for articles about autism and toxins broadly defined.
here for articles documenting those with ASD have
biological vulnerability to toxins.
here for documentation of the reality of autism increase.
here for articles about vaccine dangers and other health outcomes.
Goodman MS. (2010).
vaccination of male neonates and autism
diagnosis, NHIS 1997-2002.
J Toxicol Environ Health A.
Stony Brook University Medical
Center, Health Sciences Center, State University of New York at Stony
Brook, Stony Brook, New York, USA
EXCERPT “Vaccination status was
determined from the vaccination record. Logistic regression was used to
estimate the odds for autism diagnosis
associated with neonatal hepatitis B
vaccination among boys age 3-17 years, born before 1999, adjusted for
race, maternal education, and two-parent household. Boys vaccinated
as neonates had threefold greater odds for
autism diagnosis compared to boys never vaccinated or vaccinated
after the first month of life. Non-Hispanic white boys were 64% less
likely to have autism diagnosis relative
to nonwhite boys. Findings suggest that U.S. male neonates vaccinated
with the hepatitis B vaccine prior to
1999 (from vaccination record) had a threefold higher risk for parental
report of autism diagnosis compared to
boys not vaccinated as neonates during that same time period.”
ML Herdman, A Marcelo, Y Huang, RM Niles
Dhar S & Kiningham
KK. (2006). Thimerosal
Induces Apoptosis in a Neuroblastoma Model via the cJun N-Terminal
Kinase Pathway. Toxicological Sciences
Department of Pharmacology, Joan
C. Edwards School of Medicine, 1542 Spring Valley Drive, Marshall
University, Huntington, WV USA
EXCERPT: In recent years, controversy
has surrounded the use of thimerosal in vaccines as mercury is a known
neurotoxin and nephrotoxin. Since the controversy began in the late
1990's, much of the thimerosal has been removed from vaccines
administered to children in the United States. However, it remains in
some, such as the influenza vaccine, and is added to multidose vials
used in countries around the world. Studies concentrating on thimerosal-induced
neurotoxicity are limited, and exposure guidelines, such as those set by
the Food and Drug Administration, are based on research with
methylmercury. Interestingly, some in vitro and in vivo
studies suggest that ethylmercury may react differently than
and Aschner, 1990;
et al., 2004;
et al., 1985).
Few studies with thimerosal have focused on determining specific
signaling pathways involved in neurotoxicity. Establishing these
pathways may be an important step in discovering methods of alleviating
toxic outcomes in patients exposed to thimerosal….Our study is the first
demonstration that thimerosal can induce the activation of JNK and AP-1
in the SK-N-SH neuroblastoma cell line.
We showed that activation of cJun and AP-1 transcriptional activity
following thimerosal treatment does not appear to be involved in the
induction of apoptosis, as demonstrated with the studies using the cJun
dominant negative. Furthermore, we were able to show that JNK is an
essential upstream component of this pathway through the use of the JNK
inhibitor SP600125. This compound was able to attenuate activation of
downstream components of mitochondrial-mediated cell death and
subsequently protect the cells from apoptosis. These results are
significant because identifying specific signaling pathways activated in
response to thimerosal exposure presents pharmacological targets for
attenuating potential toxicity in patients exposed to thimerosal-containing
Singh VK, Lin
SX, Newell E, Nelson
antibodies and CNS autoimmunity in children with autism.
J Biomed Sci. 2002
Department of Biology and
Biotechnology Center, Utah State University, Logan, Utah 84322, USA.
EXCERPT: Autoimmunity to the central
nervous system (CNS), especially to myelin basic protein (MBP), may play
a causal role in autism, a neurodevelopmental disorder. Because many
autistic children harbor elevated levels of measles antibodies, we
conducted a serological study of measles-mumps-rubella (MMR) and MBP
autoantibodies. Using serum samples of 125 autistic children and 92
control children…Immunoblotting analysis revealed the presence of an
unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control
sera….the MMR antibody in autistic sera detected measles HA protein,
which is unique to the measles subunit of the vaccine. Furthermore, over
90% of MMR antibody-positive autistic sera were also positive for MBP
autoantibodies, suggesting a strong association between MMR and CNS
autoimmunity in autism. Stemming from this evidence, we suggest that
an inappropriate antibody response to MMR, specifically the measles
component thereof, might be related to pathogenesis of autism.
Follow up research/ replications
Holland, M. , Conte
L, Krakow R. & Colin, L. (2011). Unanswered
Questions: A Review of Compensated Cases of Vaccine-Induced Brain Injury
Pace Environmental Law Review, vol. 28
NYU School of Law, New York, USA
The Vaccine Injury
Compensation Program (VICP) has compensated claims of vaccine injury
since the inception of the program. This study found 83 cases of
acknowledged vaccine-induced brain damage that include autism.
Yel L, Brown LE, Su
K, Gollapudi S, Gupta S (2005).
neuronal cell apoptosis by causing cytochrome c and apoptosis-inducing
factor release from mitochondria.
International Journal of Molecular
Medicine, 16 (6) 971-977.
Medicine, University of California, Irvine, CA 92697, USA.
EXCERPT: 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
Tomljenovic L, Shaw
Do aluminum vaccine adjuvants
contribute to the rising prevalence of autism? (2011). J Inorg Biochem.
Neural Dynamics Research Group,
Department of Ophthalmology and Visual Sciences, University of British
Columbia, 828 W. 10th Ave, Vancouver, BC, Canada
Autism spectrum disorders (ASD) are
serious multisystem developmental disorders and an urgent global public
health concern. Dysfunctional immunity and impaired brain function are
core deficits in ASD. Aluminum (Al), the most commonly used vaccine
adjuvant, is a demonstrated neurotoxin and a strong immune stimulator.
Hence, adjuvant Al has the potential to induce neuroimmune disorders.
When assessing adjuvant toxicity in children, two key points ought to be
considered: (i) children should not be viewed as "small adults" as their
unique physiology makes them much more vulnerable to toxic insults; and
(ii) if exposure to Al from only few vaccines can lead to cognitive
impairment and autoimmunity in adults, is it unreasonable to question
whether the current pediatric schedules, often containing 18 Al
adjuvanted vaccines, are safe for children? By applying Hill's criteria
for establishing causality between exposure and outcome we investigated
whether exposure to Al from vaccines could be contributing to the rise
in ASD prevalence in the Western world. Our results show that: (i)
children from countries with the highest ASD prevalence appear to have
the highest exposure to Al from vaccines; (ii) the increase in
exposure to Al adjuvants significantly correlates with the increase in
ASD prevalence in the United States observed over the last two decades
(Pearson r=0.92, p<0.0001); and (iii) a significant correlation exists
between the amounts of Al administered to preschool children and the
current prevalence of ASD in seven Western countries, particularly at
3-4months of age (Pearson r=0.89-0.94, p=0.0018-0.0248). The
application of the Hill's criteria to these data indicates that the
correlation between Al in vaccines and ASD may be causal. Because
children represent a fraction of the population most at risk for
complications following exposure to Al, a more rigorous evaluation of
Al adjuvant safety seems warranted.
Olczak M, Duszczyk M,
Mierzejewski P, Wierzba-Bobrowicz T, Majewska MD. (2010).
neuropathological changes in rat brain after intermittent neonatal
administration of thimerosal.
Folia Neuropathol. 48(4): 258-69.
