Photography's Underappreciated Contributions to Neuropsychiatry: The Photographs of W. Eugene Smith in Minamata, Japan.

Photographers and filmmakers have made important contributions to the international mental health community through documentation and social commentary, leveraging the power of visual imagery. To illustrate, this article uses the example of W. Eugene Smith who photographed the catastrophic effects of methylmercury poisoning from industrial pollution in the region around Minamata Bay, Japan. Although many art forms have been comfortably integrated into mainstream psychiatry and neuropsychiatry, photography has been underappreciated and underutilized.

Elevated mercury bound to serum proteins in methylmercury poisoned rats after selenium treatment.

Methylmercury is a toxic pollutant and is generated by microbial methylation of elemental or inorganic mercury in the environment. Previous study found decreased hepatic MDA levels and urinary mercury levels in methylmercury poisoned rats after sodium selenite treatment. This study further found increased mercury levels in serum samples from methylmercury poisoned rats after selenium treatment. By using size exclusion chromatography coupled to inductively coupled plasma mass spectrometry, three Hg- binding protein fractions and two Se-binding protein fractions were identified with the molecular weight of approximately 21, 40, and 75 kDa and of 40 and 75 kDa, respectively. Elevated mercury level in the 75 kDa protein fraction was found binding with both Hg and Se, which may explain the decreased urinary Hg excretion in MeHg poisoned rats after Se treatment. MALDI-TOF-MS analysis of the serum found that the 75 kDa protein fractions were albumin binding with both Hg and Se and the 21 kDa fraction was Hg- binding metallothionein.

Selenium Health Benefit Values: Updated Criteria for Mercury Risk Assessments.

Selenium (Se)-dependent enzymes (selenoenzymes) protect brain tissues against oxidative damage and perform other vital functions, but their synthesis requires a steady supply of Se. High methylmercury (CH3Hg) exposures can severely diminish Se transport across the placenta and irreversibly inhibit fetal brain selenoenzymes. However, supplemental dietary Se preserves their activities and thus prevents pathological consequences. The modified Se health benefit value (HBVSe) is a risk assessment criterion based on the molar concentrations of CH3Hg and Se present in a fish or seafood. It was developed to reflect the contrasting effects of maternal CH3Hg and Se intakes on fetal brain selenoenzyme activities. However, the original equation was prone to divide-by-zero-type errors whereby the calculated values increased exponentially in samples with low CH3Hg contents. The equation was refined to provide an improved index to better reflect the risks of CH3Hg exposures and the benefits provided by dietary Se. The HBVSe provides a biochemically based perspective that confirms and supports the FDA/EPA advice for pregnant and breast-feeding women regarding seafoods that should be avoided vs. those that are beneficial to consume. Since Se can be highly variable between watersheds, further evaluation of freshwater fish is needed to identify locations where fish with negative HBVSe may arise and be consumed by vulnerable subpopulation groups.

Response inhibition is impaired by developmental methylmercury exposure: acquisition of low-rate lever-pressing.

Developmental methylmercury (MeHg) exposure produces response perseveration on discrimination reversal procedures, disrupts sensitivity to reinforcement, and enhances sensitivity to dopamine agonists - a profile suggesting a deficit in behavioral inhibition. To examine inhibition, we examined MeHg's effects on the acquisition and persistence of low-rate lever-pressing following a history of high-rate responding. Additionally, we examined whether chronic exposure to selenium protects against MeHg's developmental neurotoxicity. Female rats were exposed in utero via maternal exposure to drinking water containing 0ppm, 0.5ppm or 5ppm of Hg as MeHg, producing approximately 0µg/kg/day, 40µg/kg/day, or 400µg/kg/day of Hg. The mothers (during gestation) and the offspring (throughout life) consumed a purified diet containing 0.06ppm or 0.6ppm of Se (as sodium selenite), forming a 2 (lifespan diet)×3 (developmental MeHg) factorial design. Adult offspring lever-pressed under two schedules of reinforcement. A differential reinforcement of high-rate (DRH) schedule imposed rigid response requirements that remained constant through the study. A high-rate percentile schedule (PCNT-H) incorporated a flexible criterion that reinforced short interresponse times using an adjusting criterion that was sensitive to recent performance. After high-rate responding stabilized, the PCNT-H schedule was abruptly inverted by reinforcing long interresponse times. Acquisition of low-rate responding was impaired in the MeHg-exposed rats because of intrusions of high-rate response bursts. DRH response rates did not change. Dietary selenium did not influence MeHg's effects. High-rate operant behavior perseverated, suggesting that gestational MeHg exposure impairs response inhibition - an effect that extends results previously reported using choice procedures or spatial and visual discrimination reversals.

