9 minute read
Fish, Mercury, and the Developing Brain
DECADES OF INSIGHTS FROM THE SEYCHELLES CHILD DEVELOPMENT STUDY
By Mark Michaud
There is a growing understanding of the role of chronic low-level exposure to environmental toxicants in human diseases. Mercury, a known neurotoxicant at a high level of exposure, is among the top chemicals identified by the World Health Organization as a “major public health concern.” The presence of mercury in fish has led the U.S. Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) to recommend that mothers limit fish consumption during pregnancy.
However, more than three decades of research in Seychelles, whose residents eat ten times more fish than in the U.S., has found no evidence of neurodevelopmental harm linked to mercury exposure via fish. In fact, the study suggests that the omega-3 fatty acids and other micro-nutrients found in fish, which are critical for brain development, may counteract any potential adverse effects of mercury.
“The associations between low level mercury exposure, nutrients, fish consumption, and child neurodevelopmental outcomes are complex. Tackling these questions, which have global health and economic implications, has required an international team,” said University of Rochester Medical Center (URMC) epidemiologist Edwin van Wijngaarden, PhD, the principal investigator of the Seychelles Child Development Study.
Origins in the Middle East
The story of the Seychelles study begins in Iraq. In the early 1970s, the country imported grain treated with a methylmercury-based fungicide used to prevent spoilage during storage and transport. While intended solely for planting, a combination of a severe famine and misunderstood labeling led to it being consumed, poisoning thousands. The symptoms, like ataxia, sensory impairment, tremors, and seizures, pointed to the neurotoxic effects of the chemical. Prenatal exposure caused devastating effects on unborn children, leading to outcomes such as cerebral palsy.
The Iraqi government reached out to Tom Clarkson, PhD, an expert in the toxicology of mercury at URMC, to help assess the extent of contamination and develop strategies to mitigate its impact. Clarkson was already studying mercury’s basic properties and effects, making him one of a handful of global authorities in the field. Alongside URMC neurologist David Marsh, MD, and others, Clarkson would visit Iraq twice a year for the next decade, collecting data and conducting evaluations. The team analyzed mercury levels in hair and blood samples, identified families affected by prenatal exposure, and studied the neurological impacts on infants and children born to exposed mothers.
Their findings provided further evidence that mercury exposure disproportionately affects the developing fetus, with mothers often asymptomatic while their children exhibit severe neurological impairments. The data also highlighted the need to differentiate between mercury exposure from acute poisoning events—like Iraq and an earlier episode in Minamata, Japan—and chronic, low-level exposure from dietary sources like fish. And while fish is an important source of protein for much of the world, this was not the case in Iraq.
The perfect partnership
Joined by URMC pediatrician Phil Davidson, PhD, and neurologist Gary Myers, MD, the team began searching for a location for a new large-scale study that would help researchers better understand the risk-benefit balance of fish consumption during pregnancy. Mercury is deposited in the oceans through pollution or natural events such as volcanoes, forest fires, and erosion. Bacteria transform it into methylmercury, which eventually works its way up the food chain to fish. The consumption of fish is the primary way humans are exposed to mercury. At the same time, fish are a rich source of nutrients essential to early brain development, including polyunsaturated fatty acids, selenium, iodine, and vitamin D.
The team scouted locations in South America and considered the Maldives.
By 1986, they settled on the Republic of Seychelles, an archipelago of 115 islands in the Indian Ocean, off East Africa. “The reason for going to Seychelles is because fish is consumed daily. We figured that if you’re going to find adverse effects from eating fish, it ought to appear in this population, compared to the U.S., where fish is consumed a couple of times a month,” said Myers, who served as study liaison with Seychelles from 1986 to 2019, and is now an emeritus professor of Neurology at URMC and still involved in the study.
A population with access to free universal care, national healthcare and education databases, limited industrial sources of pollution, and easy international access all made Seychelles an ideal location for researchers to recruit and follow study participants over the length of the study. This was a long time, as it would turn out. Some volunteers have been enrolled for more than three decades and counting.
Most importantly, the study had a champion in Conrad Shamlaye, MD, an epidemiologist who worked closely with the Seychelles Minister of Health. From the start, the Seychelles government was a full partner and would be involved throughout the research process, from the study design through its implementation to the dissemination of study findings.
“The partnership meant that the study would have access to the expertise and experience of Seychelles professionals, and the results would benefit the population,” said Shamlaye. Health and Education Ministries members helped craft the study instruments and translate protocols and instruments into local language and context. The collection of additional data important to the government was integrated into the study design.
