Journal of the Neurological Sciences
Volume 280, Issue 1 , Pages 101-108 , 15 May 2009

Biomarkers of environmental toxicity and susceptibility in autism

  • David A. Geier

      Affiliations

    • Institute of Chronic Illnesses, Inc., Silver Spring, Maryland, USA
    • CoMeD, Inc., Silver Spring, Maryland, USA
    • ,
  • Janet K. Kern

      Affiliations

    • Autism Treatment Center, Dallas, Texas, USA
    • University of Texas Southwestern Medical Center, Dallas, Texas, USA
    • ,
  • Carolyn R. Garver

      Affiliations

    • Autism Treatment Center, Dallas, Texas, USA
    • ,
  • James B. Adams

      Affiliations

    • Arizona State University, Tempe, Arizona, USA
    • ,
  • Tapan Audhya

      Affiliations

    • Vitamin Diagnostics, Cliffwood Beach, New Jersey, USA
    • ,
  • Robert Nataf

      Affiliations

    • Laboratoire Philippe Auguste, Paris, France
    • ,
  • Mark R. Geier

      Affiliations

    • The Genetic Centers of America, Silver Spring, Maryland, USA
    • Corresponding Author InformationCorresponding author. 14 Redgate Ct., Silver Spring, MD 20905, USA. Tel.: +1 301 989 0548; fax: +1 301 989 1543.

Received 21 May 2008 ,Revised 11 August 2008 ,Accepted 15 August 2008.

