - 2013/06/06/revised PY - 2013/06/06/accepted PY - 2013/6/18/entrez PY - 2013/6/19/pubmed PY - 2014/11/19/medline KW - 3,4-dihydroxyphenylacetic acid KW - 3-MT KW - 3-methoxy-4-hydroxyphenylglycol KW - 3-methoxytyramine KW - 5-HIAA KW - 5-HT KW - 5-hydroxyindoleacetic acid KW - AChE KW - ANOVA KW - ATR KW - Atrazine KW - DA KW - DACT KW - DAT KW - DOPAC KW - Dopamine KW - Drd1 KW - Drd2 KW - Drd4 KW - FST KW - Forced swim test KW - HRP KW - HVA KW - LOAEL KW - MHPG KW - N KW - NE KW - NOR KW - Newton KW - Novel object recognition test KW - Nurr1 KW - PD KW - Parkinson's disease KW - Pesticides KW - TH KW - VMAT-2 KW - VTA KW - acetylcholine esterase KW - analysis of variance KW - atrazine, 2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine KW - didealkylatrazine, 2-chloro-4,6-diamino-1,3,5-triazine KW - dopamine KW - dopamine receptor D1 KW - dopamine receptor D2 KW - dopamine receptor D4 KW - dopamine transporter KW - forced swim test KW - homovanillic acid KW - horseradish peroxidase KW - intraperitoneal KW - ip KW - lowest observed adverse effect level KW - norepinephrine KW - novel object recognition test KW - nuclear receptor related 1 KW - serotonin KW - tyrosine hydroxylase KW - ventral tegmental area KW - vesicular monoamine transporter 2 SP - 26 EP - 35 JF - Neurotoxicology and teratology JO - Neurotoxicol Teratol VL - 39 N2 - 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. SN - 1872-9738 UR - https://www.unboundmedicine.com/medline/citation/23770127/Short_term_atrazine_exposure_causes_behavioral_deficits_and_disrupts_monoaminergic_systems_in_male_C57BL/6_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0892-0362(13)00157-8 DB - PRIME DP - Unbound Medicine ER -