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THE THYROID AUTISM CONNECTION

THE THYROID AUTISM CONNECTION. THE ROLE OF ENDOCRINE DISRUPTORS. by Raphael Kellman, M.D. EPIDEMIC ONE AUTISM AND NEURO-DEVELOPMENTAL DISORDERS. According to the CDC 1 in 110 US eight year olds have autism spectrum disorder.

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THE THYROID AUTISM CONNECTION

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  1. THE THYROID AUTISM CONNECTION THE ROLE OF ENDOCRINE DISRUPTORS by Raphael Kellman, M.D.

  2. EPIDEMIC ONEAUTISM AND NEURO-DEVELOPMENTAL DISORDERS • According to the CDC 1 in 110 US eight year olds have autism spectrum disorder. • US Centers for Disease Control and Prevention (CDC) 2007. Counting Autism • According to US centers for disease control and prevention (CDC) approximately 4.5 million children have been diagnosed with ADHD. • CDC 2007 Summary Health Statistics for US Children: National Health Interview Survey, 2006 • Prevalence of learning disabilities in United States’ children is approximately 9.7% according to a 2007 pediatrics article. • Altakac M. et al • 2007 Lifetime Prevalence of Learning Disability among US Children, 119; 77-83

  3. According to a 1994 study 16% of US children have a developmental disability. • Boyle CA et al • Prevalence of Health Impact of Developmental Disabilities in US Children • Pediatrics 93 (3): 399-403 • According to an article in JAMA in 2007 developmental disorders and chronic conditions in general is on the rise. • Perrin JM • The Increase of Childhood Chronic Conditions in the United States • JAMA 297 (24): 2755- 9

  4. EPIDEMIC TWOTHYROID DISEASE • According to the Colorado Thyroid Disease Prevalence Study in 2000 • The prevalence of abnormal thyroid function is 9.5% • If the upper level of TSH reference range is reduced to 2.5, as suggested by the National Academy of Clinical Biochemistry, this number will at least double • 24% of women older than 60 have hypothyroidism • G. Canaris et al • The Colorado Thyroid Disease Prevalence Study • Arch Intern Med 2000; 160:526-534

  5. Thyroid cancer is rising in incidence faster than any other cancer in the United States According to the NCI, thyroid cancer is increasing by 6.5% per year since 1997 Papillary carcinoma between 1999 and 2005, and 2003 and 2005 increased nearly 100% Enewald V. et al Rising Thyroid Cancer Incidence in the US by Demographic Tumor Characteristics 1980-2005 Cancer Epidemiology Biomarkers 2009; 18:784-791 Increasing Incidence of elevated TSH levels in newborn screening in Northern England Pearce MS et al J. Thyroid Research, Jan 2010

  6. Thyroid auto-immune disease is the most common auto-immune disease 7-8% of the population, totaling 24 million Dayan CM et al Chronic Autoimmune Thyroiditis New England Journal of Medicine 1996; 335: 99-107 Because only one-third of those with autoimmune diseases are diagnosed, the statistics are estimated to be 3x higher than that, as high as 72 million NIH Autoimmune Coordinating Committee Autoimmune Research, 2005 US Dept. of Health and Human Services, NHI pub March 25

  7. IS THE EPIDEMIC OF NEURO-DEVELOPMENTAL DISEASES LARGELY REDUCIBLE TO A MORE PRIMARY DISORDER - HYPOTHYROIDISM?

  8. EVIDENCE SUPPORTING THYROID-AUTISM CONNECTION Many of the same chemicals that are associated with autism, also cause thyroid disease Toxins thought to contribute to the development of autism and ASD mediate their effects via their adverse effects on the thyroid Thyroid hormone known to play a critical role in orchestrating brain development Thyroid dysfunction in utero, and neonates leads to many of the same symptoms associated with autism and ASD

  9. Celiac disease/gluten intolerance is associated with hypothyroidism. Gluten-free diets known to help with autism, may mediate via its positive effects on the thyroid • Autism and ASD frequently associated with auto-immune diseases. A percentage of thyroid disease is auto-immune in nature • Mitochondrial dysfunction found to be associated with autism -hypothyroidism causes mitochondrial dysfunction • Hypothyroidism contributes to methylation defects