Building one of the largest longitudinal studies
The URMC team arrived in Seychelles in 1986 and started recruiting a pilot cohort, which would ultimately consist of 759 children. Data from this cohort was the basis for a National Institutes of Health award in 1990, a grant that has since been continuously funded. Data from the pilot cohort suggested that, while there might be evidence of mercury risk, other fish nutrients may be covering up the adverse effects.
In 2000, a second group of volunteers was recruited, called the first nutrition cohort, to be followed by a larger second nutritional cohort in 2008. The researchers collected hair, blood, urine samples, and cord blood from infants, and child development was assessed regularly and over several years. In total, the Seychelles study includes 3,000 mothers and children across multiple cohorts, creating a large and unique set of longitudinal data. The oldest cohort is still being tracked after more than three decades, providing researchers with insights across the lifespan.
As the study expanded, so did the need for additional research expertise in nutrition, genetics, cardiovascular, and mental health outcomes. Teams from Ulster University, led by JJ Strain, PhD, and Karin Broberg, PhD, with the Karolinska Institute at Lund University in Sweden, and Pascal Bovet, MD, MPH, from the University of Lausanne in Switzerland, joined the study, along with the growing ranks of researchers at the University of Rochester, including biostatistician Sally Thurston, PhD, dental researcher Gene Watson II, DDS, MS, PhD, cardiologist Wojciech Zareba, MD, PhD, and audiologist Mark Orlando, PhD, MBA, among others.
Genetic and basic science insights
Matt Rand, PhD, at the time with the University of Vermont, became involved in the Seychelles study after being invited to participate in a National Institute of Environmental Health Sciences grant application in 2012. This collaboration would expand the project’s scope. Rand, who moved to the URMC Department of Environmental Medicine later that year, and his colleagues are studying the mechanisms of mercury toxicity and its effects on development, leveraging model organisms like Drosophila.
The Seychelles study has upended assumptions about mercury’s toxicity and pointed to evidence of either protective genetic factors, dietary components, or both. Researchers in the Rand Lab have been trying to untangle these questions. Their work has identified rare genetic variations that may increase mercury toxicity risk. More recent findings indicate the gut microbiome plays a role in mercury elimination, suggesting a potential target for interventions to mitigate mercury exposure risks.
“Our findings underscore the importance of considering genetic variability when assessing the risks associated with methylmercury exposure from fish consumption,’ said Rand. “They also highlight the need for personalized approaches in public health advisories, as genetic predispositions can influence individual susceptibility to environmental toxins by several-fold.”
Challenging conventional wisdom
Decades of research in Seychelles have shown no evidence of neurodevelopmental harm from prenatal mercury exposure from fish consumption. Yet, the FDA and EPA’s guidelines continue to advise expecting mothers to limit fish intake based on mercury neurotoxicity.
“Seychelles has never issued any advisories restricting fish consumption because of toxicological concerns. The overall study findings support the continuing consumption of a large variety of ocean fish, which is not only a traditional way of life but also has health benefits,” said Shamlaye.
Myers agrees and believes fish consumption advisories can be “overly cautious and counterproductive” and have been shown to discourage fish consumption despite its nutritional benefits, especially to the developing brain. In his opinion, the scientific evidence from the Seychelles study does not support their need, especially at the mercury exposure levels encountered through typical fish consumption. “Given that billions of people across the globe depend on fish for daily nutrition and malnutrition is a global problem, the wisdom of advisories is questionable.”
Lasting impact and future directions
Shamlaye points to how the study exposed the country’s health and education professionals to colleagues in the US and Europe. The project also permitted Seychelles to contribute to international forums, including the World Health Organization and the United Nations. “Health programs for children have benefitted from additional input from the study, for example, in defining standard growth charts for Seychellois children and screening tests for child development. Study findings have also supported health, social, and education programs in Seychelles.”
The work in the Seychelles continues, and researchers plan to expand beyond mercury to explore other environmental exposures, such as endocrine disruptors, PFAs, and PFOAs. Researchers also plan to examine the role of dietary factors and exposures in aging, neurodevelopment, and epigenetics. During the course of the study, Seychelles faced rapid social and economic development, leading to changing consumption patterns towards more meat and less fish, increased calorie intake, and less physical activity. This new research will further our understanding of lifespan health outcomes linked to fish consumption and other environmental factors.
