Susceptibility factors in
mercury toxicity: immune reactivity, detoxification system function, enzymatic
blockages, synergistic exposures. B.
Windham (Ed.)
It is
well documented in the medical literature that the major factors in mercury
toxicity effects, in addition to dose, are susceptibility factors like immune
reactivity(1,2), degree of other toxic exposures and synergisms (3,15,27,32),
systemic detoxification ability based on blood allele type(4,15,27) or
metallothionein function(5), sulfur detoxification deficiencies(6), or other mutated
or inhibited enzymatic processes related to detoxification (7-10,27,33,35,40)
or methylation (27,28,33,35,39). It has been shown that such susceptibility
factors can play a larger role in effects than dose among a population with
significant exposure to mercury and at extremely low levels of exposure. Toxic
metals such as aluminum and lead have been documented to have synergistic effects
with mercury, increasing mercury effects significantly. Aluminum and other
toxic metals have their own toxic effects, plus increasing mercury effects by
depleting glutathione. Dioxins and mercury have also been documented to have
synergistic effects that are more than individual effects (32).
Inherited defects or differences in the body’s ability to detoxify
can contribute to heavy metal accumulation and toxicity (27,4,11,15,33, etc.). Deficiencies
of certain minerals, vitamins, and amino acids reduce the body’s ability to
excrete toxins following exposure (27). Those with the genetic
allele ApoE4 protein in the blood have been found to detoxify metals poorly and
to be much more genetically susceptible to chronic neurological conditions than
those with types ApoE2 or E3(4,11,15). Researchers have shown that genetic carriers of the brain protein
APO E2 are protected against Alzheimer's disease (AD) whereas genetic carriers
of the APO E4 genotype are at enhanced risk factor for developing AD and other
degenerative neurological conditions. APO E proteins are synthesized in the
brain with the assigned physiological task of carrying waste material from the
brain to the cerebrospinal fluid, across the blood brain barrier into the
plasma where the material is cleared by the liver. The biochemical difference
between APO E2 and APO E4 is that APO E2 has two additional thiol groups,
capable of binding and removing mercury (and ethyl mercury) that APO E4 does
not have. The second highest concentration of APO E proteins is in the
cerebrospinal fluid. Therefore, the protective effects of APO E2 is due to its
ability to protect the brain from exposure to oxidants like mercury and ethyl
mercury by binding these toxicants in the cerebrospinal fluid and keeping them
from entering the brain.
A significant percent of ALS cases are of
the familial type that has been linked to a mutation of the copper/zinc super
oxide dismustase gene (Cu/Zn SOD) (33a). In a mouse study of the ALS model transgenic
mice, concentrations of Cu, Zn and Fe were significantly elevated in
muscle tissue of the SOD1 transgenic mice. In a study of amalgam filling effect
on women, Hg, Ag, Al and Ba metak levels increased in
women who had dental amalgam fillings for long periods and Hg had a positive
correlation with SOD-1. SOD-1 may be a possible biomarker for assessing chronic
Hg toxicity(33d). Significant elevation in mercury or other toxic metal
concentration in muscle tissue from SOD1-G93a transgenic individuals appear to
facilitate the development of ALS, making transgenic individuals more
susceptible to mercury and metal exposures and imbalances (33bc). Resveratrol
was found to be protective against such effects(33c).
Glutathione is produced
by methylation that’s responsible for brain neurotransmitter production, immune
function, and detoxification. DNA methylation and
other epigenetic factors are important in the pathogenesis of late-onset
Alzheimer's disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR)
gene mutations occur in most elderly patients with memory loss (39). MTHFR is critical for production of
S-adenosyl-l-methionine (SAMe), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase
(CTH) gene affects the enzyme that converts cystathionine to cysteine in
the transsulfuration pathway causing plasma elevation
of total homocysteine (tHcy) or hyperhomocysteinemia-a
strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors,
and deficiencies of B vitamins.
The progressive loss of
motor control due to reduction of dopamine-producing neurons in the substantia nigra pars compacta and decreased striatal dopamine levels
are the classically described features of Parkinson disease (PD).
Neuronal damage also progresses to other regions of the brain, and additional
non-motor dysfunctions are common Mutations of Parkinson’s
disease protein DJ-1 are known to cause a form of recessive early onset Parkinson
disease, highlighting an important functional role for DJ-1 in early disease prevention. Study
results show that expression of DJ-1 enhances the cells' protective mechanisms
against induced metal toxicity and that this protection is lost for DJ-1 PD
mutations A104T and D149A (40).
