111300 The Effect of Multiple Environmental Toxins on the Developing Brain, Bowel, and Immune System

1. 1+1+1=300The Effect of Multiple Environmental Toxins on the DevelopingBrain, Bowel, and Immune System Cindy Schneider, MD Medical Director Center for Autism Research and Education

2. Regression

3. Emerging Symptoms digestive problems self-limited diets allergies sleep disorders hyperactivity hypotonia

4. Environmental Factors infections nutritional deficiencies prenatal events perinatal events toxins

5. Toxins Lead Mercury Arsenic Cadmium Organoposphate pesticides Alcohol Tobacco

6. Lead

7. Lead Lead pipes or solder Brass Pre 1978 paint Soil Crystal Candle wicks

8. Lead Fish Cigarette smoke Ceramics Toys Lipstick

9. Lead Municipal water in more than 800 US cities has Pb levels exceeding EPA action level Over half of US cities still have Pb lined pipes and/or Pb solder

10. Lead Toxicity and Pregnancy Outcomes Infertility Miscarriages Low birth weight Preterm labor Stillbirths Macrocephaly HTN at age 7-8

11. Lead Toxicity Mental retardation Developmental delays Hypertension/CAD/stroke Kidney disease Anemia

12. Lead Toxicity Adults absorb 10% of ingested lead Children absorb up to 40% Immature neurons are more at risk Absorption increases when Fe, Ca, or Zn are deficient Fetal concentrations = maternal

13. Symptoms of Lead Toxicity Anorexia Constipation Headaches Sleep disorders Joint pain/gout Irritability Tremor

14. Lead Toxicity Impairs mitochondrial function Disrupts amino acid metabolism Alters neurotransmiter metabolism Inhibits microtubule synthesis Causes NFT in prefrontal cortex, hippocampus, and cerebellum

15. Neurological InflammationDiana Vargas 2005 11 postmortem exams Patients age 5-44 6 CSF studies on living patients Activation of glial and microglial cells Increased inflammatory cytokines

16. Neurological Sequelae Blood levels poor reflection of brain levels Toxic at levels well below current acceptable blood level of 10 Children with blood level of 10 had IQs 7.4 points below children with levels of 1

17. University of BristolEmond A et al Archives of Dis in Child Sept 17, 2009 Measured lead levels in 488 2� y.o. Performed IQ testing at age 7-8 Children with blood levels of 5-10: Reading scores were 49% lower Writing scores were 51% lower Authors recommend lowering acceptable serum lead level to 0-5

18. Risk Factors for Lead Toxicity Young age Pica: Fe, Ca, Zn deficiency Smoking Maternal fish consumption ALAD2 allele (delta aminolevulinic acid dehydratase)

19. Washington DC 2001-2004 Pb contaminated drinking water in thousands of homes > 400% increased in cases of Pb poisoning 2007 CDC study again documented high prevalence of Pb poisoning in DC children

20. Lead Toxicity and Brain Size Prospective study of 120 children Gray matter volume was inversely proportional to Pb levels Prefrontal cortex affected Executive functioning Impulse control Mood Males more affected

21. Cigarette Smoking Nicotine, lead, mercury, and cadmium Increases risk of stillbirths, SIDS, preterm labor, IUGR, and placental abruption Cord blood lead levels increase 15% for every 10 cigarettes smoked per day Doubles cadmium content of breast milk

22. Screening for Lead Toxicity Delta aminolevulinic acid Coproporphyrin Serum lead Hair lead level EDTA challenge

23. Urinary Porphyrins Derivatives of heme synthesis Levels increase with exposure to mercury and/or lead Nataf found elevated in children with autism (n-106) Geier identified elevated porphyrin levels in children with ASD (n=26) and CP correlated with CARS scores J of Toxicology and Env Health, Part A 72: 1585-1591, 2009

24. Detoxification of Lead Primary excretion is in urine Half life is 3-7 weeks in soft tissue, up to 20 years in bone IV CaEDTA or oral DMSA Glutathione Optimize zinc levels

25. Mercury

26. High Mercury Fish Tuna Shark Swordfish Mackerel Tilefish

27. Fish Intake 8% of US women of childbearing age have Hg levels above the EPA threshold of concern (5.8 mcg/L) 3 or more servings per month increase Hg level 4-fold

28. Other Sources of Mercury Amalgams Coal burning power plants Drinking water Ear, nose, and eye drops Fabric softeners Fertilizers Mascara