Department of Pharmacology and
Physiology of the Nervous System, Institute of Psychiatry and Neurology,
Thimerosal, an organomercurial added
as a preservative to some vaccines, is a suspected iatrogenic factor,
possibly contributing to paediatric neurodevelopmental disorders
including autism. We examined
the effects of early postnatal administration of thimerosal (four i.m.
injections, 12 or 240 μg THIM-Hg/kg, on postnatal days 7, 9, 11 and 15)
on brain pathology in Wistar rats. Numerous neuropathological changes
were observed in young adult rats which were treated postnatally with
thimerosal. They included: ischaemic degeneration of neurons and "dark"
neurons in the prefrontal and temporal cortex, the hippocampus and the
cerebellum, pathological changes of the blood vessels in the
temporal cortex, diminished synaptophysin reaction in the hippocampus,
atrophy of astroglia in the hippocampus and cerebellum, and positive
caspase-3 reaction in Bergmann astroglia. These findings document
neurotoxic effects of thimerosal, at doses equivalent to those used in
infant vaccines or higher, in developing rat brain, suggesting likely
involvement of this mercurial in neurodevelopmental disorders.
Full text. (Note: Below are two related
follow up works which support and extend the findings above,
importantly, the latter shows how investigating these effects may lead
Olczak M, Duszczyk
behavioral impairments and alterations of brain dopamine system after
early postnatal administration of thimerosal in rats.
Behav Brain Res.
Department of Pharmacology and
Physiology of the Nervous System, Institute of Psychiatry and Neurology,
EXCERPT: Previously we showed that
neonatal administration of THIM at doses equivalent to those used in
infant vaccines or higher, causes lasting alterations in the brain
opioid system in rats. Here we investigated neonatal treatment with THIM
(at doses 12, 240, 1440 and 3000 μg Hg/kg) on behaviors, which are
characteristically altered in autism... In animals of both sexes treated
with the highest THIM dose, the frequency of prosocial interactions was
reduced, while the frequency of asocial/antisocial interactions was
increased in males, but decreased in females. Neonatal THIM treatment
did not significantly affect spatial learning and memory. THIM-exposed
rats also manifested reduced haloperidol-induced catalepsy, accompanied
by a marked decline in the density of striatal D₂
receptors, measured by immunohistochemical staining, suggesting
alterations to the brain dopaminergic system. Males were more sensitive
than females to some neurodisruptive/neurotoxic actions of THIM.
These data document that early postnatal THIM administration causes
lasting neurobehavioral impairments and neurochemical alterations in the
brain, dependent on dose and sex. If similar changes occur in THIM/mercurial-exposed
children, they could contribute do neurodevelopmental disorders.
M, Olczak M, Lehner M, Majewska MD. (2012).
thimerosal to infant rats increases overflow of glutamate and aspartate
in the prefrontal cortex: protective role of dehydroepiandrosterone
Neurochem Res. 37 (2):436-47.
Department of Pharmacology and
Physiology of Nervous System, Institute of Psychiatry and Neurology,
important research shows how investigating - rather than denying -
vaccine effects may lead to prevention of vaccine injuries).
We previously showed that its
administration to infant rats causes behavioral, neurochemical and
neuropathological abnormalities similar to those present in autism. Here
we examined, using microdialysis, the effect of thimerosal on
extracellular levels of neuroactive amino acids in the rat prefrontal
cortex (PFC). Thimerosal administration (4 injections, i.m., 240 μg
Hg/kg on postnatal days 7, 9, 11, 15) induced lasting changes in amino
acid overflow: an increase of glutamate and aspartate accompanied by a
decrease of glycine and alanine; measured 10-14 weeks after the
injections. Four injections of thimerosal at a dose of 12.5 μg Hg/kg did
not alter glutamate and aspartate concentrations at microdialysis time
(but based on thimerosal pharmacokinetics, could have been effective
soon after its injection). Application of thimerosal to the PFC in
perfusion fluid evoked a rapid increase of glutamate overflow.
Coadministration of the neurosteroid, dehydroepiandrosterone sulfate (DHEAS)
prevented the thimerosal effect on glutamate and aspartate; the
steroid alone had no influence on these amino acids. Coapplication of
DHEAS with thimerosal in perfusion fluid also blocked the acute action
of thimerosal on glutamate. In contrast, DHEAS alone reduced overflow of
glycine and alanine, somewhat potentiating the thimerosal effect on
these amino acids. Since
excessive accumulation of extracellular glutamate is linked with
excitotoxicity, our data imply that neonatal exposure to thimerosal-containing
vaccines might induce excitotoxic brain injuries, leading to
neurodevelopmental disorders. DHEAS
may partially protect against mercurials-induced neurotoxicity.
Petrik MS, Wong MC,
Tabata RC, Garry RF, Shaw CA.
linked to gulf war illness induces motor neuron death in mice
Neuromolecular Med. 2007;9(1):83-100.
Ophthalmology and Program in Neuroscience, University of British
Columbia, Vancouver, British Columbia, Canada.
EXCERPT: Gulf War
illness (GWI) affects a significant percentage of veterans of the 1991
conflict, but its origin remains unknown. Associated with some cases of
GWI are increased incidences of amyotrophic lateral sclerosis and
other neurological disorders. Whereas many environmental factors
have been linked to GWI, the role of the anthrax vaccine has come
under increasing scrutiny. Among the vaccine's potentially toxic
components are the adjuvants aluminum hydroxide and squalene. Young,
male colony CD-1 mice were injected with the adjuvants at doses
equivalent to those given to US military service personnel. All mice
were subjected to a battery of motor and cognitive-behavioral tests over
a 6-mo period postinjections. Following sacrifice, central nervous
system tissues were examined using immunohistochemistry for evidence of
inflammation and cell death. Behavioral testing showed motor deficits
in the aluminum treatment group that expressed as a progressive
decrease in strength measured by the wire-mesh hang test (final deficit
at 24 wk; about 50%). Significant cognitive deficits in water-maze
learning were observed in the combined aluminum and squalene group (4.3
errors per trial) compared with the controls (0.2 errors per trial)
after 20 wk. Apoptotic neurons were identified in aluminum-injected
animals that showed significantly increased activated caspase-3 labeling
in lumbar spinal cord (255%) and primary motor cortex (192%) compared
with the controls. Aluminum-treated groups also showed significant motor
neuron loss (35%) and increased numbers of astrocytes (350%) in the
lumbar spinal cord. The findings suggest a possible role for the
aluminum adjuvant in some neurological features associated with GWI and
possibly an additional role for the combination of adjuvants.
Molina V. & Shoenfeld Y. (2005). Infection,
vaccines and other environmental triggers of autoimmunity.
Department of Medicine B and The
Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer,
Israel. The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv,
EXCERPT: Many environmental factors are
known to affect the immune system and may play a role as triggers of the
autoimmune mosaic…. This was studied for some syndromes as for the
association between SLE and EBV infection, pediatric autoimmune
neuropsychiatric disorders associated with streptococcal infection and
more. Vaccines, in several reports were found to be temporally followed
by a new onset of autoimmune diseases. The same mechanisms that act in
infectious invasion of the host, apply equally to the host response to
vaccination. It has been accepted for diphtheria and tetanus toxoid,
polio and measles vaccines and GBS. Also this theory has been accepted
for MMR vaccination and development of autoimmune thrombocytopenia, MS
has been associated with HBV vaccination.
DeLonga, G. (2011).
Association found between Autism Prevalence and Childhood Vaccination
uptake across the U.S. Population.