Dietary selenium's protective effects against methylmercury toxicity.

Dietary selenium (Se) status is inversely related to vulnerability to methylmercury (MeHg) toxicity. Mercury exposures that are uniformly neurotoxic and lethal among animals fed low dietary Se are far less serious among those with normal Se intakes and are without observable consequences in those fed Se-enriched diets. Although these effects have been known since 1967, they have only lately become well understood. Recent studies have shown that Se-enriched diets not only prevent MeHg toxicity, but can also rapidly reverse some of its most severe symptoms. It is now understood that MeHg is a highly specific, irreversible inhibitor of Se-dependent enzymes (selenoenzymes). Selenoenzymes are required to prevent and reverse oxidative damage throughout the body, particularly in the brain and neuroendocrine tissues. Inhibition of selenoenzyme activities in these vulnerable tissues appears to be the proximal cause of the pathological effects known to accompany MeHg toxicity. Because Hg's binding affinities for Se are up to a million times higher than for sulfur, its second-best binding partner, MeHg inexorably sequesters Se, directly impairing selenoenzyme activities and their synthesis. This may explain why studies of maternal populations exposed to foods that contain Hg in molar excess of Se, such as shark or pilot whale meats, have found adverse child outcomes, but studies of populations exposed to MeHg by eating Se-rich ocean fish observe improved child IQs instead of harm. However, since the Se contents of freshwater fish are dependent on local soil Se status, fish with high MeHg from regions with poor Se availability may be cause for concern. Further studies of these relationships are needed to assist regulatory agencies in protecting and improving child health.

The chemical nature of mercury in human brain following poisoning or environmental exposure.

Methylmercury is among the most potentially toxic species to which human populations are exposed, both at high levels through poisonings and at lower levels through consumption of fish and other seafood. However, the molecular mechanisms of methylmercury toxicity in humans remain poorly understood. We used synchrotron X-ray absorption spectroscopy (XAS) to study mercury chemical forms in human brain tissue. Individuals poisoned with high levels of methylmercury species showed elevated cortical selenium with significant proportions of nanoparticulate mercuric selenide plus some inorganic mercury and methylmercury bound to organic sulfur. Individuals with a lifetime of high fish consumption showed much lower levels of mercuric selenide and methylmercury cysteineate. Mercury exposure did not perturb organic selenium levels. These results elucidate a key detoxification pathway in the central nervous system and provide new insights into the appropriate methods for biological monitoring.

Neurodevelopmental toxicity of methylmercury: Laboratory animal data and their contribution to human risk assessment.

Methylmercury (MeHg) is one of the most significant public health hazards. The clinical findings in the victims of the Japanese and Iraqi outbreaks have disclosed the pronounced susceptibility of the developing brain to MeHg poisoning. This notion has triggered worldwide scientific attention toward the long-term consequences of prenatal exposure on child development in communities with chronic low level dietary exposure. MeHg neurodevelopmental effects have been extensively investigated in laboratory animals under well-controlled exposure conditions. This article provides an updated overview of the main neuromorphological and neurobehavioral changes reported in non-human primates and rodents following developmental exposure to MeHg. Different aspects of MeHg's effects on the immature organism are reported, with particular reference to the delayed onset of symptoms and the persistency of central nervous system (CNS) injury/dysfunction. Particular attention is paid to the comparative toxicity assessment across species, and to the degree of concordance/discordance between human and animal data. The contribution of animal studies to define the role of potential effect modifiers and variables on MeHg dose-response relationships is also addressed. The ultimate goal is to discuss the relevance of laboratory animal results, as a complementary tool to human data, with regard to the human risk assessment process.