29. Other Sources of Mercury Latex paint prior to 1990 Fungicides and some pesticides Thermometers Fluorescent light bulbs Thimerosal

30. Amalgam Fillings Release 43.5 mcg Hg/cm2/day Chewing, grinding, brushing, and consuming hot food or liquids increase level of Hg vapors May enter brain through CP Infant hair Hg levels correlate with # of maternal fillings

31. Mercury Toxicity Accumulates in brain, kidneys, liver, heart, and blood Half life in blood is 3 days Suppresses T lymphocytes Increases allergy/autoimmune responses Fetal levels higher than maternal

32. Symptoms of Mercury Toxicity Tremor Anorexia and weight loss Agitation/mania Insomnia Speech disorders Memory loss Sensory sensitivities

33. Symptoms of Mercury Toxicity Poor coordination Chewing Swallowing Gait Blurred vision Restricted visual fields Involuntary motor movements

34. Thimerosal

35. Thimerosal Toxicity Destroys tubulin in axons ? NFTs Destroys actin Neurotoxic at levels 10,000 times lower than those in vaccines Toxicity increased by Ampicillin, Tetracycline, and acetaminophen

36. Thimerosal Toxicity Ethyl mercury in thimerosal inactivates intracellular proteins by binding to their cysteine �SH groups GSH�s �SH group binds to Hg and protects essential proteins Hg bound to GSH is excreted in the urine and bile

37. Variation in Vulnerability Age/timing of exposure Gender Total body burden: cumulative and concurrent exposures Nutritional status Methylation and detoxification genetics Lifestyle Antibiotics, Tylenol, and other drug use

39. Jill James, PhD NAC and GSH protect against the toxicity of Hg in neuronal cells 33 children with ASD tested had low levels of methionine, cysteine, and GSH with high SAH 8 entered a trial of supplement designed to increase MS activity

41. Treating a Genetic Weakness 800 mcg of folinic acid BID and 1000 mg of betaine BID for 3 months Methionine, cysteine, and SAM increased GSH levels significantly improved, but did not normalize Further improvement noted with MeB12: GSH and cysteine levels normalized

42. Methionine Synthase Inhibited by thimerosal at levels well below those in vaccines Providing methyl B12 bypasses this inhibition. Other forms of B12 do not. Also inhibited by adenosine

43. Gender Females have higher MS activity Females have higher GSH levels Estrogen is protective Testosterone increases toxicity of mercury

44. MTHFR

46. Adding a methyl group � CH3 Methylation:

49. MTHFR Alleles C677T: 50-60% less active than normal variant Less common in females A1298C and C677T mutations frequent

50. MTHFR C677T Allele <1% of African Americans 20% of Italians 21% of US Latinos 11% of Irish Caucasians 13% of British Caucasians 8% of German Caucasians 10-14% of other Caucasians 11% of Asians

51. MTHFR C677T Allele RR of spina bifida = 1.8 Anencephaly and other cranial defects Heart defects, cleft lip/palate, limb red Down syndrome Miscarriage IUGR Placental abruption

52. Decreased MTHFR Activity Heart disease, high cholesterol, high triglycerides Diabetes and insulin resistance Inflammatory bowel disease Psychiatric disorders Colon cancer and leukemias Childhood brain cancers

54. RR of Autism C677T Allele: 2.8 C677T and A1298C alleles: 8

55. Arsenic

56. Arsenic Toxicity Bladder, lung, kidneys, and colon cancer Heart disease 10 PPB �acceptable� Risk of carcinogenesis 1 in 2000 Up to 50 PPB allowed until 2006

57. Arsenic Chromated copper arsenate in pretreated lumber: stricter regulations put in place in 2004 Chicken: 75% are fed arsenic Soil Rice

58. Cadmium

59. Cadmium Water pipes Paints, glazes, and pigments Nickel/cadmium batteries Cigarettes: 0.1-0.2 mcg/cigarette PVC Rubber tires Electroplating: nuts, bolts Shellfish

60. Cadmium Dentures Bridges Levels often elevated in smokers and dentists

61. Cadmium Toxicity Hypertension Kidney damage Proteinuria Glucosuria Calciuria Fatigue Weight loss Muscle weakness: poisons mitochondria

62. Cadmium Detoxification Primarily excreted through feces Half-life in body 10-33 years Zinc is protective Oral DMSA or IV EDTA effective Glutathione