Journal of Toxicology and Environmental Health, Part A: Current Issues
Volume 74, Issue 14, 2011, Pages 903 –
Department of Economics and Finance,
Baruch College/City University of New York, New York, New York,
reason for the rapid rise of autism in the United States that began in
the 1990s is a mystery. Although individuals probably have a genetic
predisposition to develop autism, researchers suspect that one or more
environmental triggers are also needed. One of those triggers might
be the battery of vaccinations that young children receive. Using
regression analysis and controlling for family income and ethnicity, the
relationship between the proportion of children who received the
recommended vaccines by age 2 years and the prevalence of autism (AUT)
or speech or language impairment (SLI) in each U.S. state from 2001 and
2007 was determined. A positive and statistically significant
relationship was found: The higher the proportion of children
receiving recommended vaccinations, the higher was the prevalence of AUT
or SLI. A 1% increase in vaccination was associated with an additional
680 children having AUT or SLI. Neither parental behavior nor access to
care affected the results, since vaccination proportions were not
significantly related (statistically) to any other disability or to the
number of pediatricians in a U.S. state. The
results suggest that although mercury has been removed from many
vaccines, other culprits may link vaccines to autism. Further
study into the relationship between vaccines and autism is warranted.
Sharpe MA, Gist TL,
Baskin DS. (2013). B-Lymphocytes
from a Population of Children with Autism Spectrum Disorder and Their
Unaffected Siblings Exhibit Hypersensitivity to Thimerosal J
Neurosurgery, The Methodist Neurological Institute, Houston, TX.
Abstract: The role of
thimerosal containing vaccines in the development of autism spectrum
disorder (ASD) has been an area of intense debate, as has the presence
of mercury dental amalgams and fish ingestion by pregnant mothers. We
studied the effects of thimerosal on cell proliferation and
mitochondrial function from B-lymphocytes taken from individuals with
autism, their nonautistic twins, and their nontwin siblings. Eleven
families were examined and compared to matched controls. B-cells were
grown with increasing levels of thimerosal, and various assays (LDH, XTT,
DCFH, etc.) were performed to examine the effects on cellular
proliferation and mitochondrial function. A subpopulation of eight
individuals (4 ASD, 2 twins, and 2 siblings) from four of the families
showed thimerosal hypersensitivity, whereas none of the control
individuals displayed this response. The thimerosal concentration
required to inhibit cell proliferation in these individuals was only 40%
of controls. Cells hypersensitive to thimerosal also had higher
levels of oxidative stress markers, protein carbonyls, and oxidant
generation. This suggests certain individuals with a mild
mitochondrial defect may be highly susceptible to mitochondrial specific
toxins like the vaccine preservative thimerosal.
Goth, SR., Chu, RA. &
Gregg, JP. (2006).
ATP-mediated Calcium Signaling and Dysregulated IL-6 Secretion in
Dendritic Cells by Nanomolar Thimerosal
Environmental Health Perspectives, 114(7): 1083-91.
University of California at Davis, Davis CA, USA
note: This study demonstrates the
mechanism whereby very low-levels of Thimerosal can contribute to immune
Dendritic cells (DCs) , a rare cell type widely distributed in
the soma, are potent antigen-presenting cells
that initiate primary immune responses. DCs rely on intracellular redox
state and calcium (Ca2+) signals for
proper development and function, but the relationship between these two
signaling systems is unclear.
Thimerosal (THI) is a mercurial used to
preserve vaccines and consumer products, and is used experimentally to
induce Ca2+ release from microsomal stores. We tested adenosine
triphosphate (ATP) -mediated Ca2+ responses of DCs transiently exposed
to nanomolar THI. Transcriptional and
immunocytochemical analyses show that murine myeloid immature DCs (IDCs)
and mature DCs (MDCs) express inositol 1,4,5-trisphosphate receptor
(IP3R) and ryanodine receptor (RyR) Ca2+ channels, known targets of THI.
IDCs express the RyR1 isoform in a punctate distribution that is densest
near plasma membranes and within dendritic
processes, whereas IP3Rs are more generally distributed. RyR1 positively
and negatively regulates purinergic signaling
because ryanodine (Ry) blockade a) recruited 80% more ATP responders, b)
shortened ATP-mediated Ca2+ transients >
2-fold, and c) produced a delayed and persistent rise (>/= 2-fold) in
baseline Ca2+. THI (100 nM, 5 min) recruited more ATP responders,
shortened the ATP-mediated Ca2+ transient
(>/= 1.4-fold) , and produced a delayed rise (>/= 3-fold) in the Ca2+
baseline, mimicking Ry. THI and Ry, in combination, produced additive
effects leading to uncoupling of IP3R and
RyR1 signals. THI altered ATP-mediated
secretion, initially enhancing the rate of cytokine
secretion but suppressing cytokine
secretion overall in DCs.DCs are
exquisitely sensitive to THI, with one mechanism involving the
uncoupling of positive and negative
regulation of Ca2+ signals contributed by RyR1.
Burbacher, TM, . Shen, DD. , N. Grant,
KS, Cernichiari, E & Thomas Clarkson , T.
Comparison of blood and brain mercury levels in infant monkeys exposed
to methylmercury or vaccines containing thimerosal. Environmental
Health Perspectives, Aug 2005.
Washington, USA; University of
Rochester School of Medicine, Rochester, New York, USA
A complex study, showing some
similarities and differences between methyl and ethyl mercury in the
body -- but it documents unequivocally that thimerosal injections (
mercury found in vaccines ) get into the brain and remain there for
many days after the injections end (see for example Figure 6).
EXCERPT: Thimerosal is a preservative
that has been used in manufacturing vaccines since the 1930s….Monkeys
were exposed to MeHg (via oral gavage) or vaccines containing thimerosal
(via intramuscular injection) at birth and 1, 2, and 3 weeks of age.
Total blood Hg levels were determined 2, 4, and 7 days after each
exposure. Total and inorganic brain Hg levels were assessed 2, 4, 7, or
28 days after the last exposure. The initial and terminal half-life of
Hg in blood after thimerosal exposure was 2.1 and 8.6 days,
respectively, which are significantly shorter than the elimination
half-life of Hg after MeHg exposure at 21.5 days. Brain concentrations
of total Hg were significantly lower by approximately 3-fold for the
thimerosal-exposed monkeys when compared with the MeHg infants, whereas
the average brain-to-blood concentration ratio was slightly higher for
the thimerosal-exposed monkeys (3.5 ± 0.5 vs. 2.5 ± 0.3). A higher
percentage of the total Hg in the brain was in the form of inorganic Hg
for the thimerosal-exposed monkeys (34% vs. 7%). The results indicate
that MeHg is not a suitable reference for risk assessment from exposure
to thimerosal-derived Hg. Knowledge of the toxicokinetics and
developmental toxicity of thimerosal is needed to afford a meaningful
assessment of the developmental effects of thimerosal-containing
Geier DA, Geier MR.
A Case Series of
Children with Apparent Mercury Toxic Encephalopathies Manifesting with
Clinical Symptoms of Regressive Autistic Disorder.
J Toxicol Environ Health A. 70 (10):
Chronic Illnesses, Inc., Silver Spring, Maryland, USA.
in social relatedness and communication, repetitive behaviors, and
stereotypic abnormal movement patterns characterize autism spectrum
disorders (ASDs). It is clear that while genetic factors are important
to the pathogenesis of ASDs, mercury exposure can induce immune,
sensory, neurological, motor, and behavioral dysfunctions similar to
traits defining or associated with ASDs. The Institutional Review Board
of the Institute for Chronic Illnesses (Office for Human Research
Protections, U.S. Department of Health and Human Services, IRB number
IRB00005375) approved the present study. A case series of nine patients
who presented to the Genetic Centers of America for a
genetic/developmental evaluation are discussed. Eight of nine patients
(one patient was found to have an ASD due to Rett's syndrome) (a) had
regressive ASDs; (b) had elevated levels of androgens; (c) excreted
significant amounts of mercury post chelation challenge; (d) had
biochemical evidence of decreased function in their glutathione
pathways; (e) had no known significant mercury exposure except from
Thimerosal-containing vaccines/Rho(D)-immune globulin preparations; and
(f) had alternate causes for their regressive ASDs ruled out. There
was a significant dose-response relationship between the severity of the
regressive ASDs observed and the total mercury dose children received
from Thimerosal-containing vaccines/Rho (D)-immune globulin
preparations. Based upon differential diagnoses, 8 of 9 patients
examined were exposed to significant mercury from Thimerosal-containing
biologic/vaccine preparations during their fetal/infant developmental
periods, and subsequently, between 12 and 24 mo of age, these previously
normally developing children suffered mercury toxic encephalopathies
that manifested with clinical symptoms consistent with regressive ASDs.
