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Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
May 05, 2009
Hypothyroidism during pregnancy may contribute to CNS development later manifested as autism. Dr. Roman's review and hypothesis derive from a substantial body of medical literature (1). Note his abstract's list of dietary and environmental factors which can lower T3 and thereby alter brain development (1; see also 2-3).
- In at least some individuals, thyroid-related environmental factors active in the mother, embryo, and fetus would seem likely to set the stage for adverse effects from postnatal exposures to pollutants including but not limited to aluminum, ethylmercury, etc (4-6; 8-9; 10-13).
A brief essay that further elaborates environmental pollutants in autism was recently posted (14; see also 15-16).
References:
1: Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents.
Román GC. J Neurol Sci. 2007 Nov 15;262(1-2):15-26.
http://linkinghub.elsevier.com/retrieve/pii/S0022-510X(07)00437-6
The incidence and prevalence of autism have increased during the past two decades. Despite comprehensive genetic studies the cause of autism remains unknown. This review emphasizes the potential importance of environmental factors in its causation. Alterations of cortical neuronal migration and cerebellar Purkinje cells have been observed in autism. Neuronal migration, via reelin regulation, requires triiodothyronine (T3) produced by deiodination of thyroxine (T4) by fetal brain deiodinases. Experimental animal models have shown that transient intrauterine deficits of thyroid hormones (as brief as 3 days) result in permanent alterations of cerebral cortical architecture reminiscent of those observed in brains of patients with autism. I postulate that early maternal hypothyroxinemia resulting in low T3 in the fetal brain during the period of neuronal cell migration (weeks 8-12 of pregnancy) may produce morphological brain changes leading to autism. Insufficient dietary iodine intake and a number of environmental antithyroid and goitrogenic agents can affect maternal thyroid function during pregnancy. The most common causes could include inhibition of deiodinases D2 or D3 from maternal ingestion of dietary flavonoids or from antithyroid environmental contaminants. Some plant isoflavonoids have profound effects on thyroid hormones and on the hypothalamus-pituitary axis. Genistein and daidzein from soy (Glycine max) inhibit thyroperoxidase that catalyzes iodination and thyroid hormone biosynthesis. Other plants with hypothyroid effects include pearl millet (Pennisetum glaucum) and fonio millet (Digitaria exilis); thiocyanate is found in Brassicae plants including cabbage, cauliflower, kale, rutabaga, and kohlrabi, as well as in tropical plants such as cassava, lima beans, linseed, bamboo shoots, and sweet potatoes. Tobacco smoke is also a source of thiocyanate. Environmental contaminants interfere with thyroid function including 60% of all herbicides, in particular 2,4-dichlorophenoxyacetic acid (2,4-D), acetochlor, aminotriazole, amitrole, bromoxynil, pendamethalin, mancozeb, and thioureas. Other antithyroid agents include polychlorinated biphenyls (PCBs), perchlorates, mercury, and coal derivatives such as resorcinol, phthalates, and anthracenes. A leading ecological study in Texas has correlated higher rates of autism in school districts affected by large environmental releases of mercury from industrial sources. Mercury is a well known antithyroid substance causing inhibition of deiodinases and thyroid peroxidase. The current surge of autism could be related to transient maternal hypothyroxinemia resulting from dietary and/or environmental exposure to antithyroid agents. Additional multidisciplinary epidemiological studies will be required to confirm this environmental hypothesis of autism.
2. A model of the development of the brain as a construct of the thyroid system.
Howdeshell KL. Environ Health Perspect. 2002 110 Suppl 3:337-48. {free online}
http://www.ehponline.org/members/2002/suppl-3/337-348howdeshell/ehp110s3p337.pdf
Thyroid hormone is essential for normal brain development. However, little is known about the molecular and cellular mechanisms that mediate thyroid hormone action on the developing brain or the developmental events selectively affected. Consequently, although a large number of environmental chemicals interfere with the thyroid system, there are few neurodevelopmental end points to recruit for toxicological studies. Therefore, my goal here is to review what is known about the relative timing of normal brain construction and thyroid system development, with special focus on the period of in utero development in humans and the comparable developmental period in laboratory rats. These data are presented as a timeline to aid in the identification of thyroid-sensitive end points in brain development and to highlight important data gaps. I discuss the known influence of certain synthetic chemicals on the thyroid system and include a brief review of the effects of developmental exposure to chemicals on thyroid system function. The relationship between the thyroid hormone and retinoic acid systems, as well as the thyroid hormone sensitivity of the developing cochlea, is also discussed.
3. Neurodevelopment and endocrine disruption.
Colborn T. Environ Health Perspect. 2004 Jun;112(9):944-9. {free online}
Environ Health Perspect. 2004 Jun;112(9):944-9.
