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. Proximity to point sources of environmental mercury release as a
predictor of autism prevalence.
Palmer RF, Blanchard S, Wood R.
Health
Place. 2009 Mar;15(1):18-24. Epub 2008 Feb 12.
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. Mixtures
& autism: Mercury & airborne pollutants: Hypospadias too
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.
Contact Teresa Binstock by email
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