Evidence for mercury intoxication should be considered in the
differential diagnosis as contributing to some regressive ASDs.
Waly M, Olteanu H,
Banerjee R, Choi SW, Mason JB, Parker BS, Sukumar S, Shim S, Sharma A,
Benzecry JM, Power-Charnitsky VA, Deth RC. (2004). Activation
of Methionine Synthase by Insulin-like Growth Factor-1 and Dopamine: a
Target for Neurodevelopmental Toxins and Thimerosal
Mol Psychiatry. 9 (4): 358-70.
Pharmaceutical Sciences, Northeastern University, Boston, MA
events play a critical role in the ability of growth factors to promote
normal development. Neurodevelopmental toxins, such as ethanol and heavy
metals, interrupt growth factor signaling, raising the possibility that
they might exert adverse effects on methylation. We found that
insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine
synthase (MS) activity and folate-dependent methylation of phospholipids
in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent
mechanism. The stimulation of this pathway increased DNA methylation,
while its inhibition increased methylation-sensitive gene expression.
Ethanol potently interfered with IGF-1 activation of MS and blocked its
effect on DNA methylation, whereas it did not inhibit the effects of
dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS
activity, as well as folate-dependent phospholipid methylation: Cu(2+)
promoted enzyme activity and methylation, while Cu(+), Pb(2+), Hg(2+)
and Al(3+) were inhibitory. The ethylmercury-containing preservative
thimerosal inhibited both IGF-1- and dopamine-stimulated methylation
with an IC(50) of 1 nM and eliminated MS activity. Our findings
outline a novel growth factor signaling pathway that regulates MS
activity and thereby modulates methylation reactions, including DNA
methylation. The potent inhibition of this pathway by ethanol, lead,
mercury, aluminum and thimerosal suggests that it may be an important
target of neurodevelopmental toxins.
Seneff, S. Davidson,
RM. & Liu J.
Empirical Data Confirm Autism Symptoms
Related to Aluminum and Acetaminophen Exposure
Entropy, 14 (11): 2227-2253.
Computer Science and Artificial
Intelligence Laboratory, Massachusetts Institute of Technology,
Cambridge, MA USA
Abstract: Autism is a
condition characterized by impaired cognitive and social skills,
associated with compromised immune function. The incidence is alarmingly
on the rise, and environmental factors are increasingly suspected to
play a role. This paper investigates word frequency patterns in the
U.S. CDC Vaccine Adverse Events Reporting System (VAERS) database. Our
results provide strong evidence supporting a link between autism and the
aluminum in vaccines. A literature review showing toxicity of
aluminum in human physiology offers further support. Mentions of
autism in VAERS increased steadily at the end of the last century,
during a period when mercury was being phased out, while aluminum
adjuvant burden was being increased. Using standard log-likelihood ratio
techniques, we identify several signs and symptoms that are
significantly more prevalent in vaccine reports after 2000, including
cellulitis, seizure, depression, fatigue, pain and death, which are also
significantly associated with aluminum-containing vaccines. We
propose that children with the autism diagnosis are especially
vulnerable to toxic metals such as aluminum and mercury due to
insufficient serum sulfate and glutathione. A
strong correlation between autism and the MMR (Measles, Mumps, Rubella)
vaccine is also observed, which may be partially explained via an
increased sensitivity to acetaminophen administered to control fever.
Humphrey ML, Cole MP,
Pendergrass JC, Kiningham KK. (2005)
mediated thimerosal-induced apoptosis in a human neuroblastoma cell line
Pharmacology, Joan C. Edwards School of Medicine, Marshall University,
Graduate Center for Toxicology, University of Kentucky, Lexington, KY USA.
Environmental exposure to mercurials continues to be a public health
issue due to their deleterious effects on immune, renal and neurological
function. Recently the safety of thimerosal, an ethyl
mercury-containing preservative used in vaccines, has been questioned
due to exposure of infants during immunization. Mercurials have been
reported to cause apoptosis in cultured neurons; however, the signaling
pathways resulting in cell death have not been well characterized.
Therefore, the objective of this study was to identify the mode of cell
death in an in vitro model of thimerosal-induced neurotoxicity, and more
specifically, to elucidate signaling pathways which might serve as
pharmacological targets. Within 2 h of thimerosal exposure (5 microM) to
the human neuroblastoma cell line, SK-N-SH, morphological changes,
including membrane alterations and cell shrinkage, were observed. Cell
viability, assessed by measurement of lactate dehydrogenase (LDH)
activity in the medium, as well as the
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)
assay, showed a time- and concentration-dependent decrease in cell
survival upon thimerosal exposure. In cells treated for 24 h with
thimerosal, fluorescence microscopy indicated cells undergoing both
apoptosis and oncosis/necrosis. To identify the apoptotic pathway
associated with thimerosal-mediated cell death, we first evaluated the
mitochondrial cascade, as both inorganic and organic mercurials have
been reported to accumulate in the organelle. Cytochrome c was shown
to leak from the mitochondria, followed by caspase 9 cleavage within 8 h
of treatment. In addition, poly(ADP-ribose) polymerase (PARP) was
cleaved to form a 85 kDa fragment following maximal caspase 3 activation
at 24 h. Taken together these findings suggest deleterious effects on
the cytoarchitecture by thimerosal and initiation of
Maha I. Sh. Kawashti,
Omnia R. Amin Nadia G. Rowehy (2006).
Immunological Disorders in Autism: Concomitant Autoimmunity and Immune
The Egyptian Journal of Immunology,
Microbiology Department, Faculty of
Medicine (For Girls), Al Azhar University, Cairo, Egypt, Psychiatry
Department, Faculty of Medicine, Cairo University, Cairo, Egypt and
Serology Lab King Fahad General Hospital, Jeddah, K.S.A.
Abstract: Autism is a
pervasive developmental disorder that affect children early in their
life. Immunological disorders is one of several contributing factors
that have been suggested to cause autism. Thirty autistic children aged
3-6 years and thirty non-autistic psychologically-free siblings were
studied. Circulating IgA and IgG autoantibodies to casein and gluten
dietary proteins were detected by enzyme-immunoassays (EIA).
Circulating IgG antibodies to measles, mumps and rubella vaccine (M.M.R)
and cytomeglovirus were investigated by EIA. Results revealed high
seropositivity for autoantibodies to casein and gluten: 83.3% and 50%
respectively in autistic children as compared to 10% and 6.7% positivity
in the control group. Surprisingly, circulating anti-measles, anti-mumps
and anti-rubella IgG were positive in only 50%, 73.3% and 53.3%
respectively as compared to 100% positivity in the control group. Anti-CMV
IgG was positive in 43.3% of the autistic children as compared to 7% in
the control group. It is concluded that, autoimmune response to
dietary proteins and deficient immune response to measles, mumps and
rubella vaccine antigens might be associated with autism, as a leading
cause or a resulting event. Further research is needed to confirm these
Hewitson L, Lopresti
B, Mason, NS, Stott C, Tomko J, Houser L, Klein EC, Castro C , Sackett
G, Gupta S, Atwood D, Wakefield AJ, (2008)
Influence Primate Behavior, and Amygdala Growth and Opioid Ligand
Presented at the International Meeting for Autism Research, London, May
Gynecology and Reproductive Sciences, University of Pittsburgh,
Pittsburgh, PA; Thoughtful House Center for Children , Austin, TX USA
Excerpt: Macaques are commonly used in pre-clinical vaccine safety
testing, but the combined childhood vaccine regimen, rather than
individual vaccines, has not been studied. Childhood vaccines are a
possible causal factor in autism, and abnormal behaviors and anomalous
amygdala growth are potentially inter-related features of this
condition. The objective of this
study was to compare early infant cognition and behavior with amygdala
size and opioid binding in rhesus macaques receiving the recommended
childhood vaccines (1994-1999), the majority of which contained the
bactericidal preservative ethylmercurithiosalicylic acid (thimerosal).