  10. THE CRITICAL ROLE OF THYROID HORMONE IN BRAIN DEVELOPMENT • Phase I • First trimester, before synthesis of fetal TH, fetus dependent on maternal TH • Proliferation, migration and differentiation of neurons that develop into the forebrain, orchestrated by TH • Phase II • Fetal TH production, some role of maternal TH • Proliferation, migration and differentiation of neurons that develop into the cerebellum • Forebrain maturation and synapse formation • Orchestrated by TH

  11. Phase III • After birth, continuation of proliferation, migration, and differentiation • Myelination, gliogenesis • Thyroid hormones act as a time clock stimulating and subsequentlyterminating proliferation,migration and differentiation at the precise time with the precise dose and in the correct sequence Central Nervous System symphony, thyroid hormone the conductor • S. Porterfield; Endocrine Reviews; 14 (1) 94-106; 1993 • If TH plays such a critical role in neurodevelopment, that is the system where we should be concentrating our efforts to better understand the origins of neuro-developmental disorders

  12. Low thyroid function in the fetus and newborn associated with similar symptoms associated with ASD and ADHD • General developmental delays • Cognitive dysfunction • Hyperactivity • Attention disorders • Speech delays • Hypotonia/Fine motor dysfunction • Repetitive behavior • Social and communication dysfunction • ZoellerRT et al • Timing of Thyroid Hormone Function in the Developing Brain: Clinical Observations and Experimental Findings • J. Neuroendocrinol 16:809-818

  13. HYPOTHYROXINEMIA IN PREGNANCY AND NEURO-DEVELOPMENTAL DYSFUNCTION IN CHILDREN • Children of mothers with low normal T4 (T4-0-10th percentile) due to iodine deficiency from early gestation to birth increases the risk of neuro-developmental delay in their offspring • Lower performance in gross and fine motor coordination • Lower performance in socialization • Delayed Neurobehavioral Development in Children Born to Pregnant Women with Mild Hypothyroxinemia During First Month of Gestation • The Importance of Early Iodine Supplementation • P.Berbel et al • Thyroid Number 6, December 19, 2009

  14. Thyroid function can be damaged by the same toxins associated with autism and other developmental disorders: • PCBs • Dioxins • Perchlorate • Phthalates • PBDEs • Lead • Mercury • Cadmium • Insecticides • Bisphenol-A • P. Landrigan • CurrOpinPediatr 2010 • What Causes Autism? Exploring the Environmental Contribution

  15. HYPOTHYROIDISM AND GLUTEN INTOLERANCE/CELIAC DISEASE • According to research reported in Digestive Diseases and Sciences: •  Gluten sensitivity/celiac disease associated with thyroid disease • Celiac disease can play a role in the etiology of thyroid disease • “We believe that undiagnosed celiac disease can cause other disorders by switching on some as yet unknown immunological mechanism. Untreated celiac patients produce organ specific antibodies.” • Digestive Diseases and Sciences • February 2000; 45:403-406

  16. HYPOTHYROIDISM AND METHYLATION PATHWAY DEFECTS • T4 regulates the conversion of riboflavin to FAD. • Levels of FAD in the liver of hypothyroid rat is similar to rats on a riboflavin-deficient diet • Erythrocyte Glutathione Reductase (EGR) an FAD enzyme – low in adults with hypothyroidism • Hypothyroidism -  conversion of riboflavin to FAD and MTHFR • J Cimino et al • Riboflavin Metabolism in the Hypothyroid Newborn • American Journal of Clinical Nutrition 1988; 47: 481-483

  17. MITOCHONDRIAL DYSFUNCTION IN AUTISM • Decreased NADH • Increased oxidative stress • Mitochondrial DNA over replication or deletion • “Whether the mitochondrial dysfunction in children with autism is primary or secondary to an as –yet unknown event remains the subject of future work; however mitochondrial dysfunction could greatly amplify and propagate brain dysfunction, such as that found in autism”. • JAMA. 2010; 304 (21):2389-2396. • JAMA Dec 1, 2010

  18. Hypothyroidism Alters Mitochondrial Morphology and Induces Release of Apoptogenic Proteins • R. Singh • J Endocrinol 2003; 176: 321-329 • TH deficiency leads to extensive apoptosis during cerebellar development • TH maintains mitochondrial architecture and inhibits release of apoptogenic molecules to prevent excess apoptosis during cerebellar development