Selenium health benefit values as seafood safety criteria.

Selenium (Se) is absolutely required for activity of 25-30 genetically unique enzymes (selenoenzymes). All forms of life that have nervous systems possess selenoenzymes to protect their brains from oxidative damage. Homeostatic mechanisms normally maintain optimal selenoenzyme activities in brain tissues, but high methylmercury (MeHg) exposures sequester Se and irreversibly inhibit selenoenzyme activities. However, nutritionally relevant amounts of Se can replace the Se sequestered by MeHg and maintain normal selenoenzyme activities, thus preventing oxidative brain damage and other adverse consequences of MeHg toxicity. Findings of studies that seem contradictory from MeHg exposure perspectives are entirely consistent from MeHg:Se molar ratio perspectives. Studies that have reported dose-dependent consequences of maternal MeHg exposures on child development uniformly involved seafoods that contained much more Hg than Se. Meanwhile more typical varieties of ocean fish contain much more Se than Hg. This may explain why maternal MeHg exposure from eating ocean fish is associated with major IQ benefits in children instead of harm. Therefore, instead of being avoided, ocean fish consumption should be encouraged during pregnancy. However, the safety of freshwater fish consumption is less certain. In freshwater fish, MeHg bioaccumulation and toxicity are both inversely related to Se bioavailability. Their Se can be far lower than their MeHg contents, potentially making them more dangerous than pilot whale meats. Therefore, to provide accurate and appropriate regulatory advice regarding maternal consumption of seafoods and freshwater fish, Hg:Se molar ratios need to be incorporated in food safety criteria.

Mercury toxicity and the mitigating role of selenium.

Mercury is a well-known environmental toxicant, particularly in its most common organic form, methylmercury. Consumption of fish and shellfish that contain methylmercury is a dominant source of mercury exposure in humans and piscivorous wildlife. Considerable efforts have focused on assessment of mercury and its attendant risks in the environment and food sources, including the studies reported in this issue. However, studies of mercury intoxication have frequently failed to consider the protective effects of the essential trace element, selenium. Mercury binds to selenium with extraordinarily high affinity, and high maternal exposures inhibit selenium-dependent enzyme activities in fetal brains. However, increased maternal dietary selenium intakes preserve these enzyme activities, thereby preventing the pathological effects that would otherwise arise in their absence. Recent evidence indicates that assessments of mercury exposure and tissue levels need to consider selenium intakes and tissue distributions in order to provide meaningful risk evaluations.

Cipura paludosa extract prevents methyl mercury-induced neurotoxicity in mice.

Cipura paludosa (Iridaceae), a native plant widely distributed in the north of Brazil, is used in traditional medicine as an anti-inflammatory and analgesic agent, against tuberculosis and gonorrhoea and for regulation of menstrual flow. However, scientific studies on the pharmacological properties of C. paludosa are scarce. We have examined the potential protective effects of the ethanolic extract of C. paludosa against methyl mercury (MeHg)-induced neurotoxicity in adult mice. MeHg was diluted in drinking water (40 mg/l, freely available) and the ethanolic C. paludosa extract (CE) was diluted in a 150 mM NaCl solution and administered by gavage (10 and 100 mg/kg body weight, respectively, twice a day). Because treatment lasted for 14 days and each animal weighed around 40 g, the total dosage of plant extract given to each mouse was 5.6 and 56 g, respectively. After the treatment period, MeHg exposure induced a significant deficit in the motor coordination, which was evident by a reduction (90%) in the falling latency in the rotarod apparatus. Interestingly, this phenomenon was completely recovered to control levels by CE co-administration, independent of dosages. MeHg exposure inhibited cerebellar glutathione peroxidase (mean percentage inhibition of 42%) - an important enzyme involved in the detoxification of endogenous peroxides - and this effect was prevented by co-administration of CE. Conversely, MeHg exposure increased cerebellar glutathione reductase activity (mean percentage inhibition of 70%), and this phenomenon was not affected by C. paludosa co-administration. Neither MeHg nor CE changed the cerebellar glutathione levels. This study has shown for the first time, the in vivo protective effects of CE against MeHg-induced neurotoxicity. In addition, our findings encourage studies concerning the beneficial effects of C. paludosa on neurological conditions related to excitotoxicity and oxidative stress.