Macaques were administered the
recommended infant vaccines, adjusted for age and thimerosal dose
(exposed; N=13), or saline (unexposed; N=3).
Primate development, cognition and
social behavior were assessed for both vaccinated and unvaccinated
infants using standardized tests developed at the Washington National
Primate Research Center. Amygdala growth and binding were measured
serially by MRI and by the binding of the non-selective opioid
antagonist [11C]diprenorphine, measured by PET, respectively, before
(T1) and after (T2) the administration of the measles-mumps-rubella
vaccine (MMR). Compared with
unexposed animals, significant neurodevelopmental deficits were evident
for exposed animals in survival reflexes, tests of color discrimination
and reversal, and learning sets.
Differences in behaviors were observed between exposed and unexposed
animals and within the exposed group before and after MMR vaccination.
Compared with unexposed animals, exposed animals showed attenuation of
amygdala growth and differences in the amygdala binding of
[11C]diprenorphine. Interaction models identified significant
associations between specific aberrant social and non-social behaviors,
isotope binding, and vaccine exposure.
Follow up comment:
; related journal article follows.
Hewitson L, Lopresti
B, Stott C, Mason, NS, , Tomko J, (2010).
pediatric vaccines on amygdala growth and opioid ligand binding in
rhesus macaque infants: A pilot study.
Acta Neurobiol Exp 70 (2): 147–164
Department of Obstetrics and Gynecology,
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
This longitudinal, case-control pilot
study examined amygdala growth in rhesus macaque infants receiving the
complete US childhood vaccine schedule (1994-1999). Longitudinal
structural and functional neuroimaging was undertaken to examine central
effects of the vaccine regimen on the developing brain.
Vaccine-exposed and saline-injected control infants underwent MRI and
PET imaging at approximately 4 and 6 months of age, representing two
specific timeframes within the vaccination schedule. Volumetric
analyses showed that exposed animals did not undergo the maturational
changes over time in amygdala volume that was observed in unexposed
animals. After controlling for left amygdala volume, the binding of the
opioid antagonist [11C]diprenorphine (DPN) in exposed animals remained
relatively constant over time, compared with unexposed animals, in which
a significant decrease in [11C]DPN binding occurred. These
results suggest that maturational changes in amygdala volume and the
binding capacity of [11C]DPN in the amygdala was significantly altered
in infant macaques receiving the vaccine schedule. The macaque
infant is a relevant animal model in which to investigate specific
environmental exposures and structural/functional neuroimaging during
HA, Geier DA, Geier MR. (2008).
exposure in infants and neurodevelopmental disorders: An assessment of
computerized medical records in the Vaccine Safety Datalink.
The George Washington University School
of Public Health and Health Services, Department of Epidemiology and
Biostatistics, United States.
The study evaluated possible
associations between neurodevelopmental disorders (NDs) and exposure to
mercury (Hg) from Thimerosal-containing vaccines (TCVs) by examining the
automated Vaccine Safety Datalink (VSD). A total of 278,624 subjects
were identified in birth cohorts from 1990-1996 that had received their
first oral polio vaccination by 3 months of age in the VSD. The birth
cohort prevalence rate of medically diagnosed International
Classification of Disease, 9th revision (ICD-9) specific NDs and control
outcomes were calculated. Exposures to Hg from TCVs were calculated by
birth cohort for specific exposure windows from birth-7 months and
birth-13 months of age. Poisson regression analysis was used to model
the association between the prevalence of outcomes and Hg doses from
significantly increased rate ratios were observed for autism, autism
spectrum disorders, tics, attention deficit disorder, and emotional
disturbances with Hg exposure from TCVs. By
contrast, none of the control outcomes had significantly increased rate
ratios with Hg exposure from TCVs. Routine childhood vaccination should
be continued to help reduce the morbidity and mortality associated with
infectious diseases, but efforts should be undertaken to remove Hg from
vaccines. Additional studies should be conducted to further evaluate the
relationship between Hg exposure and NDs.
Gallagher C., Goodman M (2008).
Hepatitis B triple series vaccine and
developmental disability in US children aged 1-9 years.
Journal Toxicological & Environmental Chemistry, Volume 90, Issue 5
September 2008 , pages 997 - 1008
Graduate Program in Public Health,
Stony Brook University Medical Center, Health Sciences Center, New York,
Abstract: This study investigated the
association between vaccination with the Hepatitis B triple series
vaccine prior to 2000 and developmental disability in children aged 1–9
years (n = 1824), proxied by parental report that their child receives
early intervention or special education services (EIS). National Health
and Nutrition Examination Survey 1999–2000 data were analyzed and
adjusted for survey design by Taylor Linearization using SAS version 9.1
software, with SAS callable SUDAAN version 9.0.1. The odds of receiving
EIS were approximately nine times as great for vaccinated boys (n = 46)
as for unvaccinated boys (n = 7), after adjustment for confounders. This
study found statistically significant evidence to suggest that boys in
United States who were vaccinated with the triple series Hepatitis B
vaccine, during the time period in which vaccines were manufactured with
thimerosal, were more susceptible to developmental disability than were
Minami T, Miyata E,
Sakamoto Y, Yamazaki H, Ichida S. (2009). Induction
of metallothionein in mouse cerebellum and cerebrum with low-dose
Cell Biology and Toxicology 26 (2): 143-52.
Department of Life Sciences, School of
Science & Engineering, Kinki University, Kowakae, Higashi-osaka, Osaka,
Thimerosal, an ethyl mercury compound,
is used worldwide as a vaccine preservative. We previously observed that
the mercury concentration in mouse brains did not increase with the
clinical dose of thimerosal injection, but the concentration increased
in the brain after the injection of thimerosal with lipopolysaccharide,
even if a low dose of thimerosal was administered. Thimerosal may
penetrate the brain, but is undetectable when a clinical dose of
thimerosal is injected; therefore, the induction of metallothionein (MT)
messenger RNA (mRNA) and protein was observed in the cerebellum and
cerebrum of mice after thimerosal injection, as MT is an inducible
protein. MT-1 mRNA was expressed at 6 and 9 h in both the cerebrum and
cerebellum, but MT-1 mRNA expression in the cerebellum was three times
higher than that in the cerebrum after the injection of 12 microg/kg
thimerosal. MT-2 mRNA was not expressed until 24 h in both organs. MT-3
mRNA was expressed in the cerebellum from 6 to 15 h after the injection,
but not in the cerebrum until 24 h. MT-1 and MT-3 mRNAs were expressed
in the cerebellum in a dose-dependent manner. Furthermore, MT-1
protein was detected from 6 to 72 h in the cerebellum after 12 microg/kg
of thimerosal was injected and peaked at 10 h. MT-2 was detected in
the cerebellum only at 10 h. In the cerebrum, little MT-1 protein was
detected at 10 and 24 h, and there were no peaks of MT-2 protein in the
cerebrum. In conclusion, MT-1 and MT-3 mRNAs but not MT-2 mRNA are
easily expressed in the cerebellum rather than in the cerebrum by the
injection of low-dose thimerosal. It is thought that the cerebellum is a
sensitive organ against thimerosal. As
a result of the present findings, in combination with the brain
pathology observed in patients diagnosed with autism, the present study
helps to support the possible biological plausibility for how low-dose
exposure to mercury from thimerosal-containing vaccines may be
associated with autism.