  19. TH REGULATES MITOCHONDRIAL ACTIVITY • Nuclear pathway • Direct mitochondrial pathway –stimulation of mitochondrial genome transcription • Both pathways –mitochondriogenesis • Mitochondrial pathway involved in regulation of cell differentiation • TH regulation of mitochondrial activity - link between metabolism and development • Thyroid Hormone Action in Mitochondria • C. Wrutniak-Cabello et al • Journal Molecular Endocrinology 2001; 26: 67-70

  20. AUTISM, ASD, PDD AND AUTOIMMUNE DISORDERS • Increased prevalence of familial autoimmune diseases in families of a child with autism Comi Am et al J. Child Neurol, June 14, 1999 (6) 388-94 • Frequency of autoimmune disorders is significantly higher in families of children with PDD compared with families of both autoimmune and healthy control bands • Hypothyroidism significantly increased in PDD families compared to autoimmune families Sweeten TL et al Pediatrics, Nov 2003, 112 (5) 420-426

  21. WHAT IS THE CAUSE OFTHE EPIDEMIC OF THYROID DISEASE?THE ROLE OF ENDOCRINEDISRUPTING CHEMICALS

  22. Endocrine disrupting chemicals, EDCs are synthetic substances in environment, food and consumer products. According to the EPA, “EDC is an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action or elimination of natural blood borne hormones that are present in the body and responsible for homeostasis reproduction and developmental processes”.

  23. ENDOCRINE DISRUPTOR THEORY GENERAL CONCEPTS • Growing list of chemicals now known to disrupt body’s communication network • Blocks or impersonate hormone messages • Scrambles messages • Sows misinformation- fools the endocrine system to accept new instructions • Toxicology I – Focus on cancer, dose makes the poison • ToxicologyII – Endocrine disrupting chemicals • Plays by different rules: • Even low doses can have devastating effects • Hormones, mostly TH, orchestrate neurological development, even low doses of EDCs that have little effect on adults, can have devastating effects on the unborn, neonate and child

  24. ENDOCRINE DISRUPTOR THEORY GENERAL CONCEPTS • ToxicologyII continued • Normal development depends on the right hormone message at the right time and the right amount – chemical ballet • Windows of vulnerability • Timing makes the poison

  25. “Thyroid system is one of the most frequent targets of synthetic chemicals” Linda Birnbaum; Director of Environmental Toxicology Division at the US Environmental Protection Agency

  26. ENDOCRINE DISRUPTORS AND ITS EFFECTS ON THE THYROID AND NEURO-DEVELOPMENT IN UTERO TO FIRST TWO YEARS OF LIFE • Effects include: • Learning disabilities • Behavioral problems • Fine motor dysfunction • Poor response to stress • Attention problems and hyperactivity • Language speech deficits • Social development deficits • S. Porterfield • Vulnerability of Developing Brain to Thyroid Abnormalities • Environmental Insults to the Thyroid Systems • Environmental Health Perspectives 1994, 102 (2): 125-130 • S. Porterfield • Thyroidal Dysfunction and Environmental Chemicals-Potential Impact on Brain Development • Environmental Health Perspectives, • Vol 108 Supplement 3 June 2000

  27. Other effects of thyroid disruption on neuro-development in infants and children: • Visuospatial deficits • Motor and visual motor delays • Decreased social and perceptual abilities • Decreased auditory discriminating abilities • JFRobet • Neurodevelopment in Infants and Preschool Children with Congenital Hypothyroidism • Etiological and Treatment Factors Affecting Outcome • Journal of Pediatric Psychology 1990, vol 17: 187-213

  28. CHRONOLOGY OF KEY EVENTS IN THE DEVELOPMENT OF THE ENDOCRINE DISRUPTOR THEORY • Wingspread Consensus Statement 1991 • “We are certain of the following: a large number of man made chemicals have the potential to disrupt the endocrine system of animals including humans. • Endocrine disruptors cause: • Thyroid dysfunction in birds and fish • Decreased fertility in birds, fish and mammals • Gross birth deformities in birds, fish and turtles • Behavioral abnormalities in animals

  29. May 1996 scientific conference in Erice, Sicily concluded: • “Endocrine disrupting chemicals at levels found in the environment and in humans threaten brain development” • “We are certain of the following: endocrine disrupting chemicals can undermine neurological and behavioral development and subsequent loss of potential of individuals exposed in the womb… This loss of potential in humans and wildlife is expressed as behavioral and physical abnormalities. It may be expressed as reduced intellectual capacity and social adaptability, as impaired responsiveness to environmental demands.”