A review of the studies of the cardiovascular health effects of methylmercury with consideration of their suitability for risk assessment.

In the 2000 report of the National Research Council's Committee on the Toxicological Effects of Methylmercury (MeHg), various adverse health effects potentially associated with MeHg exposure including cardiovascular effects were considered. At that time, the committee concluded that neurodevelopmental toxicity was the most sensitive endpoint but recognized emerging evidence of potential cardiovascular effects at low levels of exposure. The committee recommended that these potential effects be addressed through the uncertainty factors applied to the development of the neurodevelopmental reference dose (RfD). This approach was adopted by the US EPA in its derivation of the methylmercury RfD. Since that time, additional studies have become available. The available studies addressing the broad categories of heart disease (including myocardial infarction (MI) and ischemic heart disease), hypertension, and heart rate variability are critically reviewed here. Overall, the evidence linking realistic rates of MeHg exposure from fish consumption to cardiovascular disease suggests an association with heart disease, particularly MI. The apparent antagonistic interaction of MeHg and n-3 fatty acids contained in fish suggests a causal mechanism. As different individuals and populations characteristically consume different species of fish, the risk of cardiovascular effects may not be a simple function of MeHg exposure but its assessment may well need to take n-3 fatty acid intake into account also. The case for significant adverse effects of MeHg on blood pressure at current levels of exposure is weaker. This effect, observed in childhood, does not appear to persist into adolescence, and animal studies are difficult to interpret given the high doses employed. The decrease in heart rate variability related to fetal exposure to MeHg in the same cohort appears to persist into early adolescence and may reflect developmental neurophysiological alterations that are consistent with the developmental neuropsychological effects also observed in that cohort. However, the cardiovascular significance of this effect with regard to its direct effect on health or its ability to predict other, more direct, health effects is unclear. At present, the studies of the Finnish cohort relating MeHg exposure to acute MI and coronary heart disease appear to provide the strongest basis for a formal quantitative risk assessment of the cardiovascular effects of MeHg.

Probiotics as an adjuvant to detoxification protocols.

Autism is a developmental disease characterized by a spectrum of symptoms ranging from decreased verbal skills and social withdrawal, to repetitive behavior and violent outbursts. Genetic analysis has yielded a few potentially interesting genes, however no clear linkage has been established. For this reason, it has been suggested that the etiology of autism may involve multiple loci. This, in large part, explains why so many different theories abound. One such theory is that of mercury poisoning. Environmentally acquired mercury, either through some causal contact or through vaccination, has been postulated as the culprit. Mercury is thought to be exerting its neurological effect on the brain. The standard treatment has been to apply chelating agents in an attempt to extricate the mercury. One missing component in the treatment is the utilization of the body's own detoxification mechanisms. Arguably the largest detoxification component of the body, the endogenous enteric bacteria are an enormous reservoir, which can be constantly and safely replenished. This paper discusses the use of high-dose probiotics as an adjuvant for detoxification protocols with an emphasis on use in autistics.

Acetylcholinesterase fluctuations in central nervous system of rat during methylmercury intoxication and chelation therapy.

