Neurotoxicity has been linked with exposure to a number of common drugs and chemicals, yet efficient, accurate, and minimally invasive methods to detect it are lacking. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid have great potential due to the relative ease of sampling but at present, data on their expression and translation are lacking or inconsistent. In this pilot study using a trimethyl tin rat model of central nervous system toxicity, we have applied state-of-the-art assessment techniques to identify potential individual biomarkers and patterns of biomarkers in serum, plasma, urine or cerebral spinal fluid that may be indicative of nerve cell damage and degeneration. Overall changes in metabolites and microRNAs were observed in biological fluids that were associated with neurotoxic damage induced by trimethyl tin. Behavioral changes and magnetic resonance imaging T2 relaxation and ventricle volume changes served to identify animals that responded to the adverse effects of trimethyl tin.
Impact statement
These data will help design follow-on studies with other known neurotoxicants to be used to assess the broad applicability of the present findings. Together this approach represents an effort to begin to develop and qualify a set of translational biochemical markers of neurotoxicity that will be readily accessible in humans. Such biomarkers could prove invaluable for drug development research ranging from preclinical studies to clinical trials and may prove to assist with monitoring of the severity and life cycle of brain lesions.
CookDBrownDAlexanderRMarchRMorganPSatterthwaiteGPangalosMN.Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework. Nat Rev Drug Discov2014;
13:419–31
2.
RobertsRAAschnerMCalligaroDGuilarteTRHanigJPHerrDWHudzikTJJerominAKallmanMJLiachenkoSLynchJJ3rdMillerDBMoserVCO'callaghanJPSlikkerWJrPauleMG.Translational biomarkers of neurotoxicity: a health and environmental sciences institute perspective on the way forward. Toxicol Sci2015;
148:332–40
3.
FodaleVTripodiVFPennaOFamaFSquadritoFMondelloEDavidA.An update on anesthetics and impact on the brain. Expert Opin Drug Saf2017;
16:997–1008
4.
VitaliMRipamontiCIRoilaFProtoCSignorelliDImbimboMCorraoGBrissaARosariaGde BraudFGarassinoMCRussoGL.Cognitive impairment and chemotherapy: a brief overview. Crit Rev Oncol Hematol2017;
118:7–14
5.
StauchKLEmanuelKLambertyBGMorseyBFoxHS.Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals. J NeurovirolEpub ahead of print 2017. doi: 10.1007/s13365-017-0573-5.
6.
BolonBGarmanRHPardoIDJensenKSillsRCRouloisARadovskyABradleyAAndrews-JonesLButtMGumprechtL.STP position paper: recommended practices for sampling and processing the nervous system (brain, spinal cord, nerve, and eye) during nonclinical general toxicity studies. Toxicol Pathol2013;
41:1028–48
7.
KohWPanWGawadCFanHCKerchnerGAWyss-CorayTBlumenfeldYJEl-SayedYYQuakeSR.Noninvasive in vivo monitoring of tissue-specific global gene expression in humans. Proc Natl Acad Sci U S A2014;
111:7361–6
8.
GuoDLiuJWangWHaoFSunXWuXBuPZhangYLiuYZhangQJiangF.Alteration in abundance and compartmentalization of inflammation-related miRNAs in plasma after intracerebral hemorrhage. Stroke2013;
44:1739–42
9.
HanigJPauleMGRamuJSchmuedLKonakTChigurupatiSSlikkerWJrSarkarSLiachenkoS.The use of MRI to assist the section selections for classical pathology assessment of neurotoxicity. Regul Toxicol Pharmacol2014;
70:641–7
10.
LiachenkoSRamuJKonakTPauleMGHanigJ.Quantitative assessment of MRI T2 response to kainic acid neurotoxicity in rats in vivo. Toxicol Sci2015;
146:183–91
11.
BalabanCDO'callaghanJPBillingsleyML.Trimethyltin-induced neuronal damage in the rat brain: comparative studies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins. Neuroscience1988;
26:337–61
12.
BrockTOO'callaghanJP.Quantitative changes in the synaptic vesicle proteins synapsin I and p38 and the astrocyte-specific protein glial fibrillary acidic protein are associated with chemical-induced injury to the rat central nervous system. J Neurosci1987;
7:931–42
13.
WoodcockJBuckmanSGoodsaidFWaltonMKZinehI.Qualifying biomarkers for use in drug development: a US Food and Drug Administration overview. Expert Opin Med Diagn2011;
5:369–74
14.
FergusonSALawCDSarkarS.Chronic MPTP treatment produces hyperactivity in male mice which is not alleviated by concurrent trehalose treatment. Behav Brain Res2015;
292:68–78
15.
MoserVCStewartNFreebornDLCrooksJMacMillanDKHedgeJMWoodCEMcMahenRLStrynarMJHerrDW.Assessment of serum biomarkers in rats after exposure to pesticides of different chemical classes. Toxicol Appl Pharmacol2015;
282:161–74
16.
ImamSZLantz-McPeakSMCuevasERosas-HernandezHLiachenkoSZhangYSarkarSRamuJRobinsonBLJonesYGoughBPauleMGAliSFBiniendaZK.Iron oxide nanoparticles induce dopaminergic damage: in vitro pathways and in vivo imaging reveals mechanism of neuronal damage. Mol Neurobiol2015;
52:913–26
17.