References 

  1. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2002 Principal Investigators. Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders—autism and developmental disabilities monitoring network, 13 sites, United States, 2002. MMWR Surveill Summ. 2007;56:12–28
  2. Eigsti IM, Shapiro T. A systems neuroscience approach to autism: biological, cognitive, and clinical perspectives. Ment Retard Dev Disabil Res Rev. 2003;9:205–215
  3. White JF. Intestinal pathophysiology in autism. Exp Biol Med. 2003;228:639–649
  4. Sweeten TL, Bowyer SL, Posey DJ, Halberstadt CM, McDougle CJ. Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics. 2003;112:e420
  5. Bolte S, Poustka F. The relation between general cognitive level and adaptive behavior domains in individuals with autism with and without co-morbid mental retardation. Child Psychiatry Hum Dev. 2002;33:165–172
  6. Herbert MR, Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG, et al. Autism and environmental genomics. Neurotoxicology. 2006;27:671–684
  7. Mutter J, Naumann J, Guethlin C. Comments on the article “the toxicology of mercury and its chemical compounds” by Clarkson and Magos (2006). Crit Rev Toxicol. 2007;37:537–549
  8. Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev. 2006;9:485–499
  9. Mutter J, Naumann J, Schneider R, Walach H, Haley B. Mercury and autism: accelerating evidence?. Neuro Endocrinol Lett. 2005;26:439–446
  10. National Institute of Environmental Health Sciences . A research-oriented framework for risk assessment and prevention of children's exposure to environmental toxicants. Environ Health Perspect. 1999;107:510
  11. Nelson BK. Evidence for behavioral teratogenicity in humans. J Appl Toxicol. 1991;11:33–37
  12. Chrysochoou C, Rutishauser C, Rauber-Luthy C, Neuhaus T, Boltshauser E, Superti-Furga A. An 11-month-old boy with psychomotor regression and auto-aggressive behavior. Eur J Pediatr. 2003;162:559–561
  13. Faustman EM, Silbernagel SM, Fenske RA, Burbacher TM, Ponce RA. Mechanisms underlying children's susceptibility to environmental toxicants. Environ Health Perspect. 2000;108(Supple 1):13–21
  14. Collaborative on Health and the Environment's Learning and Developmental Disabilities Initiative. In: LDDI Scientific consensus statement on environmental agents associated with neurodevelopmental disorders. 2008;p. 1–35
  15. Ballatori N, Clarkson TW. Biliary secretion of glutathione and of glutathione–metal complexes. Fundam Appl Toxicol. 1985;5:816–831
  16. Ahearn GA, Mandal PK, Mandal A. Mechanisms of heavy metal sequestration and detoxification in crustaceans: a review. J Comp Physiol [B]. 2004;174:439–452
  17. Woods JS. Altered porphyrin metabolism as a biomarker of mercury exposure and toxicity. Can J Physiol Pharmacol. 1996;74:210–215
  18. Schopler E, Reichler RJ, DeVellis RF, Daly K. Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J Autism Dev Disord. 1980;10:91–103
  19. Nataf R, Skorupka C, Amet L, Lam A, Springbett A, Lathe R. Porphyrinuria in childhood autistic disorder: implications for environmental toxicity. Toxicol Appl Pharmcol. 2006;214:99–108
  20. Bouligand J, Deroussent A, Paci A, Morizet J, Vassal G. Liquid chromatography-tandem mass spectrometry assay of reduced and oxidized glutathione and main precursors in mice liver. J Chromatogr B Analyt Technol Biomed Life Sci. 2006;832:67–74
  21. Han Q, Xu M, Tang L, Sun X, Zhang N, Tan X, et al. Homogeneous enzymatic colorimetric assay for total cysteine. Clin Chem. 2004;50:1229–1231
  22. Richie JP, Lang CA. The determination of glutathione, cyst(e)ine, and other thiols and disulfides in biological samples using high-performance liquid chromatography with dual electrochemical detection. Anal Biochem. 1987;163:9–15
  23. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968;25:192–205
  24. Chattaraj S, Das AK. Indirect atomic absorption spectrometric determination of sulfate in human blood serum. Analyst. 1992;117:413–416
  25. Boismenu D, Robitaille L, Hamadeh MJ, Hongsprabhas P, Hoffer LJ, Mamer OA. Measurement of sulfate concentrations and tracer/tracee ratios in biological fluids by electrospray tandem mass spectrometry. Anal Biochem. 1998;261:93–99
  26. Watanabe N, Kamei S, Ohkubo A, Yamanaka M, Ohsawa S, Makino K, et al. Urinary protein as measured with a pyrogallol red-molybdate complex, manually and in a Hitachi 726 automated analyzer. Clin Chem. 1986;32:1551–1554
  27. Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med. 2001;30:1191–1212
  28. Dickinson DA, Moellering DR, Iles KE, Patel RP, Levonen AL, Wigley A, et al. Cytoprotection against oxidative stress and the regulation of glutathione synthesis. Biol Chem. 2003;384:527–537
  29. Klatt P, Lamas S. Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur J Biochem. 2000;267:4928–4944
  30. Dickinson DA, Forman HJ. Glutathione in defense and signaling: lessons from a small thiol. Ann NY Acad Sci. 2002;973:488–504
  31. Sagrista ML, Garcia AF, De Madariaga MA, Mora M. Antioxidant and pro-oxidant effect of the thiolic compounds N-acetyl-l-cysteine and glutathione against free radical-induced lipid peroxidation. Free Radic Res. 2002;36:329–340
  32. Deplancke B, Gaskins HR. Redox control of the transsulfuration and glutathione biosynthesis pathways. Curr Opin Clin Nutr Metab Care. 2002;5:85–92
  33. Pastore A, Federici G, Bertini E, Piemonte F. Analysis of glutathione: implication in redox and detoxification. Clin Chim Acta. 2003;333:19–39
  34. Hall AG. The role of glutathione in the regulation of apoptosis. Eur J Clin Invest. 1999;29:238–245