A study (41) found that PARK2 mutant neuroprogenitors showed increased cytotoxicity with copper
(Cu) and cadmium (Cd) exposure. PARK2 mutant neuroprogenitors
also showed a substantial increase in mitochondrial fragmentation, initial ROS
generation, and loss of mitochondrial membrane potential following Cu exposure.
Reduced levels of magnesium
and zinc are related to metabolic syndrome, insulin resistance, and brain
inflammation and are protective against these conditions (35). Mercury, cadmium,
and other toxic metals inhibiting magnesium and zinc levels as well as
inhibiting glucose transfer are other mechanisms by which mercury and toxic
metals are factors in metabolic syndrome and insulin resistance/diabetes (35-38),
which are factors in other chronic neurological conditions. Such toxic
exposures thus have synergistic effects, so relatively low exposures to toxics
can add up to major effects.
Another study found that
polymorphisms in glutamyl-cysteine ligase and glutathione S-tranferases
genes modify mercury retention in humans exposed to elemental mercury vapor.
Genotypes with decreased GSH availability for mercury conjugation affect the
metabolism of inorganic mercury, increasing mercury retention (26). Similarly,
many people lack a Metallothionene related
glutathione-S-Transferase gene called GSTM1 or have a related polymorphism that
appears to be key for proper functioning of the body’s own natural
detoxification mechanisms. This may explain at least in part why some
people develop the chronic health problems linked to heavy metals while others
who are similarly exposed do not. (31)
Recent studies found
that prenatal mercury exposures from
mother’s amalgams and other sources along with susceptibility factors such as
ability to excrete mercury appear to be major factors in those with chronic
neurological conditions like autism and ADHD(11,15,20,27). Infants whose
mothers received prenatal Rho D immunoglobulin injections containing mercury
thimerosal for RH factor or whose mother’s had high levels of amalgam fillings
had a much higher incidence of autism. While the hair test levels of mercury of
infants without chronic health conditions like autism were positively
correlated with the number of the mother’s amalgam fillings, vaccination
thimerosal exposure, and mercury from fish, the hair test levels of those with
chronic neurological conditions such as autism were much lower than the levels
of controls and those with the most severe effects had the lowest hair test
levels, even though they had high body mercury levels. This is consistent with
past experience of those treating children with autism and other chronic
neurological conditions(12). Exposure to toxics
such as mercury have been found to inhibit enzymes needed to digest wheat
gluten and milk casein, resulting in symptoms of autism,
ADHD, diabetes, etc. after chronic exposure to gluten or
casein. These conditions commonly significantly improve after avoidance of
gluten and casein. Some cases of hypothyroidism are
driven by immune reactions to gluten in celiac disease (27) Genetic or toxic
exposure related impairments in methylation function,
detoxification, clearance
of catecholamines, or in the clearance of adrenalin may contribute to symptoms
in autism or ADD/ADHD for those subjected to stress or inadequate nutrition to
overcome impairments (27). Prenatal and neonatal toxic exposures also can cause
leaky gut in infants; ‘Leaky gut’ in autism can
promote toxic burden in the body, as well as the development of food
allergies(27) which have been found to often be factors in
autism symptoms.
Within a population of dentists and dental assistance with
exposure to mercury in their work, increased symptoms of depression,
anxiety, and memory are associated with the 5-HTTLPR serotonin transporter
polymorphism among both males and females (42).
Studies have
documented that prenatal mercury exposure causes lasting effects that causes
increased susceptibility to future toxic exposures. The effects of chronic,
low-dose fetal and lactational organic (MeHgCl) and
inorganic (HgCl2) mercury intoxication on epilepsy/seizures were
investigated and compared in rats and were found to have significant
correlations between seizure susceptibility and cortical mercury level(16)
Inorganic mercury exposure facilitated the duration of seizure discharges in
younger animals and appeared to be more permanent than methyl mercury exposure.
Another researcher had similar findings for infants (17). A study of children
of mothers consuming a marine diet which exposes them to mercury, found that
there are significant cardiovascular effects as birth mercury blood level
increases from 1 microgram per liter to 10 ug/L(a),
as well as effects on ability to respond to sensory stimuli in exposed children
later in life (18). Children with lower birth weights experienced blood
pressure increases about 50% higher than normal birth weight children having
similar mercury levels. At seven years of age, clear dose-response
relationships were observed for deficits in attention, language, and memory(b).
Thus a levels of exposure below current Government
health safety limits, mercury is documented to have significant cardiovascular
effects and the recommended limit for mercury has been decreased from the
former limit of 10 ug/L in blood.