63. Alcohol

64. Alcohol 32% of infants born to heavy drinkers have birth defects 14% of infants born to moderate drinkers have birth defects Individual variations in metabolism make risk impossible to calculate

65. Fetal Alcohol Syndrome IUGR Microcephaly MR or DD Malformations of upper jaw and lip Heart defects Close-set eyes

67. Met Receptor Tyrosine Kinase

68. Hepatocyte Growth Factor Embryogenesis Metastasis Regeneration of hepatic cells Intestinal epithelial integrity Immune function GABA interneuron migration and organization

69. Embryogenesis Placenta Liver Muscle Tolerance of foreign tissue Development of cortex, hippocampus, and cerebellum

70. Regeneration of Hepatic Cells Up to 2/3 liver may be regenerated Met mutant mice die after resection Weak activity would compromise ability to clear toxins

71. Intestinal Epithelial Integrity HGF enhances epithelial proliferation Inhibits apoptosis Decreases inflammation Suppresses Th1 cytokines: IL-12, IF-?, TNF-a

72. MET C Allele Associated with autism and GI disease, but not with autism without GI disease MET protein levels are significantly decreased in temporal cortex gray matter

73. C Allele 50% reduction of Met receptor protein RR of autism is 2.27 for CC genotype Association confined to multiplex families

74. MET C Allele 1st vulnerability gene to explain the multisystem complications of autism: Neurological changes GI pathology Immune disregulation Impaired detoxification

75. Organophosphate Pesticides

76. Developmental NT Conducted on only 9 pesticides in use today Most pesticide testing is performed on adult animals Single animal species data No burden of proof of safety exists

77. Single Species Studies Ability to clear toxins varies Structure and development of brain varies

78. Organophosphate Pesticides 80-90% of households use pesticides 20 of 20 newborn meconium samples contained OPP metabolites

79. Prenatal Pesticide Exposure Reduced head circumference Memory deficits Increased reaction time Hypertension in childhood Diminished ability to copy geometric figures at age 7-8 (DD of 4 years)

80. Paraoxonase PON1

81. Metabolizes OPP Reverses damage caused by HCTL Weak activity associated with increased inflammation Weak enzyme common in individuals with ASD living in areas of high OPP usage PON1/HCYTLase

82. PON1/HCYTLase Protective activity of �good� cholesterol Reduces inflammation in blood vessels and other tissues Protects against tissue damage that could lead to autoimmune disease

84. Paraoxonase Gene Reelin activity is potently inhibited by organophosphates PON1 gene maps to 7q31 40-fold inter-individual variance in paraoxonase activity Expression low until 12-18 months

85. Regression

86. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions Persico AM et al Molecular Psychiatry (2005) 1-11

87. Weak PON1 Activity Associated with autism in US Not associated with autism in Italian children Coinheritance of less active reelin and PON1 genes associated with autism in the US

89. PON1 R192 Allele Preferentially transmitted to affected offspring Associated with lower serotonin levels, lower urinary peptides, and increased HC (95th %ile) in US children, but not Italians Macrocephaly = neural inflammation?

90. MacrocephalyMartha Herbert 20% of children with autism experience accelerated head growth after birth White matter is 28% of total brain volume, but represents 65% of this increase The cortex is typically 54% of total brain volume, but represents only 18% of this increase

91. Combined Toxicities Lead arsenate pesticides: used until late 1950�s Cd, Pb in cigarette smoke/Hg in fillings Al, Hg, formaldehyde in vaccines Thimerosal and live viral vaccines

92. Synergistic Toxicity Hermans: Combined 33 chemicals at concentrations only 4% of NOEC Produced 50% mortality in fish

93. Synergistic Toxicity Varying vs same mode of toxicity Simultaneous vs sequential exposure Critical stage of development

94. Synergistic Toxicity Alcohol increases the toxicity of arsenic 100-fold LD1 of Hg + 1/20 LD1 of Pb ? 100% mortality Schubert 1978 Cd, Hg, and Pb: DNA damage Fl and Al: synergistic neurotoxicity

95. Summary Unprecedented number of toxins Individuals with certain genetic backgrounds will be less able to clear these toxins Common nutritional deficiencies are risk factors Enhancing methylation capacity can be very beneficial

96. Reduction in exposure is critical

97. Center for AutismResearch and Education www.center4autism.org (602) 277- care