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The Putative Role of Environmental Mercury in the Pathogenesis and Pathophysiology of Autism Spectrum Disorders and Subtypes

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G. Morris
G. Morris
G. Morris
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Basant K Puri at C.A.R.
Basant K Puri
  • C.A.R.
Richard E Frye at University of Arizona
Richard E Frye
Michael Maes at University of Electronic Science and Technology of China
Michael Maes
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Abstract

Exposure to organic forms of mercury has the theoretical capacity to generate a range of immune abnormalities coupled with chronic nitro-oxidative stress seen in children with autism spectrum disorder (ASD). The paper discusses possible mechanisms explaining the neurotoxic effects of mercury and possible associations between mercury exposure and ASD subtypes. Environmental mercury is neurotoxic at doses well below the current reference levels considered to be safe, with evidence of neurotoxicity in children exposed to environmental sources including fish consumption and ethylmercury-containing vaccines. Possible neurotoxic mechanisms of mercury include direct effects on sulfhydryl groups, pericytes and cerebral endothelial cells, accumulation within astrocytes, microglial activation, induction of chronic oxidative stress, activation of immune-inflammatory pathways and impairment of mitochondrial functioning. (Epi-)genetic factors which may increase susceptibility to the toxic effects of mercury in ASD include the following: a greater propensity of males to the long-term neurotoxic effects of postnatal exposure and genetic polymorphisms in glutathione transferases and other glutathione-related genes and in selenoproteins. Furthermore, immune and inflammatory responses to immunisations with mercury-containing adjuvants are strongly influenced by polymorphisms in the human leukocyte antigen (HLA) region and by genes encoding effector proteins such as cytokines and pattern recognition receptors. Some epidemiological studies investigating a possible relationship between high environmental exposure to methylmercury and impaired neurodevelopment have reported a positive dose-dependent effect. Retrospective studies, on the other hand, reported no relationship between a range of ethylmercury-containing vaccines and chronic neuropathology or ASD. On the basis of these results, we would argue that more clinically relevant research is required to examine whether environmental mercury is associated with ASD or subtypes. Specific recommendations for future research are discussed.
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The Putative Role of Environmental Mercury in the Pathogenesis
and Pathophysiology of Autism Spectrum Disorders and Subtypes
G. Morris
1
&B. K. Puri
2
&R. E. Frye
3
&M. Maes
4
Received: 19 March 2017 /Accepted: 13 July 2017 /Published online: 22 July 2017
#Springer Science+Business Media, LLC 2017
Abstract Exposure to organic forms of mercury has the the-
oretical capacity to generate a range of immune abnormalities
coupled with chronic nitro-oxidative stress seen in children
with autism spectrum disorder (ASD). The paper discusses
possible mechanisms explaining the neurotoxic effects of mer-
cury and possible associations between mercury exposure and
ASD subtypes. Environmental mercury is neurotoxic at doses
well below the current reference levels considered to be safe,
with evidenceof neurotoxicity in children exposed to environ-
mental sources including fish consumption and ethylmercury-
containing vaccines. Possible neurotoxic mechanisms of mer-
cury include direct effects on sulfhydryl groups, pericytes and
cerebral endothelial cells, accumulation within astrocytes,
microglial activation, induction of chronic oxidative stress,
activation of immune-inflammatory pathways and impairment
of mitochondrial functioning. (Epi-)genetic factors which may
increase susceptibility to the toxic effects of mercury in ASD
include the following: a greater propensity of males to the
long-term neurotoxic effects of postnatal exposure and genetic
polymorphisms in glutathione transferases and other
glutathione-related genes and in selenoproteins. Furthermore,
immune and inflammatory responses to immunisations with
mercury-containing adjuvants are strongly influenced by poly-
morphisms in the human leukocyte antigen (HLA) region and
by genes encoding effector proteins such as cytokines and pat-
tern recognition receptors. Some epidemiological studies inves-
tigating a possible relationship between high environmental
exposure to methylmercury and impaired neurodevelopment
have reported a positive dose-dependent effect. Retrospective
studies, on the other hand, reported no relationship between a
range of ethylmercury-containing vaccines and chronic neuro-
pathology or ASD. On the basis of these results, we would
argue that more clinically relevant research is required to exam-
ine whether environmental mercury is associated with ASD or
subtypes. Specific recommendations for future research are
discussed.
Keywords Autism spectrum disorders .Mercury .Immune .