A daily dose of 1 mg/kg and 10 mg/kg of methylmercury chloride (MMC) was injected to separate sets of rats for 2 days, 7 days, and 15 days. Low and high doses of four MMC antagonists, namely N-acetyl-DL-homocysteine thiolactone (NAHT), glutathione (GSH), D-penicillamine (DPA), and sodium selenite (SEL) were injected intramuscularly (i.m.) to MMC-treated animals after an interval of half an hour. The animals were sacrificed on the 3rd, 8th, and 16th day, respectively. An additional group of rats was treated with MMC for 7 days; thereafter, it was kept free of toxic exposure for 7 days and sacrificed on the 15th day. The brain was dissected and separated into olfactory bulbs, cerebral hemispheres, cerebellum, and medulla oblongata. Each part of the central nervous system (CNS) was studied separately. We found a dose- and duration-related acetylcholinesterase (AChE) inhibition in all CNS areas. The use of antagonists showed different effects in different CNS areas, but no appreciable recovery of AChE activity could be obtained with the doses used.

Cytochemical demonstration of mercury deposits in trout liver and kidney following methyl mercury intoxication: differentiation of two mercury pools by selenium.

The amount and the ultrastructural distribution of mercury was studied in seven different organs of rainbow trout (Salmo gairdneri) fingerlings following exposure to methyl mercury (MeHg)-contaminated fodder for periods of 2 and 7 weeks. The amounts of mercury retained by the whole fish and the selected organs were determined by measuring the uptake of 203Hg-labeled MeHg. Spleen, liver, and kidney had the highest concentrations after both experimental periods, while the largest relative increases were found in brain, muscle, and kidney. The subcellular distribution of mercury accumulations was demonstrated cytochemically in liver and kidney using the silver enhancement method by which accumulations of mercury-sulfides and/or mercury-selenides are made visible for light and electron microscopy. When sections prepared from the liver and kidney from fish, injected with selenium 2 hr prior to being killed, were compared with those of fish not treated with selenium, two distinct pools of mercury could be demonstrated, the HgS pool, and the HgSe pool. The HgS pool, supposed to represent inorganic mercury, was found exclusively within lysosomes. The increase of this pool from 2 to 7 weeks was most pronounced in the kidney. The HgSe pool, supposed to represent methyl mercury, was shown by the presence of silver deposits at new locations as well as by an increase in the amount of deposits within lysosomes. The new locations included (1) secretory-like vesicles and the bile canaliculi of the liver, suggesting a biliary excretion of this mercury pool; (2) microvilli and endosomes of kidney tubular cells, suggesting a glomerular filtration and subsequent reabsorption; and (3) mitochondria of proximal tubule cells.

Review of the health effects of methylmercury.

The study critically reviews recent data relating to the health effects of methylmercury in man and the attendant dose-response relationships. New data obtained from animal studies, including pre-and postnatal exposure, are also examined. The consumption of fish and fish produce represents the major source of methylmercury exposure in the general population. Reported mercury concentrations in fish throughout the world are examined, particularly in the Mediterranean Sea. Here there is limited knowledge of methylmercury intake in critically exposed populations such as fishermen, employees of the fish industries and their families. The measurement of mercury in hair is now regarded as the most useful indicator of exposure but more experimental data are still required to increase the value of this index. The threshold levels of methylmercury in blood, hair and for dietary intake, as estimated by the World Health Organization, have been largely endorsed. However, new information from Japan and Canada suggests the existence of a latency period for some effects, so that the frequency or probability of their occurrence is inversely related to the duration of exposure. Incorporation of such findings would therefore lead to the designation of lower threshold values than are presently recognized. Pregnant women and the fetus have been identified as groups that are at special risk. The fetal blood mercury level is up to twice that of the mother and the sensitivity of both mother and fetus may be higher than in non-pregnant adults. This should be taken into account when assigning protective threshold concentrations.