title: Dietary administration of paraquat for 13 weeks does not result in a loss of dopaminergic neurons in the substantia nigra of C57BL/6J mice.
abstract: Several investigations have reported that mice administered paraquat dichloride (PQ·Cl2) by intraperitoneal injection exhibit a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, male and female C57BL/6J mice were administered PQ·Cl2 in the diet at concentrations of 0 (control), 10, and 50ppm for a duration of 13weeks. A separate group of mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) during week 12 as positive controls to produce a loss of dopaminergic neurons in the SNpc. The comparative effects of PQ and MPTP on the SNpc and/or striatum were assessed using neurochemical, neuropathological, and stereological endpoints. Morphological and stereological assessments were performed by investigators 'blinded' to the origin of the tissue. Neither dose of PQ·Cl2 (10 or 50 ppm in the diet) caused a loss of striatal dopamine or dopamine metabolite concentrations in the brains of mice. Pathological assessments of the SNpc and striatum showed no evidence of neuronal degeneration or astrocytic/microglial activation. Furthermore, the number of tyrosine hydroxylase-positive (TH(+)) neurons in the SNpc was not reduced in PQ-treated mice. In contrast, MPTP caused a decrease in striatal dopamine concentration, a reduction in TH(+) neurons in the SNpc, and significant pathological changes including astrocytic and microglial activation in the striatum and SNpc. The MPTP-induced effects were greater in males than in females. It is concluded that 13weeks of continuous dietary exposure of C57BL/6J mice to 50ppm PQ·Cl2 (equivalent to 10.2 and 15.6mg PQ ion/kg body weight/day for males and females, respectively) does not result in the loss of, or damage to, dopaminergic neurons in the SNpc.
authors.affiliation: Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419-8300, USA. Electronic address: daniel.minnema@syngenta.com.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Minnema
authors.affiliation: Syngenta Limited, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK.
authors.forename: Kim Z
authors.initials: KZ
authors.lastname: Travis
authors.affiliation: Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419-8300, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Breckenridge
authors.affiliation: Syngenta Limited, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Sturgess
authors.affiliation: Tox Path Specialists, LLC, 8420 Gas House Pike, Frederick, MD 21701-2607, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Butt
authors.affiliation: Experimental Pathology Laboratories, Inc., 45600 Terminal Drive, Sterling, VA 20166, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Wolf
authors.affiliation: Experimental Pathology Laboratories, Inc., 45600 Terminal Drive, Sterling, VA 20166, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Zadory
authors.affiliation: WIL Research Laboratories, Ltd., Ashland, OH 44805, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Beck
authors.affiliation: RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Mathews
authors.affiliation: Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419-8300, USA.
authors.forename: Merrill O
authors.initials: MO
authors.lastname: Tisdel
authors.affiliation: Syngenta Limited, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cook
authors.affiliation: Syngenta Limited, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Botham
authors.affiliation: University of Leicester, University Road, Leicester, LE1 7RH, UK.
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Smith
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006540:Herbicides / Q000008:administration & dosage / Q000633:toxicity*; D020267:MPTP Poisoning / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010269:Paraquat / Q000008:administration & dosage / Q000633:toxicity*; D012737:Sex Factors; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D006540:Herbicides; D014446:Tyrosine 3-Monooxygenase; D010269:Paraquat; D004298:Dopamine
keywords: C57BL/6J mice; Dopamine; MPTP; Paraquat; Substantia nigra