Cytokines .Inflammation .Oxidative stress
Introduction
Autism spectrum disorders (ASD) are a heterogeneous group
of illnesses currently defined diagnostically by the presence of
impaired social communication, a pattern of restricted inter-
ests, and, in many instances, repetitive behaviours [1].
Importantly, these illnesses are currently defined solely on
the basis of observable behaviours and clinical history rather
than measurable biomarkers. However, a rapidly accumulat-
ing body of evidence is beginning to provide the basis for
defining ASD in terms of physiology and identifying the pres-
ence of discrete subgroups, henceforth described as
endophenotypes [2]. One such proposed endophenotype is
based on the presence of abnormalities in the performance of
the innate and humoral immune systems, which has been
*G. Morris
activatedmicroglia@gmail.com
1
Tir Na Nog, Bryn Road seaside 87, Llanelli, Wales SA152LW, UK
2
Department of Medicine, Hammersmith Hospital, Imperial College
London, London W12 0HS, UK
3
Division of Child and Adolescent Neurology and Children’s
Learning Institute, Department of Pediatrics, University of Texas,
Austin, TX, USA
4
Department of Psychiatry, Chulalongkorn University,
Bangkok, Thailand
Mol Neurobiol (2018) 55:4834–4856
DOI 10.1007/s12035-017-0692-2
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Reportedly, children with ASD exhibit dysregulated biochemical and cellular processes such as intestinal dysbiosis, impairment of mitochondrial function, immune system dysfunction, elevated exposure to toxic metals, and stimulation of neuroglial cells (49)(50)(51)(52). Recent findings suggest that the determination of ASD pathogenesis is influenced by the balance of oxidant-antioxidant and TLR4-related signaling. ...
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Long term changes in health complaints after removal of amalgam restorations
Article
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Article
  • Sep 2016
Autoimmune diseases result from an interplay of genetic predisposition and factors which stimulate the onset of disease. Mercury (Hg), a well-established toxicant, is an environmental factor reported to be linked with autoimmunity. Hg exists in several chemical forms and is encountered by humans in dental amalgams, certain vaccines, occupational exposure, atmospheric pollution and seafood. Several studies have investigated the effect of the various forms of Hg, including elemental (Hg?), inorganic (iHg) and organic mercury (oHg) and their association with autoimmunity. In vitro studies using peripheral blood mononuclear cells (PBMC) from healthy participants have shown that methylmercury (MeHg) causes cell death at lower concentrations than iHg albeit exposure to iHg results in a more enhanced pro-inflammatory profile in comparison to MeHg. In vivo research utilising murine models susceptible to the development of metal-induced autoimmunity report that exposure to iHg results in a lupus-like syndrome, whilst mice exposed to MeHg develop autoimmunity without the formation of immune complexes. Furthermore, lower concentrations of IgE are detected in MeHg-treated animals in comparison with those treated with iHg. It appears that, oHg has a negative impact on animal models with existing autoimmunity. The research conducted on humans in this area is diverse in study design and the results are conflicting. There is currently no evidence to implicate a role for Hg? exposure from dental amalgams in the development or perpetuation of autoimmune disease, apart from some suggestion of individual sensitivity. Several studies have consistently shown a positive correlation between iHg exposure and serum autoantibody concentrations in gold miners, although the clinical impact of iHg remains unknown. Furthermore, a limited number of studies have reported individuals with autoimmune disease have higher concentrations of blood Hg compared to healthy controls. In summary, it appears that iHg perpetuates markers of autoimmunity to a greater extent than oHg, albeit the impact on clinical outcomes in humans is yet to be elucidated.
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The Role of the Immune System in Autism Spectrum Disorder
Article
  • Aug 2016
  • NEUROPSYCHOPHARMACOL
Autism is a neurodevelopmental disorder characterized by deficits in communication and social skills as well as repetitive and stereotypical behaviors. While much effort has focused on the identification of genes associated with autism, research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in Autism Spectrum Disorders (ASD). Further, it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions. This review will focus on the two main axes of immune involvement in ASD, namely dysfunction in the prenatal and postnatal periods. During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child. Similarly, the presence of maternally derived anti-brain autoantibodies found in approximately 20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD. The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within in the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both maternal and child immune systems, and the role they play in diagnosis and treatment.Neuropsychopharmacology Reviews accepted article preview online, 18 August 2016. doi:10.1038/npp.2016.158.
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