Large
studies of U.S. dentists and dental assistants have found that mercury level in
urine is significantly associated with neurological dysfunction using several
different measures, but that among a population with low level mercury
exposure those with a polymorphism in blood heme
(CPOX4) or to a polymorphism in neurofactor (BDNF) or to a functional single
nucleotide polymorphism (Val158Met) in the gene encoding the catecholamine
catabolic enzyme catechol O-methyltransferase (COMT) were more susceptible to
neurological effects or deficits(19). An association in a population with low
level mercury exposure between such polymorphisms and mood disorders was found
only for female dental assistants. The associations between a polymorphism
of the serotonin transporter gene (5-HTTLPR), dental mercury exposure, and
self-reported symptoms were evaluated among 157 male dentists and 84 female dental
assistants. The findings suggest that within this restricted population of
mercury exposed workers, increased symptoms of depression, anxiety, and memory
are associated with the 5-HTTLPR polymorphism among both males and
females(19d).
Inherited
impairments in methylation or toxic related inhibition of functional
methylation by toxics such as mercury can have a dramatic effect on mood
regulation and depression (27,28). Genetic
related or toxic exposure related hormone imbalances are documented to make
people more susceptible to depression
and anxiety disorders(27). Many patients with
depression suffer from thyroid hormone imbalances that may make them more
treatment-resistant, or imbalances of DHEA or cortisol(27), which can be
related to genetic susceptibility or toxic
exposures to toxics such as mercury. Thyroid
imbalances can strain the adrenal glands; or adrenal imbalances can also
disrupt normal thyroid function; either making an individual more susceptible
to depression or anxiety disorders(27).
Malabsorption in
genetically or toxic related celiac disease can
interfere with mood regulating neurotransmitters and nutrients such as vitamin
B12 (27).
Inherited
defects in detoxification of environmental chemicals (as previously documented)
may promote toxicity and fatigue in
CFS, and inherited tendencies toward inflammation and methylation
defects can exacerbate the chronic pain of fibromyalgia(27). Exposures to heavy
metal toxins can impair energy production and further burden the detoxification
system. Stress can over time cause hormonal imbalances and deficiencies and
leaky gut and malabsorption of essential nutrients either genetic or related to
toxic exposures can result in inability to detoxify harmful substances and
waste products (27), enabling chronic conditions.
Mercury (Hg) is neurotoxic, and children may be
particularly susceptible to this effect. Metallothioneins (MTs) are a family of
metal-binding proteins virtually expressed in all organisms including
prokaryotes, lower eukaryotes, invertebrates and mammals. These proteins
regulate homeostasis of zinc (Zn) and copper (Cu), mitigate heavy metal
poisoning, and alleviate superoxide stress. In a study to assess the effects of
genetic polymorphisms in MT, among boys, numerous significant interaction
effects between variants of MT1M and MT2A, alone and combined, with Hg exposure
were observed spanning multiple domains of neurobehavioral function (44). All
dose-response associations between Hg exposure and test performance were
restricted to boys and were in the direction of impaired performance. These
findings suggest increased susceptibility to the adverse neurobehavioral
effects of Hg among children with relatively common genetic variants of MT.
Chronic exposure to toxic
substances such as mercury can facilitate overgrowths of pathogenic bacteria,
viruses, and yeast (27), leading to chronic conditions. Thyroid
imbalances related to genetic susceptibility or toxic exposures can
strain the adrenal glands; or adrenal imbalances in similar regards can disrupt
normal thyroid function (27).
Genetic factors or toxic
exposures that weaken the immune
system can result in increased susceptibility to allergies and
biological pathogens.
Inherited impairments in
detoxification function can also interact with environmental factors to promote
multiple chemical sensitivity(MCS) (27).
Defects in the body’s ability to neutralize environmental chemicals lead
directly to the accumulation of toxins, and the body’s ability to neutralize
and excrete environmental toxins depends on the availability of key nutrients (27).
Some cases of MCS may be secondary to ‘leaky
gut’ and the passage of toxins or food particles into the system. Arthritis is
an inflammatory condition also often secondary to ‘leaky gut’, which can be
caused by toxic exposures, and to the related passage of toxins or undigested
food particles into the system (27). Individuals with asthma often have an
inherited predisposition to produce excessive inflammatory mediators(27)
or increased inflammatory cytokines related
to either prenatal or later toxic
exposures to toxics such as mercury.
Inherited
defects in methylation or control of inflammation in the body or similar
toxic related effects can influence the
course of heart disease (27).
