Arsenic metabolism has typically been studied by administering arsenate or arsenite into animals and humans and then studying the metabolites excreted in the urine. Although such studies have yielded information about the beginning and the end of the metabolic pathways for the metabolism of inorganic arsenic compounds, any statements as to the molecular mechanisms of these reactions have had to be highly speculative. Now that the rabbit and the rhesus monkey liver enzymes that transfer methyl groups from S-adenosylmethionine to arsenite and monomethlyarsonic acid have been purified and the reactions characterized, meaningful investigations of species diversity and polymorphism of these enzymes have become possible. New World animals studied thus far appear to be deficient in or totally lacking these enzymes. Old World animals, with the exception of the chimpanzee, have ample amounts of arsenite and monomethylarsonic acid methyltransferases. A hypothesis that the lack of arsenite methyltransferases may have had an evolutionary advantage for certain species is proposed.

Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity

Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case–control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case–control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose–effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), δ-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.

/pdf/environmental-toxicants-and-autism-spectrum-disorders-a-4p1z1vfehd.pdf

Environmental toxicants and autism spectrum disorders: a systematic review

Chronic, low level exposure to toxic metals is an increasing global problem. The symptoms associated with the slow accumulation of toxic metals are multiple and rather nondescript, and overt expression of toxic effects may not appear until later in life. The sulfhydryl-reactive metals (mercury, cadmium, lead, arsenic) are particularly insidious and can affect a vast array of biochemical and nutritional processes. The primary mechanisms by which the sulfhydryl-reactive metals elicit their toxic effects are summarized. The pro-oxidative effects of the metals are compounded by the fact that the metals also inhibit antioxidative enzymes and deplete intracellular glutathione. The metals also have the potential to disrupt the metabolism and biological activities of many proteins due to their high affinity for free sulfhydryl groups. Cysteine has a pivotal role in inducible, endogenous detoxication mechanisms in the body, and metal exposure taxes cysteine status. The protective effects of glutathione and the metallothioneins are discussed in detail. Basic research pertaining to the transport of toxic metals into the brain is summarized, and a case is made for the use of hydrolyzed whey protein to support metal detoxification and neurological function. Metal exposure also affects essential element status, which can further decrease antioxidation and detoxification processes. Early detection and treatment of metal burden is important for successful detoxification, and optimization of nutritional status is paramount to the prevention and treatment of metal toxicity.

Cysteine metabolism and metal toxicity.

For more than 160 years dentistry has used silver amalgam, which contains approximately 50% Hg metal, as the preferred tooth filling material. During the past decade medical research has demonstrated that this Hg is continuously released as vapor into mouth air; then it is inhaled, absorbed into body tissues, oxidized to ionic Hg, and finally covalently bound to cell proteins. Animal and human experiments demonstrate that the uptake, tissue distribution, and excretion of amalgam Hg is significant, and that dental amalgam is the major contributing source to Hg body burden in humans. Current research on the pathophysiological effects of amalgam Hg has focused upon the immune system, renal system, oral and intestinal bacteria, reproductive system, and the central nervous system. Research evidence does not support the notion of amalgam safety.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.9.7.7737458

Mercury exposure from "silver" tooth fillings: emerging evidence questions a traditional dental paradigm.

Mercury is one of the most toxic substances known to humans. It has been introduced into the human environment and has also been widely used in medicine. Since circumstantial evidence exists that the pathology of Alzheimer's disea se (AD) might be in part caused or exacerbated by inorganic mercury, we conducted a systematic review using a comprehensive search strategy. Studies were screened according to a pre-defined p rotocol. Two reviewers extracted relevant data independent of each other. One thousand and forty one references were scrutinized, and 106 studies fulfilled the inclusion criteria. Most st udies were case control or comparative cohort studies. Thirty-two studies, out of 40 testing memory in individuals exposed to inorganic mercury, found significant memory deficits. Some autopsy stu dies found increased mercury levels in brain tissues of AD patients. Measurements of mercury levels in blood, urine, hair, nails, and cerebrospinal fluid were inconsistent. In vitro models showed that inorganic mercury reproduces all pathological changes seen in AD, and in animal models inorganic mercury produced changes that are similar to those seen in AD. Its high affinity for selenium and selenoproteins suggests that inorganic mercury may promote neurodegenerative disorders via disruption of redox regulation. Inorganic mercury may play a role as a co-factor in the development of AD. It may also increase the pathological influence of other metals. Our mechanistic model describe s potential causal pathways. As the single most effective public health primary preventive measure, industrial, and medical usage of mercury should be eliminated as soon as possible.

/pdf/does-inorganic-mercury-play-a-role-in-alzheimer-s-disease-a-v4vxosgdpf.pdf

Does inorganic mercury play a role in Alzheimer's disease? A systematic review and an integrated molecular mechanism.

The sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS) challenge test (300 mg p.o. after an 11-hr fast) was given in Monterrey, Mexico to dental and nondental personnel. Urine samples were collected and analyzed for total mercury. The mean mercury urinary excretion (+/- S.E.) for 6 hr before and 6 hr after DMPS administration for 10 dental technicians, who formulate amalgam, was 4.84 micrograms +/- 0.742 and 424.0 micrograms +/- 84.9; for 5 dentists, who use amalgam in their practice, 3.28 micrograms +/- 1.11 and 162.0 micrograms +/- 51.2; and for 13 nondental personnel, 0.783 microgram +/- 0.189 and 27.3 micrograms +/- 3.19. The urinary coproporphyrin levels before DMPS administration, which are indicative of renal mercury content, were quantitatively associated with the urinary mercury levels among the three study groups after DMPS administration. This was not so if the urinary mercury level before DMPS administration was compared with the urinary coproporphyrin concentration. The urinary mercury level after DMPS administration is a better indicator of exposure and renal mercury burden than is the mercury level measured in the urine before DMPS is given. Regression analysis showed that the coefficient of urinary mercury was statistically and adversely associated with complex attention (switching task), the perceptual motor task (symbol-digit substitution), symptoms and mood. The easily performed DMPS-mercury challenge test is useful for monitoring dental personnel for mercury vapor exposure.

Sodium 2,3-dimercaptopropane-1-sulfonate challenge test for mercury in humans: II. Urinary mercury, porphyrins and neurobehavioral changes of dental workers in Monterrey, Mexico

P Junco-Munoz

Papers

Sodium 2,3-dimercaptopropane-1-sulfonate challenge test for mercury in humans: II. Urinary mercury, porphyrins and neurobehavioral changes of dental workers in Monterrey, Mexico