Olczak M, Duszczyk M,
Mierzejewski P, Majewska MD. (2009).
administration of a vaccine preservative, thimerosal, produces lasting
impairment of nociception and apparent activation of opioid system in
Brain Res. 2009 Dec 8;1301:143-51.
Department of Pharmacology and
Physiology of the Nervous System, Institute of Psychiatry and Neurology,
Thimerosal (THIM), an organomercury
preservative added to many child vaccines is a suspected factor in
pathogenesis of neurodevelopmental disorders.
We examined the pharmacokinetics of Hg in the brain, liver and kidneys
after i.m. THIM injection in suckling rats and we tested THIM effect on
nociception. THIM solutions were injected to Wistar and Lewis rats in a
vaccination-like mode on PN days 7, 9, 11 and 15 in four equal doses.
For Wistar rats these were: 12, 48, 240, 720, 1440, 2160, 3000 microg
Hg/kg and for Lewis: 54, 216, 540 and 1080 microg Hg/kg. Pharmacokinetic
analysis revealed that Hg from THIM injections accumulates in the rat
brain in significant amounts and remains there longer than 30 days after
the injection. At the 6th week of age animals were examined for pain
sensitivity using the hot plate test. THIM treated rats of both strains
and sexes manifested statistically significantly elevated pain threshold
(latency for paw licking, jumping) on a hot plate (56 degrees C). Wistar
rats were more sensitive to this effect than Lewis rats. Protracted THIM-induced
hypoalgesia was reversed by naloxone (5 mg/kg, i.p.) injected before the
hot plate test, indicative of involvement of endogenous opioids. This
was confirmed by augmented catalepsy after morphine (2.5 mg/kg, s.c.)
injection. Acute THIM injection to 6-week-old rats also produced
hypoalgesia, but this effect was transient and was gone within 14 days. Present
findings show that THIM administration to suckling or adult rats impairs
sensitivity to pain, apparently due to activation the endogenous opioid
Bernard Rimland, PhD,
Woody McGinnis, MD (2002).
Vaccines and Autism.
Laboratory Medicine 33 (9).
Institute, San Diego, CA
Note: It is
important to note that the late Dr. Rimland was the founder (1967) of
the Autism Research Institute, and the founder of the Autism Society of
America in 1965. According to Wikipedia, “Rimland was long an
internationally recognized authority on autism spectrum disorders.” His
opinion speaks to the range and reality of actual expert and scientific
"Vaccinations may be one of the triggers for autism. Substantial data
demonstrate immune abnormality in many autistic children consistent with
impaired resistance to infection, activation of inflammatory response,
and autoimmunity. Impaired resistance may predispose to vaccine injury
in autism." And, “we submit that MMR (usually at 15 months) may result
in chronic infection of the gut by vaccinial measles and trigger
regressed autism. Thimerosal injections in series prior to or at the
time of MMR may potentiate injury…”
Wilson K, Hawken S,
Kwong JC, Deeks S, Crowcroft NS, Van Walraven C, Potter BK, Chakraborty
P, Keelan J, Pluscauskas M, Manuel D. (2011). Adverse
events following 12 and 18 month vaccinations: a population-based,
self-controlled case series analysis.
PLoS One. 6(12):e27897.
Department of Medicine, Ottawa Hospital
Research Institute, University of Ottawa, Ottawa, CANADA
Live vaccines have distinct safety
profiles, potentially causing systemic reactions one to 2 weeks after
administration. Using the
self-controlled case series design we examined 271,495 12 month
vaccinations and 184,312 18 month vaccinations to examine the relative
incidence of the composite endpoint of emergency room visits or hospital
admissions in consecutive one day intervals following vaccination. These
were compared to a control period 20 to 28 days later. In a post-hoc
analysis we examined the reasons for emergency room visits and the
average acuity score at presentation for children during the at-risk
period following the 12 month vaccine.
Four to 12 days post 12 month
vaccination, children had a 1.33 (1.29-1.38) increased relative
incidence of the combined endpoint compared to the control period, or at
least one event during the risk interval for every 168 children
vaccinated. Ten to 12 days post 18 month vaccination, the relative
incidence was 1.25 (95%, 1.17-1.33) which represented at least one
excess event for every 730 children vaccinated. The primary reason for
increased events was statistically significant elevations in
emergency room visits following all vaccinations. There were
non-significant increases in hospital admissions. There
were an additional 20 febrile seizures for every 100,000 vaccinated at
12 months…. Future studies should examine whether these events could
be predicted or prevented.
Full text with illustrations.
Dórea JG, (2011).
Integrating experimental (in vitro and
in vivo) neurotoxicity studies of low-dose thimerosal relevant to
Neurochem Res. 36(6):
Faculty of Health Sciences,
Universidade de Brasília, BRAZIL
EXCERPT: This review integrates
information derived from emerging experimental studies (in vitro and in
vivo) of low-dose Thimerosal (sodium ethyl mercury thiosalicylate).
Major databases (PubMed and Web-of-science) were searched for in vitro
and in vivo experimental studies that addressed the effects of low-dose
Thimerosal (or ethylmercury) on neural tissues and animal behaviour.
Information extracted from studies indicates that: (a) activity of
low doses of Thimerosal against isolated human and animal brain cells
was found in all studies and is consistent with Hg neurotoxicity; (b)
the neurotoxic effect of ethylmercury has not been studied with
co-occurring adjuvant-Al in TCVs; (c) animal studies have shown that
exposure to Thimerosal-Hg can lead to accumulation of inorganic Hg in
brain, and that (d) doses relevant to TCV exposure possess the potential
to affect human neuro-development. Thimerosal at concentrations relevant
for infants' exposure (in vaccines) is toxic to cultured human-brain
cells and to laboratory animals.
Hamza H, Cao J, Li X,
Li C, Zhu M, Zhao S.(2012).
Hepatitis B vaccine
induces apoptotic death in Hepa1-6 cells.
College of Animal Science and
Technology, Huazhong Agricultural University, Wuhan, CHINA.
Vaccines can have adverse
side-effects, and these are predominantly associated with the inclusion
of chemical additives such as aluminum hydroxide adjuvant.
The objective of this study was to establish an in vitro model system
amenable to mechanistic investigations of cytotoxicity induced by
hepatitis B vaccine, and to investigate the mechanisms of
vaccine-induced cell death. The mouse liver hepatoma cell line Hepa1-6
was treated with two doses of adjuvanted (aluminium hydroxide) hepatitis
B vaccine (0.5 and 1 μg protein per ml) …Vaccine exposure was
accompanied by significant increases in the levels of activated caspase
3, a key effector caspase in the apoptosis cascade. Upregulation of
cleaved caspase 3,7 were detected by western blot in addition to Apaf-1
and caspase 9 expressions argues that cell death takes place via the
intrinsic apoptotic pathway in which release of cytochrome c from the
mitochondria triggers the assembly of a caspase activation complex. We
conclude that exposure of Hepa1-6 cells to a low dose of adjuvanted
hepatitis B vaccine leads to loss of mitochondrial integrity, apoptosis
induction, and cell death, apoptosis effect was observed also in
C2C12 mouse myoblast cell line after treated with low dose of vaccine
(0.3, 0.1, 0.05 μg/ml). In addition In vivo apoptotic effect of
hepatitis B vaccine was observed in mouse liver.
