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Heavy metals--mercury, lead, cadmium, selenium, and arsenic-- are important teratogens and can affect the development of the brain (Gagnon-Chauvin et al 2020), and they were some of the first indicators that modern technologies were interacting deleteriously with human development. In the 1960s, there were very few warnings that embryos might be endangered by the progress of human technologies. One of the disasters that raised the public’s awareness was the outbreak of Minamata Disease in Japan. Throughout the 1950s, a chemical company had been dumping mercury into the bay, and this mercury had been converted into organic, methylmercury, by microbes. Fish ate and concentrated the methylmercury. Fish were a major part of the diet of the townspeople in the area, and pregnant women inadvertently gave their fetuses high doses of this compound. Brain and eye deficiencies could be caused both by transmission of the mercury across the placenta and by its transmission through mother’s milk. Mercury is selectively absorbed by regions of the developing cerebral cortex (Eto 2000; Kondo 2000; Eto et al. 2001), and when pregnant mice are given mercury on day 9 of gestation, nearly half of the pups are born with small brains or small eyes (O’Hara et al. 2002).
The Chisso Corporation had run a chemical plant on Minamata Bay, making numerous organic chemicals (among them acetylene, vinyl chloride, and octanol). After World War II, this factory made over 50% of Japan’s acetaldehyde, over 6,000 tons per year by 1951. A byproduct of the catalytic cycle (which uses mercuric sulfate to oxidize acetylene into acetaldehyde) is mercury, which the company dumped into the bay. Here, the mercury was converted into methylmercury by microbes and concentrated in the shellfish and fish that constituted the diet of the townspeople.
In the 1950s, it was noted that cats were having convulsions and dying, crows were falling from the sky, and fish were floating dead on the bay. Some villagers began having problems speaking and walking. Eventually, these people would have difficulties seeing, hearing, and swallowing. By October 1956, 40 such patients had been discovered, of which 14 had died with convulsions. In November, a research team from Kumamoto University concluded that these symptoms were not due to contagious microorganisms but to a heavy metal. When mercury was investigated, the amounts were shocking.
In the Chisso wastewater canal, there was over 2 Kg of mercury per ton of sludge. (It was actually profitable to mine!) In response, the Chisso Company changed where it was dumping its mercury (thereby killing the fish in the Minamata River and causing Minamata Disease to occur in new areas) and the company prevented its own investigator from releasing his findings that water from the factory could cause neurological problems in previously healthy cats. Moreover, the factory published its own research indicating that factors other than its wastes might be the cause of the disease. Moreover, the governmental authorities whose investigations also revealed extremely large amounts of mercury in the body of the Minamata victims failed to publish their findings (see Harada 1972; Ui, 1992).
One of the most important findings of Masazumi Harada and his team of physicians was that children born of unaffected mothers could be severely damaged by the methylmercury (Figure 3). It had been thought that the placenta would protect the fetus; but the placenta probably concentrates methylmercury and presents it to the fetus. This forced a shift in thinking about the ability of the fetus to be protected against environmental chemicals. It also set in motion a change in attitudes concerning the responsibility of corporations to be legally responsible for their actions and for governments to be legally responsible for policing such corporations. The litigation in Japan is still ongoing.
Unfortunately, as chemical and mining industries move across the world, Minamata Disease has also traveled, and it has affected indigenous populations in Ontario, Canada, and in Brazil's Amazon basin (Harada 1976, 1996; Gilbertson 2004). In the former Soviet Union, the unregulated "industrial production at all costs" approach left behind a legacy of soaring birth defect rates. In some regions of Kazakhstan, heavy metals are found in high concentrations in drinking water, vegetables, and the air. In such locations, nearly half the people tested have extensive chromosome damage, and in some areas, the incidence of birth defects has doubled since 1980 (Edwards 1994).
Despite this, in the United States, industrial dumping of selenium, mercury, cadmium, and lead1 and the lax enforcement of antipollution laws have created a situation where lakes throughout the country have warnings against eating fish caught therein. The International Joint Commission of the United States and Canada (2000) warns that “eating Great Lakes sport fish may lead to birth anomalies and serious health problems for children and women of childbearing age.” In Idaho, recent photographs of two-headed trout caused public recognition that selenium levels in lakes in the southern part of the state were much higher than government regulations supposedly permit (Kaufman 2012; USDI 2012). The selenium appears to be coming from mining tailings that flow down streams from the mines to the lakes. The cleanup of the lakes a river basins in mining states such as Idaho remain major projects.