In this article I explore the possibility that contaminants contribute to the increasing prevalence of attention deficit hyperactivity disorder, autism, and associated neurodevelopmental and behavioral problems in developed countries. I discuss the exquisite sensitivity of the embryo and fetus to thyroid disturbance and provide evidence of human in utero exposure to contaminants that can interfere with the thyroid. Because it may never be possible to link prenatal exposure to a specific chemical with neurodevelopmental damage in humans, I also present alternate models where associations have been made between exposure to specific chemicals or chemical classes and developmental difficulties in laboratory animals, wildlife, and humans.
4. Some aspects of astroglial functions and aluminum implications for neurodegeneration
Aremu DA, Meshitsuka S. Brain Res Rev. 2006 Aug 30;52(1):193-200.
The present decade had witnessed an unprecedented attention focused on glial cells as a result of their unusual physiological roles that are being unraveled. It is now known that, rather than being a mere supporter of neurons, astroglia are actively involved in their modulation. The aluminum hypothesis seems to have been laid to rest, probably due to contradictory epidemiological reports on it as a causative factor of neurodegenerative diseases. Surprisingly, newer scientific evidences continue to appear and recent findings have implicated astrocytes as the principal target of its toxic action. In view of the likely detrimental effects of the interaction between these two infamous partners in neuroscience on neurons and nervous system, we have reviewed some aspects of glia-neuron interaction and discussed the implications of aluminum-impaired astrocytic functions on neurodegeneration. Because sporadic causes still account for the majority of the neurodegenerative diseases of which Alzheimer's disease is the most prominent, it has been suggested that neurotoxicologists should not relent in screening for the environmental agents, such as aluminum, and that considerable attention should be given to glial cells in view of the likely implications of environmental toxicants on their never-imagined newly reported roles in the central nervous system (CNS).
5. Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells.
Lemire J et al. J Neurosci Res. 2009 May 1;87(6):1474-83.
Although aluminum (Al), a known environmental toxin, has been implicated in a variety of neurological disorders, the molecular mechanism responsible for these conditions is not fully understood. In this report, we demonstrate the ability of Al to trigger mitochondrial dysfunction and ineffective adenosine triphosphate (ATP) production. This situation severely affected cytoskeletal dynamics. Whereas the control cells had well-defined structures, the Al-exposed astrocytoma cells appeared as globular structures. Creatine kinase (CK) and profilin-2, two critical modulators of cellular morphology, were markedly diminished in the astrocytoma cells treated with Al. Antioxidants such as alpha-ketoglutarate and N-acetylcysteine mitigated the occurrence of the globular-shaped cells promoted by Al toxicity. Taken together, these data reveal an intricate link between ATP metabolism and astrocytic dysfunction and provide molecular insights into the pathogenesis of Al-induced neurological diseases.
6. Effects of acute exposure to aluminum on blood-brain barrier and the protection of zinc.
Song Y et al. Neurosci Lett. 2008 Nov 7;445(1):42-6.
Aluminum and zinc are two important trace elements in an organism. Although several studies have demonstrated their impacts on the intelligence, very little was known about their effects on the integrity of blood-brain barrier (BBB). To study the effects of aluminum and zinc on the permeability of BBB, different doses of aluminum and appropriate zinc were administered to rats. Evans blue was detected in brain to determine the permeability of BBB. The ultrastructure of BBB was observed under the transmission electron microscope. Immunohistochemistry and Western blot method were used to detect the expression of skeleton protein F-actin and tight junction protein occludin in brain capillary endothelium. The data indicated that compared with the control group, Evans blue in brains increased (P < 0.01), the ultrastructure of BBB changed and the expression of F-actin and occludin decreased (P < 0.01) in the aluminum-toxic group. Compared with the aluminum-toxic groups, the permeability of BBB to Evans blue decreased (P < 0.01), the damage of the BBB ultrastructure was attenuated and the expression of F-actin and occludin increased (P < 0.05) in the aluminum-zinc group. Our present studies suggest that aluminum increases the permeability of BBB by changing its ultrastructure and the expression of occludin and F-actin. Zinc can protect the integrity of BBB in juvenile rats that are exposed to aluminum and inhibit the decrease of tight junction protein occludin and F-actin expression in BBB.
7. Thimerosal induces neuronal cell apoptosis by causing cytochrome c and apoptosis-inducing factor release from mitochondria.
Yel L et al. Int J Mol Med. 2005 Dec;16(6):971-7.