  30. “The extreme sensitivity of the developing brain to chemical disruption of the endocrine system…[can cause] reduced intelligence, learning disabilities, attention deficit problems and intolerance to stress.” • “ Many of the endocrine disrupting chemicals can affect the thyroid which plays a key role in brain development.”

  31. August 1996 Food Quality Protection Act passed • Requires the EPA to obtain data about the potential hormone disrupting effects of pesticides in food. • October 1996 EPA forms Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) • The EDSTAC establishes a comprehensive screening and testing program for pesticides and other chemicals • The EDSTAC decides program should focus on estrogen, testosterone and thyroid hormone disruptors • The EDSTAC charged to coordinate research in the field of endocrine disruptors to more accurately characterize the risks of endocrine disruptors • March 1996 publication of Our Stolen Future

  32. THYROID DISRUPTING CHEMICALS

  33. THYROID DISRUPTING CHEMICALSMUTIPLE MECHANISMS

  34. THYROID DISRUPTING CHEMICALSMUTIPLE MECHANISMS

  35. THYROID DISRUPTING CHEMICALSMUTIPLE MECHANISMS

  36. Endocrine disruptors may have similar or different effects on the thyroid. This can create a cumulative and/or synergistic effect. • Crofton K.M. et al • Thyroid Hormone Disrupting Chemicals: Evidence for Dose Dependent Additivity or Synergism. • Environmental Health Perspectives • 2005, 113; 1549-1554

  37. PCBs “There is substantial evidence that polychlorinated biphenyls dioxins and furans cause hypothyroidism in exposed animals, and that environmentally occurring doses affect human thyroid homeostasis.” “Thyroid disruption may be caused by a variety of mechanisms as different chemicals interfere with the hypothalamic-pituitary thyroid axis at different levels.”

  38. “Growth and development in fetal life and childhood is highly dependent on normal levels of TH (thyroid hormone). Normal levels of THs are crucial for the development of the Central Nervous System. This critical phase may be vulnerable to even subtle effects of synthetic chemicals. Such developmental deficiencies may not be identifiable until late in life.” European Journal of Endocrinology. Environmental Chemicals and Thyroid Function. Malene Boas et al 2006, vol. 154 Issue 5: 599-611

  39. PCBs in maternal blood during pregnancy. Negative correlation between maternal TT3 and PCBs, three pesticides (p-ṕ-DDE , cis-nonachlor, hexachlorobenzene) and inorganic mercury at low levels of exposure. Positive correlation to fetal TSH L. Takser et al Thyroid Hormones in Pregnancy in Relation to Environmental Exposure to Organochlorine Compounds and Mercury Environmental Health Perspective 113: 1039-1045 (2005)

  40. PCBs interfere with HPT axis by producing a subnormal response of the pituitary to TRH stimulation. Khan & Hansen 2003. Orthosubstituted, PCB Congeners (95 or 101) Decrease Pituitary Response to Thyrotropen Releasing Hormone. ToxicolLett. 144; 173-182 In human adults, adolescents and children from highly exposed areas: PCB levels correlated negatively to TH levels. Hagmar C. et al PCB toxicity in children: Positive correlation between PCB exposure and TSH levels. Osius N et al Exposure to PCB’s and Levels of Thyroid Hormones in Children. Environmental Health Perspectives 1999. 107 843-849

  41. Positive Association Between PCB levels in breast milk and TSH levels in infants Koopman-Esseboom et al Effects of Dioxins and Polychlorinated Biphenyls on Thyroid Hormone Status of Pregnant Women and Their Infants Pediatric Research 36: 468-473, 1994 1971 Women in Taiwan consumed cooking oil contaminated with PCBs and furans 128 Children studied who were in womb: Impairment in mental and motor abilities Behavioral problems Hyperactivity – Attention deficits W Rogan et al Congenital Poisoning by PCBs and Their Contaminants in Taiwan Science 241: 334-336; 1998