Sulkowski ZL, Chen
T, Midha S, Zavacki
AM, Sajdel-Sulkowska EM
Maternal thimerosal exposure results in
aberrant cerebellar oxidative stress, thyroid hormone metabolism, and
motor behavior in rat pups; sex- and strain-dependent effects.
Department of Psychiatry, Harvard
Medical School and Brigham and Women's Hospital, Boston, MA, USA.
Abstract: Methylmercury (Met-Hg) and
ethylmercury (Et-Hg) are powerful toxicants with a range of harmful
neurological effects in humans and animals. While Met-Hg is a recognized
trigger of oxidative stress and an endocrine disruptor impacting
neurodevelopment, the developmental neurotoxicity of Et-Hg, a metabolite
of thimerosal (TM), has not been explored. We hypothesized that TM
exposure during the perinatal period impairs central nervous system
development, and specifically the cerebellum, by the mechanism involving
oxidative stress. To test this, spontaneously hypertensive rats (SHR)
or Sprague-Dawley (SD) rat dams were exposed to TM (200 μg/kg body
weight) during pregnancy (G10-G15) and lactation (P5-P10). Male and
female neonates were evaluated for auditory and motor function;
cerebella were analyzed for oxidative stress and thyroid metabolism. TM
exposure resulted in a delayed startle response in SD neonates and
decreased motor learning in SHR male (22.6%), in SD male (29.8%), and in
SD female (55.0%) neonates. TM exposure also resulted in a significant
increase in cerebellar levels of the oxidative stress marker
3-nitrotyrosine in SHR female (35.1%) and SD male (14.0%) neonates. The
activity of cerebellar type 2 deiodinase, responsible for local
intra-brain conversion of thyroxine to the active hormone,
3',3,5-triiodothyronine (T3), was significantly decreased in TM-exposed
SHR male (60.9%) pups. This coincided with an increased (47.0%)
expression of a gene negatively regulated by T3, Odf4 suggesting local
intracerebellar T3 deficiency. Our data thus demonstrate a negative
neurodevelopmental impact of perinatal TM exposure which appears to be
both strain- and sex-dependent.
Blaxill MF, Redwood L, Bernard S.
Thimerosal and autism? A plausible
hypothesis that should not be dismissed.
Safe Minds (Sensible Action For
Ending Mercury-Induced Neurological Disorders), New Jersey USA.
Abstract: The autism-mercury hypothesis
first described by Bernard et al. has generated much interest and
controversy. The Institute of Medicine (IOM) reviewed the connection
between mercury-containing vaccines and neurodevelopmental disorders,
including autism. They concluded that the hypothesis was biologically
plausible but that there was insufficient evidence to accept or reject a
causal connection and recommended a comprehensive research program.
Without citing new experimental evidence, a number of observers have
offered opinions on the subject, some of which reject the IOM's
conclusions. In a recent review, Nelson and Bauman argue that a link
between the preservative thimerosal, the source of the mercury in
childhood vaccines, is improbable. In their defense of thimerosal, these
authors take a narrow view of the original hypothesis, provide no new
evidence, and rely on selective citations and flawed reasoning. We
provide evidence here to refute the Nelson and Bauman critique and to
defend the autism-mercury hypothesis.
Christian LM, Iams JD, Porter K, Glaser
Inflammatory Responses to Trivalent
Influenza Virus Vaccine Among Pregnant Women
Department of Psychiatry, The Ohio
State University Medical Center, Columbus, OH
EXCERPT: In the U.S., seasonal
trivalent influenza vaccination (TIV) is currently universally
recommended for all pregnant women. However, data on the maternal
inflammatory response to vaccination is lacking and would better
delineate the safety and clinical utility of immunization. Women
were assessed prior to and at one day (n=15), two days (n=10), or
approximately one week (n=21) following TIV. Serum interleukin (IL)-6,
tumor necrosis factor (TNF)-α, C-reactive protein (CRP), and macrophage
migration inhibitory factor (MIF) were determined by high sensitivity
immunoassay. Significant increases in CRP were seen at one and two
days post-vaccination (ps <.05). A similar effect was seen for TNF-α,
for which an increase at two days post-vaccination approached
statistical significance (p = .06). There was considerable variability
in magnitude of response; coefficients of variation for change at two
days post-vaccination ranged from 122% to 728%, with the greatest
variability in IL-6 responses at this timepoint. The inflammatory
response elicited by vaccination is substantially milder and more
transient than seen in infectious illness, arguing for the clinical
value of vaccination. However, further research is needed to confirm
that the mild inflammatory response elicited by vaccination is benign in
These articles are not
presented as an exhaustive list of scientific publications (by any
means!). These are intended to represent good places to start reading if
the goal is to understand expert views regarding how and why
developmental disabilities occur in predisposed individuals.
Additional articles may be
added from time to time. Check back.
Persons with ASD may have a biological vulnerability to toxins.
Obviously not everyone
exposed to a toxin develops a lifelong disability, the idea is that some
do -- and -- that the vulnerability can be discovered leading to
Sharpe MA, Gist TL, Baskin DS.(2013). B-Lymphocytes
from a Population of Children with Autism Spectrum Disorder and Their
Unaffected Siblings Exhibit Hypersensitivity to Thimerosal
Abstract: The role of thimerosal containing vaccines in the development
of autism spectrum disorder (ASD) has been an area of intense debate, as
has the presence of mercury dental amalgams and fish ingestion by
pregnant mothers. We studied the effects of thimerosal on cell
proliferation and mitochondrial function from B-lymphocytes taken from
individuals with autism, their nonautistic twins, and their nontwin
siblings. Eleven families were examined and compared to matched
controls. B-cells were grown with increasing levels of thimerosal, and
various assays (LDH, XTT, DCFH, etc.) were performed to examine the
effects on cellular proliferation and mitochondrial function. A
subpopulation of eight individuals (4 ASD, 2 twins, and 2 siblings) from
four of the families showed thimerosal hypersensitivity, whereas none of
the control individuals displayed this response. The thimerosal
concentration required to inhibit cell proliferation in these
individuals was only 40% of controls. Cells hypersensitive to thimerosal
also had higher levels of oxidative stress markers, protein carbonyls,
and oxidant generation. This suggests certain individuals with a mild
mitochondrial defect may be highly susceptible to mitochondrial specific
toxins like the vaccine preservative thimerosal.
James, SJ, Cutler, P, Melnyk, S, Jernigan, S, Janak, L, Gaylor, DW,
Neubrander JA, (2004).
Metabolic biomarkers of increased
oxidative stress and impaired methylation capacity in children with
Journal of Clinical Nutrition, 80 (6), 1611-1617.
EXCERPT: Although abnormal metabolism of methionine and homocysteine
has been associated with other neurologic diseases, these pathways have
not been evaluated in persons with autism.
Plasma concentrations of methionine, S-adenosylmethionine
(SAM), S-adenosylhomocysteine (SAH), adenosine, homocysteine,
cystathionine, cysteine, and oxidized and reduced glutathione were
measured in 20 children with autism and in 33 control children. On the
basis of the abnormal metabolic profile, a targeted nutritional
intervention trial with folinic acid, betaine, and methylcobalamin was
initiated in a subset of the autistic children.
Relative to the control children, the
children with autism had significantly lower baseline plasma
concentrations of methionine, SAM, homocysteine, cystathionine, cysteine,
and total glutathione and significantly higher concentrations of SAH,
adenosine, and oxidized glutathione. This metabolic profile is
consistent with impaired capacity for methylation
(significantly lower ratio of SAM to SAH) and increased oxidative stress
(significantly lower redox ratio of reduced glutathione to oxidized
glutathione) in children with autism. The intervention trial was
effective in normalizing the metabolic imbalance in the autistic
Kern JK, Jones AM. (2006).