There is a worldwide increasing concern over the neurological risks of thimerosal (ethylmercury thiosalicylate) which is an organic mercury compound that is commonly used as an antimicrobial preservative. In this study, we show that thimerosal, at nanomolar concentrations, induces neuronal cell death through the mitochondrial pathway. Thimerosal, in a concentration- and time-dependent manner, decreased cell viability as assessed by calcein-ethidium staining and caused apoptosis detected by Hoechst 33258 dye. Thimerosal-induced apoptosis was associated with depolarization of mitochondrial membrane, generation of reactive oxygen species, and release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol. Although thimerosal did not affect cellular expression of Bax at the protein level, we observed translocation of Bax from cytosol to mitochondria. Finally, caspase-9 and caspase-3 were activated in the absence of caspase-8 activation. Our data suggest that thimerosal causes apoptosis in neuroblastoma cells by changing the mitochondrial microenvironment.
8. Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway.
Makani S et al. Genes Immun. 2002 Aug;3(5):270-8. {free online}
http://www.nature.com/gene/journal/v3/n5/pdf/6363854a.pdf
The major source of thimerosal (ethyl mercury thiosalicylate) exposure is childhood vaccines. It is believed that the children are exposed to significant accumulative dosage of thimerosal during the first 2 years of life via immunization. Because of health-related concerns for exposure to mercury, we examined the effects of thimerosal on the biochemical and molecular steps of mitochondrial pathway of apoptosis in Jurkat T cells. Thimerosal and not thiosalcylic acid (non-mercury component of thimerosal), in a concentration-dependent manner, induced apoptosis in T cells as determined by TUNEL and propidium iodide assays, suggesting a role of mercury in T cell apoptosis. Apoptosis was associated with depolarization of mitochondrial membrane, release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria, and activation of caspase-9 and caspase-3, but not of caspase-8. In addition, thimerosal in a concentration-dependent manner inhibited the expression of XIAP, cIAP-1 but did not influence cIAP-2 expression. Furthermore, thimerosal enhanced intracellular reactive oxygen species and reduced intracellular glutathione (GSH). Finally, exogenous glutathione protected T cells from thimerosal-induced apoptosis by upregulation of XIAP and cIAP1 and by inhibiting activation of both caspase-9 and caspase-3. These data suggest that thimerosal induces apoptosis in T cells via mitochondrial pathway by inducing oxidative stress and depletion of GSH.
9. Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts.
Baskin DS et al. Toxicol Sci. 2003 Aug;74(2):361-8. {free online}
http://toxsci.oxfordjournals.org/cgi/reprint/74/2/361
Thimerosal is an organic mercurial compound used as a preservative in biomedical preparations. Little is known about the reactions of human neuronal and skin cells to its micro- and nanomolar concentrations, which can occur after using thimerosal-containing products. A useful combination of fluorescent techniques for the assessment of thimerosal toxicity is introduced. Short-term thimerosal toxicity was investigated in cultured human cerebral cortical neurons and in normal human fibroblasts. Cells were incubated with 125-nM to 250-microM concentrations of thimerosal for 45 min to 24 h. A 4', 6-diamidino-2-phenylindole dihydrochloride (DAPI) dye exclusion test was used to identify nonviable cells and terminal transferase-based nick-end labeling (TUNEL) to label DNA damage. Detection of active caspase-3 was performed in live cell cultures using a cell-permeable fluorescent caspase inhibitor. The morphology of fluorescently labeled nuclei was analyzed. After 6 h of incubation, the thimerosal toxicity was observed at 2 microM based on the manual detection of the fluorescent attached cells and at a 1-microM level with the more sensitive GENios Plus Multi-Detection Microplate Reader with Enhanced Fluorescence. The lower limit did not change after 24 h of incubation. Cortical neurons demonstrated higher sensitivity to thimerosal compared to fibroblasts. The first sign of toxicity was an increase in membrane permeability to DAPI after 2 h of incubation with 250 microM thimerosal. A 6-h incubation resulted in failure to exclude DAPI, generation of DNA breaks, caspase-3 activation, and development of morphological signs of apoptosis. We demonstrate that thimerosal in micromolar concentrations rapidly induce membrane and DNA damage and initiate caspase-3-dependent apoptosis in human neurons and fibroblasts. We conclude that a proposed combination of fluorescent techniques can be useful in analyzing the toxicity of thimerosal.
10. 1: Health Place. 2009 Mar;15(1):18-24. Epub 2008 Feb 12.
Related Articles, Links
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Proximity to point sources of environmental mercury release as a predictor of autism prevalence.
Palmer RF, Blanchard S, Wood R.