The mechanisms by which heavy metals cause brain damage is still under investigation, and there may be many routes by which these metals cause anomalies in brain development. The glutamate-sensitive NMDA receptor is important for maturing synaptic connections between developing neurons (Hou and Zhang 2017), and methylmercury, lead, cadmium, and arsenic each bind to it (Karri et al 2016). In rats, methylmercury exposure suppresses the plasticity of synapses in the hippocampus (Wang et al 2022). It has also been shown (Sen et al 2015) that high levels of lead in maternal blood correlate with altered DNA methylation patterns in the germ cells of the fetuses. This would be the first demonstration that environmental exposure to heavy metals in pregnant mothers could epigenetic effect on the DNA of her grandchildren. The methylation abnormalities appeared to normalize during the post-natal development. It is not yet known whether these differences cause neuronal anomalies, though, and the mechanisms by which heavy metals affect brin development have yet to be delineated.
References
Edwards, M. 1994. Pollution in the former Soviet Union: Lethal legacy. Natl. Geog. 186(2): 70–115.
Eto, K. 2000. Minamata disease. Neuropathology 20 (Suppl.): S14–S19.
Eto, K. and 7 others. 2001. Methylmercury poisoning in common marmosets: A study of selective vulnerability within the cerebral cortex. Toxicol. Pathol. 29: 565–573.
Gagnon-Chauvin, A., Bastien, K., Saint-Amour, D., 2020. Environmental toxic agents: the impact of heavy metals and organochlorides on brain development. Handb. Clin. Neurol., pp. 423–442
Gilbertson, M. 2004.Male cerebral palsy hospitalization as a potential indicator of neurological effects of methylmercury in Great Lakes communities. Environ.Res. 95: 375 – 384.
Harada, M. 1972. Minamata Disease. Kumamoto Nichinichi Shinbun Centre & Information Center/Iwanami Shoten Publishers.
Harada M. 1996. Characteristics of industrial poisoning and environmental contamination in developing countries, Environ. Sci.4 Suppl: 157-169.
Harada, M., Fujino, T., Akagi, T. and Nishigaki, S.1976. Epidemiological and clinical study and historical background of mercury pollution on Indian Reservations in Northwestern Ontario,Canada, Bulletin of the Institute of Constitutional Medicine 26: 169-184
Hou G, Zhang ZW. NMDA Receptors Regulate the Development of Neuronal Intrinsic Excitability through Cell-Autonomous Mechanisms. Front Cell Neurosci. 2017 Nov 7;11:353. doi: 10.3389/fncel.2017.00353
International Joint Commission of the United States and Canada. 2000. Tenth Biennial Report of Great Lakes Water Quality. IJC, Ottawa.
Karri V, Schuhmacher M, Kumar V. Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: A general review of metal mixture mechanism in brain. Environ Toxicol Pharmacol. 2016 Dec;48:203-213. doi: 10.1016/j.etap.2016.09.016
Kaufman, L. 2012. Mutated trout raise new concerns around mine sites. New York Times Feb. 23, 2012.
Kondo, K. 2000. Congenital Minamata disease: Warnings from Japan’s experience. J. Child Neurol. 15: 458–464.
O’Hara, M. F., J. H. Charelap, R. C. Craig and T. B. Knudsen. 2002. Mitochondrial transduction of ocular teratogenesis during methylmercury exposure. Teratology 65: 131–144.
Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X, Dereski MO, Ruden DM. Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. Sci Rep. 2015 Sep 29;5:14466. doi: 10.1038/srep14466
Ui, J. 1992. Industrial Pollution in Japan. United Nations University Press. http://www.unu.edu/unupress/unupbooks/uu35ie/uu35ie00.htm#Contents
Wang W, Zhang L, Deng C, Chen F, Yu Q, Hu Y, Lu Q, Li P, Zhang A. In utero exposure to methylmercury impairs cognitive function in adult offspring: Insights from proteomic modulation. Ecotoxicol Environ Saf. 2022 Feb;231:113191. doi: 10.1016/j.ecoenv.2022.113191
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1Lead, another heavy metal, damages the developing brain in prenatal and childhood stages (Bellinger et al. 1987; Baghurst et al. 1992; Dietrich et al. 1993) and contributes to developmental delays and mental disabilities. Lead paint was banned in Europe in 1955, but lobbying efforts by the paint industry in the United States succeeded in keeping lead in American paints until 1977 (see Steingraber 2003). The usage of selenium as a teratogen is used as the basis for a Dick Francis mystery novel.