  35. Griffith OW. Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med. 1999;27:922–935
  36. Konstantareas MM, Homatidis S. Ear infections in autistic and normal children. J Autism Dev Disord. 1987;17:585–594
  37. Zimmerman AW, Jyonouchi H, Comi AM, Connors SL, Milstien S, Varsou A, et al. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol. 2005;33:195–201
  38. Horvath K, Perman JA. Autistic disorder and gastrointestinal disease. Curr Opin Pediatr. 2002;14:583–587
  39. Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B. Dysregulated innate immune responses in young children with autism spectrum disorders: Their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51:77–85
  40. Yorbik O, Sayal A, Akay C, Akbiyik DI, Sohmen T. Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot Essent Fatty Acids. 2002;67:341–343
  41. Chauhan A, Chauhan V, Brown WT, Cohen I. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferring—the antioxidant proteins. Life Sci. 2004;75:2539–2549
  42. Zoroglu SS, Armutcu F, Ozen S, Gurel A, Sivasli E, Yetkin O, et al. Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism. Eur Arch Psychiatry Clin Neurosci. 2004;254:143–147
  43. Alberti A, Pirrone P, Elia M, Waring RH, Romano C. Sulphation deficit in ‘low-functioning’ autistic children: a pilot study. Biol Psychiatry. 1999;46:420–424
  44. Strous RD, Golubchik P, Maayan R, Mozes T, Tuati-Werner D, Weizman A, et al. Lowered DHEA-S plasma levels in adult individuals with autistic disorder. Eur Neuropsychopharmacol. 2005;15:305–309
  45. Yazbak FE, Lang-Radosh KL. Increasing incidence of autism. Adverse Drug React Toxicol Rev. 2001;20:60–63
  46. McFadden SA. Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus on sulfur-dependent detoxification pathways. Toxicology. 1996;111:43–65
  47. Lee A, Beck L, Brown RJ, Markovich D. Identification of a mammalian brain sulfate transporter. Biochem Biophys Res Commun. 1999;263:123–129
  48. Parsons RB, Waring RH, Williams AC, Ramsden DB. Cysteine dioxygenase: regional localization of protein and mRNA in rat brain. J Neurosci Res. 2001;65:78–84
  49. Kern JK. Purkinje cell vulnerability and autism: a possible etiological connection. Brain Dev. 2003;25:377–382
  50. Thomas DJ, Fisher HL, Sumler MR, Hall LL, Mushak P. Sexual differences in the excretion of organic and inorganic mercury by methyl mercury-treated rats. Environ Res. 1987;43:203–216
  51. Oliveira FR, Ferreira JR, dos Santos CM, Macedo LE, de Oliveira RB, Rodrigues JA, et al. Estradiol reduces cumulative mercury and associated disturbances in the hypothalamus-pituitary axis of ovariectomized rats. Ecotoxicol Environ Saf. 2006;63:488–493
  52. Kane RE, Tector J, Brems JJ, Li AP, Kaminski DL. Sulfation and glucuronidation of acetaminophen by cultured hepatocytes replicating in vivo metabolism. ASAIO Trans. 1990;36:M607–M610
  53. Prudova A, Albin M, Bauman Z, Lin A, Vitvitsky V, Banerjee R. Testosterone regulation of homocysteine metabolism modulates redox status in human prostate cancer cells. Antioxid Redox Signal. 2007;9:1875–1881
  54. Clarkson TW, Nordberg GF, Sager PR. Reproductive and developmental toxicity of metals. Scand J Work Environ Health. 1985;11:145–154
  55. Geier DA, Geier MR. A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies. Neuro Endocrinol Lett. 2007;28:565–573
  56. Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108(Suppl 3):511–533
  57. Stringari J, Nunes AK, Franco JL, Bohrer D, Garcia SC, Dafre AL, et al. Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain. Toxicol Appl Pharmacol. 2008;227:147–154
  58. James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2006;141:947–956
  59. Geier DA, Geier MR. A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders. Horm Res. 2006;66:182–188
  60. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80:1611–1617
  61. Waring RH, Klovrza LV. Sulphur metabolism in autism. J Nutr Environ Med. 2000;10:25–32
  62. Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Geier MR. A prospective study of transsulfuration biomarkers in autistic disorders. Neurochem Res in press.
  63. Geier DA, Geier MR. A prospective study of mercury toxicity biomarkers in autistic spectrum disorders. J Toxicol Environ Health A. 2007;70:1723–1730
  64. Geier DA, Geier MR. A prospective assessment of porphyrins in autistic disorders: a potential marker for heavy metal exposure. Neurotox Res. 2006;10:57–64
  65. Sajdel-Sulkowska EM, Lipinski B, Windom H, Audhya T, McGinnis W. Oxidative stress in autism: elevated cerebellar 3-nitrotyrosine levels. Am J Biochem Biotechnol. 2008;4:73–84
  66. Desoto MC, Hitlan RT. Blood levels of mercury are related to diagnosis of autism: a reanalysis of an important data set. J Child Neurol. 2007;22:1308–1311
  67. Adams JB, Romdalvik J, Ramanujam VM, Legator MS. Mercury, lead, and zinc in baby teeth of children with autism versus controls. J Toxicol Environ Health A. 2007;70:1046–1051
  68. Adams JB, Romdalvik J, Levine KE, Hu LW. Mercury in first-cut baby hair of children with autism vs. typically developing children. Toxicol Environ Chem in press.
  69. Geier DA, Geier MR. A case series of children with apparent mercury toxic encephalopathies manifesting with clinical symptoms of regressive autistic disorders. J Toxicol Environ Health A. 2007;70:837–851

☆ For further discussion and comment, refer to pages 127–130 of this issue; doi:10.1016/j.jns.2009.02.309.

PII: S0022-510X(08)00431-0

doi: 10.1016/j.jns.2008.08.021

Journal of the Neurological Sciences
Volume 280, Issue 1 , Pages 101-108 , 15 May 2009

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