University of Texas Health Science Center, San Antonio Department of Family and Community Medicine, 7703 Floyd Curl Drive, San Antonio Texas, Mail Code 7794, TX 78229-3900, USA. palmerr@uthscsa.edu
The objective of this study was to determine if proximity to sources of mercury pollution in 1998 were related to autism prevalence in 2002. Autism count data from the Texas Educational Agency and environmental mercury release data from the Environmental Protection Agency were used. We found that for every 1000 pounds of industrial release, there was a corresponding 2.6% increase in autism rates (p<.05) and a 3.7% increase associated with power plant emissions(P<.05). Distances to these sources were independent predictors after adjustment for relevant covariates. For every 10 miles from industrial or power plant sources, there was an associated decreased autism Incident Risk of 2.0% and 1.4%, respectively (p<.05). While design limitations preclude interpretation of individual risk, further investigations of environmental risks to child development issues are warranted.
11. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the san francisco bay area.
Windham GC et al. Environ Health Perspect. 2006 Sep;114(9):1438-44. {free online}
http://www.ehponline.org/members/2006/9120/9120.pdf
OBJECTIVE: To explore possible associations between autism spectrum disorders (ASD) and environmental exposures, we linked the California autism surveillance system to estimated hazardous air pollutant (HAP) concentrations compiled by the U.S. Environmental Protection Agency. METHODS: Subjects included 284 children with ASD and 657 controls, born in 1994 in the San Francisco Bay area. We assigned exposure level by census tract of birth residence for 19 chemicals we identified as potential neurotoxicants, developmental toxicants, and/or endocrine disruptors from the 1996 HAPs database. Because concentrations of many of these were highly correlated, we combined the chemicals into mechanistic and structural groups, calculating summary index scores. We calculated ASD risk in the upper quartiles of these group scores or individual chemical concentrations compared with below the median, adjusting for demographic factors. RESULTS: The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs) , 1.1-2.1], but not for aromatic solvents. Adjusting for these three groups simultaneously led to decreased risks for the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7 ; 95% CI, 1.0-3.0 ; third quartile = 1.95 ; 95% CI, 1.2-3.1) . The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride. CONCLUSIONS: Our results suggest a potential association between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence, requiring confirmation and more refined exposure assessment in future studies.
12. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions.
D'Amelio M et al. Mol Psychiatry. 2005 Nov;10(11):1006-16.
Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene-environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 C-108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case-control contrasts (Q192R: chi2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT chi2=5.26, 1 df, P<0.025), family-based association tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively, P<0.025), and haplotype-based association tests (L55/R192: HBAT Z=2.430, P<0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.
13. A case for revisiting the safety of pesticides: a closer look at neurodevelopment
Colborn T. Environ Health Perspect. 2006 114(1):10-7. {free online}
http://www.ehponline.org/realfiles/members/2005/7940/7940.pdf
The quality and quantity of the data about the risk posed to humans by individual pesticides vary considerably. Unlike obvious birth defects, most developmental effects cannot be seen at birth or even later in life. Instead, brain and nervous system disturbances are expressed in terms of how an individual behaves and functions, which can vary considerably from birth through adulthood. In this article I challenge the protective value of current pesticide risk assessment strategies in light of the vast numbers of pesticides on the market and the vast number of possible target tissues and end points that often differ depending upon timing of exposure. Using the insecticide chlorpyrifos as a model, I reinforce the need for a new approach to determine the safety of all pesticide classes. Because of the uncertainty that will continue to exist about the safety of pesticides, it is apparent that a new regulatory approach to protect human health is needed.
14. Autism and mercury, pesticides, solvents, thimerosal.
http://www.generationrescue.org/autism/00-mercury-pesticides-solvents-thimerosal-autism.htm
15. The Dangers of Excessive Childhood Vaccinations
By Russell L. Blaylock, M.D.
http://articles.mercola.com/sites/articles/archive/2008/04/01/the-dangers-of-excessive-childhood-vaccinations.aspx
16. Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders.
Blaylock RL, Strunecka A.
Curr Med Chem. 2009;16(2):157-70.
Despite the great number of observations being made concerning cellular and the molecular dysfunctions associated with autism spectrum disorders (ASD), the basic central mechanism of these disorders has not been proposed in the major scientific literature. Our review brings evidence that most heterogeneous symptoms of ASD have a common set of events closely connected with dysregulation of glutamatergic neurotransmission in the brain with enhancement of excitatory receptor function by pro-inflammatory immune cytokines as the underlying mechanism. We suggest that environmental and dietary excitotoxins, mercury, fluoride, and aluminum can exacerbate the pathological and clinical problems by worsening excitotoxicity and by microglial priming. In addition, each has effects on cell signaling that can affect neurodevelopment and neuronal function. Our hypothesis opens the door to a number of new treatment modes, including the nutritional factors that naturally reduce excitotoxicity and brain inflammation.
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