Chemical forms of metal associated with neurodegenerative diseases influence toxic effects

A study conducted at a Brazilian institution evaluates the level of neurological toxicity of metals associated with Alzheimer’s disease and Parkinson’s disease.

By Elton Alisson

Agência FAPESP – Chronic exposure to metals such as manganese and aluminum could contribute to the development of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, according to several studies conducted in different countries, including Brazil.

Now, a new study conducted at the Bio-Inorganic and Environmental Toxicology Laboratory (Labita) within the Institute of Environmental, Chemical and Pharmaceutical Sciences (ICAQF) at Universidade Federal de São Paulo (Unifesp) indicates that the chemical form of these metals could directly and differently influence their level of neurotoxicity on animals and humans.

Developed in collaboration with researchers at Universidade de São Paulo (USP), Spain’s Biomedical Research Institute and Germany’s Helmholtz Centre for Environmental Research (UFZ) in Leipzig, the study was conducted under the auspices of a FAPESP-funded research project.

Some of the aluminum-related results – which are part of the master’s study of Pollyana Ferreira de Carvalho – were presented during the 2nd Ibero-American Toxicology and Environmental Health Meeting held in Ribeirão Preto, São Paulo. The study won an award from English publisher Taylor & Francis, which releases books on toxicology.

“We found that the chemical speciation of manganese and aluminum can directly influence the neurotoxic effects caused by these metals in animals and humans,” said Raúl Bonne Hernández, professor at ICAQF and coordinator of the project.

According to the researcher, the studies indicated that chronic exposure to manganese and aluminum promotes changes in the energetic metabolism of animals and humans, contributing to a reduction in cognitive and motor functions.

Through studies with zebrafish (Danio rerio) – a fish whose genome is 70% similar to the human genome – researchers confirmed this hypothesis and observed that manganese and aluminum promoted different neurotoxic effects in animals according to the connection with other chemical elements.

With regard to aluminum, the scientists found that the metal in an aqua-hydroxy complex (connected to water molecules or hydroxyls) and in polymers seemed more toxic to the zebrafish than soluble metal that was linked to citrate and tartrate salts, for example, those used in food preservatives.

After exposing zebrafish to the metal between 2 and 122 hours after fertilization, the larvae presented a reduction in heartbeat and changes in spontaneous or stimulated body movements.

“These results collectively indicate a partial confirmation of our hypothesis that the chemical form of aluminum and manganese influences the neurotoxicity level in animals and humans,” said Hernández.

According to Hernández, for a long time, it was thought that aluminum was an innocuous element. For this reason, over the last few years, many foods and beverages have been packaged in aluminum metal containers.

What was determined more recently, however, is that the ingredients used to preserve food and beverages in this type of packaging – such as citrates and tartrates – are capable of solubilizing small fractions of aluminum.

“These small fractions of metal solubilized by citrates and tartrates can influence events related to aluminum exposure through food, although they are considered non-acute events,” he affirmed.

Manganese

By exposing zebrafish in different stages of development to several mixtures of manganese with other chemical elements, the researchers found that manganese causes more toxic effects and induced more neurocognitive and locomotive alterations in animals in the presence of citrate than in its pure form.

“These result contradict predictive models of metal toxicity, which suggested that non-complex species are more toxic,” commented Hernández.

“On the other hand, they corroborate other international studies with primary cultures of mice cerebellar neurons published by different research groups – including ours – which suggest that the physiological molecule, such as citrate, could further facilitate metal transportation and passage through hematoencephalic barriers of the other chemical connections, such as pyrophosphate, causing neurotoxicological effects in glutamatergic neurons [which use glutamate as a neurotransmitter],” commented Hernández.

Some of the main alterations promoted by manganese linked to citrate in the animal’s cerebellum could be associated with dysfunction in several protein synthesis pathways, such as the amyloid beta – which accumulate and form plaque in regions of the brain responsible for memory and language in patients with Alzheimer’s disease – and other metabolites that change in patients with Parkinson’s disease.

Through gene expression studies, the researcher observed that the mt-co1 mitochondrial genes (related to processes such as oxy reduction, metal transport, and exposure response to chemical elements) and hspb11 (linked to stress response) of zebrafish exposed to manganese in the presence of citrate were deregulated.

Because these genes are also present in the human genome, the researchers estimate that similar molecular pathways in humans could be affected by exposure to manganese.

“The results found in zebrafish can help us to better understand the development of neurodegenerative disease and improve both the studies that are being developed in humans and animals, reducing the time and quantity of mice used in research,” commented the researcher.

“Since the zebrafish genome has an almost 60% similarity with that of mice, it can replace mice as an animal model,” he affirmed.

Cases of exposure

Because manganese is an essential element for human beings, especially during development, it was thought that exposure limits to this metal could be a little bit higher than those established today. As a result, acute and chronic exposure to the metal in air in the form of particle matter was largely the focus, rather than ingestion of food or water.

Workers in the steel and mining sectors were considered to be among the human groups vulnerable to manganese exposure because they work in areas that are more likely to have direct contact with contaminated air.

In the last few years, the World Health Organization has called attention to the fact that there are several places on the planet, including developed and developing countries – where they have observed a reduction in the cognitive capacity of children exposed to large concentrations of manganese in the water and air, mainly in mining areas, stressed the researcher.

“Today we are observing cases of manganese exposure in regions of very low economic development such as Bangladesh and in more developed regions such as China and Canada, where there are reports of populations that consume water with manganese levels within the limits permitted by the country’s environmental laws but that have problems with reduced cognitive and motor function,” he added.

In Brazil, according to Hernández, epidemiological studies conducted between 2000 and 2011 also identified cases of children and pregnant women in the mining town of Simões Filho (Bahia State) with neurobehavioral changes after chronic exposure to manganese particulate matter in concentrations considered safe by organizations such as the U.S. Environmental Protection Agency and its counterpart in the European Union.

One of the factors that contributed to this problem, according to the researcher, is that safe metal exposure levels were estimated based on epidemiological data on adult exposure at work – such as steel and mining sector workers – and were extrapolated to children.

“This indicates the need for more studies in animal models during their development and the integration of the results of these studies with epidemiological evaluations,” said Hernández.

Because acute and chronic exposure to these metals and varied pollutants begins in the first years of life, largely in urban centers because they concentrate greater industrial activity, the researchers also intend to conduct studies with zebrafish to evaluate whether environmental exposure to manganese and aluminum could produce some characteristics of neurodegenerative diseases that are only clinically identified in humans many years later as adults.

“We want to study what happens in animals exposed to aluminum and manganese in different stages of their development and if prolonged exposure to these metals in lower concentrations can cause the same neurological effects provoked by acute exposure,” he added.