Evidence of Toxicity, Oxidative
Stress, and Neuronal Insult in Autism
J Toxicol Environ Health B Crit Rev.
Abstract: According to the Autism Society of America, autism is now
considered to be an epidemic. The increase in the rate of autism
revealed by epidemiological studies and government reports implicates
the importance of external or environmental factors that may be
changing. This article discusses the evidence for the case that some
children with autism may become autistic from neuronal cell death or
brain damage sometime after birth as result of insult; and addresses the
hypotheses that toxicity and oxidative stress may be a cause of neuronal
insult in autism. The article first describes the Purkinje cell loss
found in autism, Purkinje cell physiology and vulnerability, and the
evidence for postnatal cell loss. Second, the article describes the
increased brain volume in autism and how it may be related to the
Purkinje cell loss. Third, the evidence for toxicity and oxidative
stress is covered and the possible involvement of glutathione is
discussed. Finally, the article discusses what may be happening over the
course of development and the multiple factors that may interplay and
make these children more vulnerable to toxicity, oxidative stress, and
James SJ, Slikker W 3rd, Melnyk S, New E, Pogribna M, Jernigan S.
Thimerosal Neurotoxicity is Associated
with Glutathione Depletion: Protection with Glutathione Precursors
Neurotoxicology. 2005 Jan;26(1):1-8.
Abstract: Thimerosol is an antiseptic containing 49.5% ethyl mercury
that has been used for years as a preservative in many infant vaccines
and in flu vaccines. Environmental methyl mercury has been shown to be
highly neurotoxic, especially to the developing brain. Because mercury
has a high affinity for thiol (sulfhydryl (-SH)) groups, the thiol-containing
antioxidant, glutathione (GSH), provides the major intracellular defense
against mercury-induced neurotoxicity. Cultured neuroblastoma cells were
found to have lower levels of GSH and increased sensitivity to
thimerosol toxicity compared to glioblastoma cells that have higher
basal levels of intracellular GSH. Thimerosal-induced cytotoxicity
was associated with depletion of intracellular GSH in both cell lines.
Pretreatment with 100 microM glutathione ethyl ester or N-acetylcysteine
(NAC), but not methionine, resulted in a significant increase in
intracellular GSH in both cell types. Further, pretreatment of the cells
with glutathione ethyl ester or NAC prevented cytotoxicity with exposure
to 15 microM Thimerosal. Although Thimerosal has been recently removed
from most children's vaccines, it is still present in flu vaccines given
to pregnant women, the elderly, and to children in developing countries.
The potential protective effect of GSH or NAC against mercury
toxicity warrants further research as possible adjunct therapy to
individuals still receiving Thimerosal-containing vaccinations.
Rossignol DA & Frye RE (2011)
dysfunction in autism spectrum disorders: a systematic review and
A comprehensive literature search was
performed to collate evidence of mitochondrial dysfunction in autism
spectrum disorders (ASDs) with two primary objectives. First, features
of mitochondrial dysfunction in the general population of children with
ASD were identified. Second, characteristics of mitochondrial
dysfunction in children with ASD and concomitant mitochondrial disease
(MD) were compared with published literature of two general populations:
ASD children without MD, and non-ASD children with MD. The prevalence of
MD in the general population of ASD was 5.0% (95% confidence interval
3.2, 6.9%), much higher than found in the general population (~0.01%).
The prevalence of abnormal biomarker values of mitochondrial dysfunction
was high in ASD, much higher than the prevalence of MD. Variances and
mean values of many mitochondrial biomarkers (lactate, pyruvate,
carnitine and ubiquinone) were significantly different between ASD and
controls. Some markers correlated with ASD severity. Neuroimaging, in
vitro and post-mortem brain studies were consistent with an elevated
prevalence of mitochondrial dysfunction in ASD. Taken together, these
findings suggest children with ASD have a spectrum of mitochondrial
dysfunction of differing severity. Eighteen publications representing a
total of 112 children with ASD and MD (ASD/MD) were identified. The
prevalence of developmental regression (52%), seizures (41%), motor
delay (51%), gastrointestinal abnormalities (74%), female gender (39%),
and elevated lactate (78%) and pyruvate (45%) was significantly higher
in ASD/MD compared with the general ASD population. The prevalence of
many of these abnormalities was similar to the general population of
children with MD, suggesting that ASD/MD represents a distinct subgroup
of children with MD. Most ASD/MD cases (79%) were not associated with
genetic abnormalities, raising the possibility of secondary
mitochondrial dysfunction. Treatment studies for ASD/MD were limited,
although improvements were noted in some studies with carnitine,
co-enzyme Q10 and B-vitamins. Many studies suffered from limitations,
including small sample sizes, referral or publication biases, and
variability in protocols for selecting children for MD workup,
collecting mitochondrial biomarkers and defining MD. Overall,
this evidence supports the notion that mitochondrial dysfunction is
associated with ASD. Additional
studies are needed to further define the role of mitochondrial
dysfunction in ASD.
Lathe R. (2006). Porphyrinuria
in childhood autistic disorder: Implications for environmental toxicity
Toxicology and Applied
Pharmacology, 2006 Jul 15;214(2):99-108. Epub 2006 Jun
To address a possible environmental
contribution to autism, we carried out a retrospective study on urinary
porphyrin levels, a biomarker of environmental toxicity, in 269 children
with neurodevelopmental and related disorders referred to a Paris clinic
(2002–2004), including 106 with autistic disorder. Urinary porphyrin
levels determined by high-performance liquid chromatography were
compared between diagnostic groups including internal and external
control groups. Coproporphyrin levels were elevated in children with
autistic disorder relative to control groups. Elevation was maintained
on normalization for age or to a control heme pathway metabolite (uroporphyrin)
in the same samples. The elevation was significant (P < 0.001).
Porphyrin levels were unchanged in Asperger's disorder, distinguishing
it from autistic disorder. The atypical molecule precoproporphyrin, a
specific indicator of heavy metal toxicity, was also elevated in
autistic disorder (P < 0.001) but not significantly in Asperger's. A
subgroup with autistic disorder was treated with oral dimercaptosuccinic
acid (DMSA) with a view to heavy metal removal. Following DMSA there was
a significant (P = 0.002) drop in urinary porphyrin excretion. These
data implicate environmental toxicity in childhood autistic disorder.
Poling JS, Frye, RE, Schoffer J, Zimmerman AW (2006).
Regression and Mitochondrial Dysfunction in a Child With Autism
J Child Neurol. 2006 Feb;21(2):170-2.
Note : this is a case study of the first author’s child, Hannah
Poling, who received significant media attention.
Abstract: Autistic spectrum disorders can be associated with
mitochondrial dysfunction. We present a singleton case of developmental
regression and oxidative phosphorylation disorder in a 19-month-old
girl. Subtle abnormalities in the serum creatine kinase level, aspartate
aminotransferase, and serum bicarbonate led us to perform a muscle
biopsy, which showed type I myofiber atrophy, increased lipid content,
and reduced cytochrome c oxidase activity. There were marked reductions
in enzymatic activities for complex I and III. Complex IV (cytochrome c
oxidase) activity was near the 5% confidence level. To determine the
frequency of routine laboratory abnormalities in similar patients, we
performed a retrospective study including 159 patients with autism
(Diagnostic and Statistical Manual of Mental Disorders-IV and Childhood
Autism Rating Scale) not previously diagnosed with metabolic disorders
and 94 age-matched controls with other neurologic disorders. Aspartate
aminotransferase was elevated in 38% of patients with autism compared
with 15% of controls (P <.0001). The serum creatine kinase level also
was abnormally elevated in 22 (47%) of 47 patients with autism. These
data suggest that further metabolic evaluation is indicated in autistic
patients and that defects of oxidative phosphorylation might be