EbertMSSharpPA.Roles for microRNAs in conferring robustness to biological processes. Cell2012;
149:515–24
18.
HaghikiaAHaghikiaAHellwigKBaraniskinAHolzmannADecardBFThumTGoldR.Regulated microRNAs in the CSF of patients with multiple sclerosis: a case-control study. Neurology2012;
79:2166–70
19.
MitchellPSParkinRKKrohEMFritzBRWymanSKPogosova-AgadjanyanELPetersonANoteboomJO'briantKCAllenALinDWUrbanNDrescherCWKnudsenBSStirewaltDLGentlemanRVessellaRLNelsonPSMartinDBTewariM.Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci UsaU S A2008;
105:10513–8
20.
MestdaghPHartmannNBaeriswylLAndreasenDBernardNChenCCheoDD'andradePDeMayoMDennisLDerveauxLFengYFulmer-SmentekSGerstmayerBGouffonJGrimleyCLaderELeeKYLuoSMouritzenPNarayananAPatelSPeifferSRubergSSchrothGSchusterDShafferJMSheltonEJSilveriaSUlmanellaUVeeramachaneniVStaedtlerFPetersTGuettoucheTWongLVandesomepleJ.Evaluation of quantitative miRNA expression platforms in the microRNA quality control (miRQC) study. Nat Meth2014;
11:809–15
21.
RegevKHealyBCKhalidFPaulAChuRTauhidSTummalaSDiaz-CruzCRahejaRMazzolaMAvon GlehnFKivisakkPDupuySLKimGChitnisTWeinerHLGandhiRBakshiR.Association between serum MicroRNAs and magnetic resonance imaging measures of multiple sclerosis severity. JAMA Neurol2017;
74:275–85
22.
LudwigNLeidingerPBeckerKBackesCFehlmannTPallaschCRheinheimerSMederBStahlerCMeeseEKellerA.Distribution of miRNA expression across human tissues. Nucleic Acids Res2016;
44:3865–77
23.
HoyeMLKovalEDWegenerAJHymanTSYangCO'brienDRMillerRLColeTSchochKMShenTKunikataTRichardJPGutmannDHMaragaskiNJKordasiewiczHBDoughertyJDMillerTM.MicroRNA profiling reveals marker of motor neuron disease in ALS models. J Neurosci2017;
37:5574–86
24.
RadhakrishnanBAlwin Prem AnandA.Role of miRNA-9 in brain development. J Exp Neurosci2016;
10:101–20
HillAB.The environment and disease: association or causation?Proc R Soc Med1965;
58:295–300
27.
MeekMEPalermoCMBachmanANNorthCMJeffrey LewisR.Mode of action human relevance (species concordance) framework: evolution of the Bradford Hill considerations and comparative analysis of weight of evidence. J Appl Toxicol2014;
34:595–606
28.
McGillMRLiFSharpeMRWilliamsCDCurrySCMaXJaeschkeH.Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans. Arch Toxicol2014;
88:391–401
29.
JonesLLMcDonaldDABorumPR.Acylcarnitines: role in brain. Prog Lipid Res2010;
49:61–75
30.
WuG.Amino acids: metabolism, functions, and nutrition. AminoAcids2009;
37:1–17
31.
ColeLKVanceJEVanceDE.Phosphatidylcholine biosynthesis and lipoprotein metabolism. Biochim Biophys Acta2012;
1821:754–61
32.
HermanssonMHokynarKSomerharjuP.Mechanisms of glycerophospholipid homeostasis in mammalian cells. Prog Lipid Res2011;
50:240–57
33.
FarooquiAAHorrocksLAFarooquiT.Glycerophospholipids in brain: their metabolism, incorporation into membranes, functions, and involvement in neurological disorders. Chem Phys Lipids2000;
106:1–29
34.
FilippiMRoccaMAArnoldDLBakshiRBarkhofFDe StefanoNFazekasFFrohmanEWolinskyJS.EFNS guidelines on the use of neuroimaging in the management of multiple sclerosis. Eur J Neurol2006;
13:313–25
35.
FilippiMWolinskyJSComiGGroupCS.Effects of oral glatiramer acetate on clinical and MRI-monitored disease activity in patients with relapsing multiple sclerosis: a multicentre, double-blind, randomised, placebo-controlled study. Lancet Neurol2006;
5:213–20
36.
SanfilipoMPBenedictRHSharmaJWeinstock-GuttmanBBakshiR.The relationship between whole brain volume and disability in multiple sclerosis: a comparison of normalized gray vs. white matter with misclassification correction. Neuroimage2005;
26:1068–77
37.
SanfilipoMPBenedictRHWeinstock-GuttmanBBakshiR.Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology2006;
66:685–92
38.
LittleARBenkovicSAMillerDBO'callaghanJP.Chemically induced neuronal damage and gliosis: enhanced expression of the proinflammatory chemokine, monocyte chemoattractant protein (MCP)-1, without a corresponding increase in proinflammatory cytokines(1). Neuroscience2002;
115:307–20
