title: Chronic low-level Pb exposure during development decreases the expression of the voltage-dependent anion channel in auditory neurons of the brainstem.
abstract: Lead (Pb) exposure is a risk factor for neurological dysfunction. How Pb produces these behavioral deficits is unknown, but Pb exposure during development is associated with auditory temporal processing deficits in both humans and animals. Pb disrupts cellular energy metabolism and efficient energy production is crucial for auditory neurons to maintain high rates of synaptic activity. The voltage-dependent anion channel (VDAC) is involved in the regulation of mitochondrial physiology and is a critical component in controlling mitochondrial energy production. We have previously demonstrated that VDAC is an in vitro target for Pb, therefore, VDAC may represent a potential target for Pb in the auditory system. In order to determine whether Pb alters VDAC expression in central auditory neurons, CBA/CaJ mice (n=3-5/group) were exposed to 0.01mM, or 0.1mM Pb acetate during development via drinking water. At P21, immunohistochemistry reveals a significant decrease for VDAC in neurons of the Medial Nucleus of the Trapezoid Body. Western blot analysis confirms that Pb results in a significant decrease for VDAC. Decreases in VDAC expression could lead to an upregulation of other cellular energy producing systems as a compensatory mechanism, and a Pb-induced increase in brain type creatine kinase is observed in auditory regions of the brainstem. In addition, comparative proteomic analysis shows that several proteins of the glycolytic pathway, the phosphocreatine circuit, and oxidative phosphorylation are also upregulated in response to developmental Pb exposure. Thus, Pb-induced decreases in VDAC could have a significant effect on the function of auditory neurons.
authors.affiliation: Center for Structural and Functional Neuroscience, Center for Environmental Health Sciences, Department of Biomedical & Pharmaceutical Sciences, College of Health Professions and Biomedical Sciences, The University of Montana, Missoula, MT 59812, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Prins
authors.forename: Diane M
authors.initials: DM
authors.lastname: Brooks
authors.forename: Charles M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Diana I
authors.initials: DI
authors.lastname: Lurie
mesh_terms: D000818:Animals; D001306:Auditory Pathways / Q000166:cytology* / Q000187:drug effects* / Q000254:growth & development; D001933:Brain Stem / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007854:Lead / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008808:Mice, Inbred CBA; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D050994:Voltage-Dependent Anion Channels / Q000096:biosynthesis*
chemical_list: D050994:Voltage-Dependent Anion Channels; D007854:Lead
references.citation: Brain. 2003 Jan;126(Pt 1):5-19
references.pmid: 12477693
references.citation: Biochim Biophys Acta. 2004 Jul 9;1657(2-3):105-14
references.pmid: 15238267
references.citation: Mol Cell Biochem. 1994 Apr-May;133-134:193-220
references.pmid: 7808454
references.citation: Hear Res. 1996 Sep 1;98(1-2):29-37
references.pmid: 8880179
references.citation: Environ Health Perspect. 2006 Dec;114(12):1904-9
references.pmid: 17185283
references.citation: Toxicol Sci. 2002 Mar;66(1):139-47
references.pmid: 11861981
references.citation: Endocrinology. 2007 Feb;148(2):627-37
references.pmid: 17082253
references.citation: Brain Lang. 2005 Dec;95(3):450-6
references.pmid: 16298671
references.citation: Toxicol Sci. 2010 Jan;113(1):169-76
references.pmid: 19822599
references.citation: Toxicol Appl Pharmacol. 2007 Nov 15;225(1):1-27
references.pmid: 17904601
references.citation: Acta Neurobiol Exp (Wars). 1996;56(2):611-7
references.pmid: 8768312
references.citation: Neurotoxicology. 2006 Sep;27(5):693-701
references.pmid: 16889836
references.citation: Brain Res Brain Res Rev. 2005 Nov;49(3):529-54
references.pmid: 16269318
references.citation: Cell Biochem Biophys. 2003;39(3):279-92
references.pmid: 14716081
references.citation: Neurochem Res. 1978 Apr;3(2):195-206
references.pmid: 673116
references.citation: Dev Neurobiol. 2007 Sep 15;67(11):1533-45
references.pmid: 17525991
references.citation: Cancer Res. 2006 Jan 15;66(2):763-9
references.pmid: 16424007
references.citation: J Neurosci Res. 2007 Nov 1;85(14):3160-70
references.pmid: 17893921
references.citation: Brain Res Brain Res Rev. 1998 Jul;27(2):168-76
references.pmid: 9622620
references.citation: J Laryngol Otol. 1986 Sep;100(9):1031-6
references.pmid: 3760684
references.citation: Neurotoxicology. 1999 Feb;20(1):71-82
references.pmid: 10091860
references.citation: J Speech Lang Hear Res. 2003 Feb;46(1):31-42
references.pmid: 12647886
references.citation: Neurotoxicology. 1993 Summer-Fall;14(2-3):191-207
references.pmid: 8247393
references.citation: Biochim Biophys Acta. 2006 Feb;1762(2):181-90
references.pmid: 16307870
references.citation: J Exp Biol. 2003 Jun;206(Pt 12):2039-47
references.pmid: 12756286
references.citation: J Membr Biol. 2005 Mar;204(2):57-66
references.pmid: 16151701
references.citation: Neurotoxicology. 2006 Jan;27(1):108-17
references.pmid: 16162360
references.citation: Environ Health Perspect. 1990 Nov;89:43-8
references.pmid: 1982434
references.citation: J Comp Neurol. 2009 Apr 10;513(5):542-58
references.pmid: 19226511
references.citation: Annu Rev Biochem. 1985;54:831-62
references.pmid: 3896131
references.citation: J Comp Neurol. 2008 Feb 20;506(6):1003-17
references.pmid: 18085597
references.citation: Brain Res Brain Res Rev. 2000 Nov;34(1-2):42-68
references.pmid: 11086186
references.citation: Cell Tissue Res. 2006 Nov;326(2):311-37
references.pmid: 16896951
references.citation: Neurotoxicology. 2000 Dec;21(6):1057-68
references.pmid: 11233752
references.citation: J Neurochem. 1981 Mar;36(3):1109-13
references.pmid: 7205261
references.citation: Curr Pharm Des. 2006;12(18):2249-70
references.pmid: 16787253
references.citation: Biochem J. 1992 Jan 1;281 ( Pt 1):21-40
references.pmid: 1731757
references.citation: Biochim Biophys Acta. 1999 Oct 13;1452(1):68-78
references.pmid: 10525161
references.citation: Annu Rev Physiol. 1999;61:477-96
references.pmid: 10099698
references.citation: Anat Rec A Discov Mol Cell Evol Biol. 2006 Apr;288(4):409-23
references.pmid: 16550588
references.citation: Brain Res Bull. 2008 Jul 1;76(4):329-43
references.pmid: 18502307