  42. DIOXINS PCDs AND PCDF Widespread and persistent and highly toxic environmental pollutants from: Industrial burning processes Production of herbicides TCDD prototype and most toxic

  43. Single dose of TCDD in rats: dose-dependently decreased T4 and free T4 and increased TSH Viluksela M. et al Tissue Specifics Effects of TCDD on the Activity of 5-Deiodinases I and II in Rats. Toxicology letters 2004:147: 133-145 In offspring a single dose of TCDD to the dam during gestation was: Correlated to decreased T4 A two-fold increase in TSH Hyperplasia of the thyroid gland Nishimura N. Rat Thyroid Hyperplasia Induced by Gestational and Lactational Exposure to TCDD. Endocrinology 2003; 144: 2075-2083

  44. Large study of Vietnam veterans Group with highest TCDD levels showed a significant increase in TSH Pavuk M. et al Serum TCDD Levels and Thyroid Function in Air Force Veterans of the Vietnam War. Annals of Epidemiology 2003 13:335-343

  45. PCBs and dioxins measured in human milk. Higher levels in human milk correlated significantly with: • Lower plasma levels of maternal TT3 and TT4 • Higher TSH levels in the infants in the second week and third month after birth. Similar study of breast-fed infants: • Chlorinated dioxins and furans (dioxins) positively correlated with TSH levels in infants. • Dioxins may interfere with transport of T4 into the cell and the conversion of T4 to T3 or binding of T3 to nuclear receptor.

  46. Inhibition of enzyme 5-deiodinase and decreased conversion of T4 to T3. • Decreased nuclear T-3 receptor occupancy. • In pituitary gland decreased nuclear T-3 occupancy stimulates TSH secretion . • Pluim J et al • Effects of dioxins on the thyroid function in newborn babies • Environmental Health Perspectives, vol 101 number 6 1993:504-508

  47. FLAME RETARDANTS TBBPA AND PBDEs PBDEs used as flame retardants in plastics, paints, electrical equipment and synthetic textiles TBPH used in electrical equipment such as televisions, computers, copying machines and video displays Commercial PBDE mixture DE-7: Decreases levels of TH Induces activity of hepatic enzymes UDPGT High doses DE-7 causes histopathological changes Zhou T. et al Effects of Short-term in Vivo Exposure to PolybrominatedDiphenyl Ethers (PBDE) Mixture on Thyroid Hormones and Hepatic Enzymes Activities in Weaning Rats Toxicological Sciences 2001: 61; 26-82

  48. INSECTICIDES AND DEVELOPMENTAL DISORDERS Maternal residence near agricultural pesticide applications during key periods of gestation could be associated with the development of autism spectrum disorder (ASD) in children ASD risk increased with the poundage of organochlorine pesticides applied and decreased with distance from field sites. Roberts EM Maternal Residence Near Agricultural Pesticide Applications and ASD among Children in California of Central Valley Environmental Health Perspectives 115 (10): 1482-1489

  49. ORGANOCHLORINE PESTICIDES Neuro-developmental effects include: Decreased psychomotor function Decreased mental function: depressed memory, attention and verbal skills Mechanism of action: thyroid disruption Jurewicz J 2008: Prenatal and Childhood Exposure to Pesticides and Neurobehavioral Development: Review of Epidemiological Studies. International Journal of Occupational Medicine. Environmental Health 21 (2): 121-132 Korrick S. et al 2008: PCBs Organochlorine Pesticides and Neuro-development Current Open Pediatric 20 (two): 178-204 Ribas-Fito N et al 2006 In utero Exposure to Background Concentrations of DDT and Cognitive Functioning among Preschoolers AM J P. Epidemiol 164:955-962

  50. BPA BPA levels correlated with increased weight of thyroid Positive finding between increasing BPA and activity of hepatic enzyme UDPGT. Tan BL et al Assessment of Pubertal Development in Juvenile Male Rats after Sub-acute Exposure to Bisphenol and Nonylphenol Toxicology letters 2003, 143; 261-270

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