Inherited risks associated with cardiovascular disease, obesity,
or estrogen metabolism may exacerbate Metabolic Syndrome, for which toxic
exposures are also significant factors. Metabolic
Syndrome increases cardiovascular risk by
promoting hyperlipidemia, clot formation, inflammation, and hypertension.
Imbalances or deficiencies in key nutrients can exacerbate metabolic imbalances
in Metabolic Syndrome and prevent healing (27). High insulin levels in
Metabolic Syndrome contribute to oxidative stress by unstable free radicals in
the body (27). As men age, declining testosterone may trigger metabolic
imbalances that promote insulin resistance with significant differences
depending on genetic factors and cumulative
toxic exposures.
Although a study of mercury in children showed
that females given the same exposure as males excrete more mercury(30) and
males are more likely to have autism, another study found that females are two
to three times more likely to develop local (e.g., lichenoid contact
stomatitis) or systemic adverse health outcomes (e.g., skin disorders) compared
with males from prolonged exposure to mercury vapor from dental amalgams(29).
Moreover, given that inorganic mercury [Hg2+] binds mainly to thiol
ligands [–SH] as homocysteine (Bridges and Zalups
2004), the authors suggest that future clinical trials addressing the role of
sex in mercury excretion should include an evaluation of serum homocysteine,
which is higher in males than in females and might account for an increased
tissue retention of mercury(29b). Toxic exposures can
facilitate dysbiosis (digestive problems) related to leaky gut,
chronic maldigestion, exposure to gut pathogens, and/or suppression of
protective microorganisms by toxic exposures (27). Chronic imbalances in the
intestinal flora can irritate the mucosa due to poor diet or toxic exposures,
allow the passage of toxins into the system, weaken the immune system, etc. (27).
Many of the same underlying environmental factors promoting dysbiosis in the
colon can encourage bacterial overgrowth in the delicate small bowel. Parasite
infestation occurs more easily with dysbiosis and deficiencies of protective
bacteria (27). ‘Leaky gut’ from intestinal irritants can allow bacterial toxins
to enter the system and promote skin inflammation such as eczema(27).
Identifying high levels of various gluten-associated antibodies
is an important first step in the diagnosis and correction of either genetic or
toxic related celiac disease (27).
Programmed
cell death (apoptosis) is documented to be a major factor in degenerative
neurological conditions like ALS, Alzheimer’s, MS, Parkinson’s, etc. Some of
the factors documented to be involved in apoptosis of neurons and immune cells
include mitochondrial membrane dysfunction (22bc,24). Mitochondrial DNA
mutations or dysfunction is fairly common, found in at least 1 in every 200 people
( 23), and toxicity effects affect this population
more than those with less susceptibility to mitochondrial
dysfunction. Mercury depletion of GSH and damage to cellular mitochrondria and the increased lipid peroxidation in
protein and DNA oxidation in the brain appear to be a major factor in
conditions such as autism, Parkinson’s disease, etc. (21-25).
Some
studies have also found persons with chronic exposured
to electromagnetic fields(EMF) or Wi-fi to have higher
levels of mercury exposure and excretion(34a) and higher likelihood of getting
chronic conditions like ALS and Alz(34b, etc).
Severe socioeconomic deprivation (SED)
and adverse
childhood experiences (ACE)
are significantly associated with the development in adulthood of (i) enhanced inflammatory status and/or
hypothalamic-pituitary-adrenal (HPA) axis dysfunction and (ii) neurological, inflammatory,
and autoimmune diseases(43). Clearly, individual with such weakened immune and
neurological systems are more susceptible to toxic exposures and other damages
suffered.
The mechanisms by which low
level chronic mercury exposure causes over 30 chronic
health conditions such as those looked
at in this review are well documented in the literature and differences in
susceptibilities are documented in all of these; and the fact that those
treated for mercury toxicity usually
recover after treatment is also well
documented by many dozens of medical studies in the literature and thousands of
clinical cases(13). Some of the autoimmune conditions commonly caused by immune
reactivity to mercury include chronic fatigue syndrome(CFS), fibromyalgia, lupus,
rheumatoid arthritis, Parkinson’s, multiple sclerosis (MS), amyotropic lateral sclerosis(ALS), depression, autism, ADHD, eczema, asthma, etc.
(14,1,2,hyperlinks). People are documented to vary significantly in immune
reactivity to toxic substances and susceptibility to these conditions. Low
level exposures and exposures to multiple toxics can have significant effects
in such individuals. (see
hyperlinks).
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