Methylmercury Toxicology Probed

Humans are exposed to more mercury from eating fish, marine mammals, and crustaceans than from any other source, according to the Food & Drug Administration and the Environmental Protection Agency. Last month, they issued a joint draft advisory about fish consumption to women who are or might become pregnant, and they plan to issue a final advisory in the coming months. According to the December advisory, nearly all fish contain at least traces of methylmercury, although the amount of mercury can vary considerably.

Methylmercury, a biologically active form of mercury, is derived from inorganic mercury. Elemental mercury vapor that occurs naturally in the environment and is released by industrial plants is oxidized to Hg²⁺ in the atmosphere and returned to Earth's surface in rainwater. Inorganic mercury from both natural and human sources is laid down in sediments in the ocean and in bodies of freshwater. Inorganic mercury is converted to methylmercury by aquatic bacteria. Plankton take it up, fish eat the plankton, bigger fish eat the smaller fish, and methylmercury bioaccumulates up the food chain. According to Joy C. Andrews, a professor of chemistry at California State University, Hayward, the accumulation can result in "mercury levels 1 million times higher in fish than in the surrounding waters."

Why methylmercury accumulates so readily in living systems partly has to do with its binding properties. "There is no methylmercury--unbound--once it gets into an organism," says Rudolfs K. Zalups, professor of medicine at Mercer University School of Medicine, Atlanta. In particular, methylmercury commonly binds to thiol groups. Methylmercury is a cation and forms "partly covalent/partly ionic bonds that are strong but reversible," says Thomas W. Clarkson, professor of environmental medicine at the University of Rochester. Clarkson emphasizes that methylmercury is not lipid-soluble like polychlorinated biphenyls (PCBs) and other organochlorine contaminants. Clarkson writes in a review that "methylmercury is present in the body as water-soluble complexes mainly, if not exclusively, attached to the sulfur atom of thiol ligands" [Environ. Health Perspect.,110, 11 (2002)]. And that often means it follows protein pathways, as opposed to lipid pathways, in the body. Last November, researchers reported an X-ray absorption study in fish that revealed methylmercury predominantly binds to cysteine thiols [Science, 301, 1203 (2003)].

Yet because of its reversible binding, methylmercury may not stay long with any one thiol, Clarkson says. It moves easily throughout a system. Once inside the human body, roughly 95% of fish-derived methylmercury is absorbed from the gastrointestinal tract and distributed widely. About 1 to 10% can be found in the blood, mostly bound to hemoglobin in red blood cells. Methylmercury enters the kidney and the liver and avidly accumulates in growing hair. Hair is often used as a biological marker for mercury exposure.

Methylmercury also crosses the blood-brain barrier. Actually, it is carried across in an intriguing example of molecular mimicry. Methylmercury easily complexes with free L-cysteine. A certain amino acid carrier, mistaking the complex for L-methionine, carries the mercury into the tightly packed endothelial cells that make up the blood-brain barrier. Inside the endothelial cells, glutathione--a tripeptide made of cysteine, glutamic acid, and glycine--picks up methylmercury. (Glutathione is found in higher concentration inside the cell than free cysteine.) "Glutathione can be pumped out of the cell on a glutathione carrier," Clarkson says. "So this is a two-step transport system for the blood-brain barrier. [Mercury] goes into the cell on the blood side as methylmercury-cysteine, and it comes out into the extracellular fluid of the brain as methylmercury-glutathione."

Methylmercury easily crosses the placental barrier as well, and the same two-step transport likely occurs there. In fact, any cell that takes up l-methionine from the extracellular matrix has a chance of welcoming in methylmercury-cysteine instead.

It is in the brain and central nervous system where methylmercury wreaks its greatest harm. Methylmercury's presence leads to loss of nerve cells, especially in pockets of the cerebrum and cerebellum. The symptoms of mercury in adults, Clarkson says, include numbness; difficulty in speaking; and loss of coordination, sight, or hearing.

Yet how it damages nerve cells is still largely unknown. Some evidence suggests that methylmercury may inhibit protein synthesis in the brain, Clarkson says. It is known that, in the brain, methylmercury demethylates slowly to inorganic mercury. Inorganic mercury builds up because it does not cross back through the blood-brain barrier. Whether inorganic mercury in the brain contributes to mercury toxicity is an open question.

In addition, before the symptoms of toxicity set in, almost every victim of mercury poisoning goes through a symptomless latent period that can last from weeks to months. Scientists can't explain it, and Clarkson calls it one of the greatest mysteries of mercury toxicity.

One well-documented case of mercury poisoning involved a chemistry professor, Karen E. Wetterhahn, at Dartmouth College. She spilled a few drops of highly toxic dimethylmercury on her gloved hand in August, and her highest exposure level, according to testing of hair samples, was in August. Yet not until December did the symptoms of mercury toxicity appear. This latent time span is unpredictable and does not seem to be dependent on dose, Clarkson says. "It is as if it triggers something--some process that takes its own time," he adds.

The extent to which methylmercury leaves the body plays a role in its toxicity. Methylmercury's exit from the body takes advantage of natural transport mechanisms. Only a small proportion of methylmercury leaves the body in urine because the kidney reabsorbs it. Yet methylmercury that gets into liver cells is pumped out into the bile as methylmercury-glutathione, according to studies conducted by Ned Ballatori at the University of Rochester. As it passes down the biliary tract, some of it converts back to methylmercury-cysteine and is reabsorbed. But some is also converted by the natural microflora in the gut to inorganic mercury, which is excreted, according to Ian Rowland, a professor at the University of Ulster, in Northern Ireland. Each day, an adult body releases about 1% of its total methylmercury burden.

METHYLMERCURY'S continual release from the body means that a consistent, low dose of methylmercury, as long as it is under a certain threshold, does not build up to a toxic dose.

For babies, the story is different. Studies in suckling rats and monkeys indicate that nursing infants may not be able to get rid of methylmercury in the same way because their microflora are not yet able to break down methylmercury. Indeed, whether infants even have a mechanism for removing methylmercury from the body is a major research question.

In addition, the infant brain sustains a different, more extensive type of damage from mercury poisoning. In 1971­72, scientists had the opportunity to observe many of the effects of mercury poisoning in both infants and adults when as many as 40,000 individuals in Iraq ate bread made from wheat treated with methylmercury as a fungicide. In children's brains, two major changes were observed: The cells appeared to stop dividing and migrating. Both of these changes caused widespread damage in the infant brains--unlike the pockets of damage observed in adult brains.

Both cell division and cell migration depend on the microtubular system, Clarkson says. And methylmercury either destroys microtubules or blocks their assembly. "People argue that's why the developing brain is so sensitive to methylmercury," Clarkson says. Researchers don't yet know how methylmercury exerts these effects, but they expect that the sulfhydryl group on tubulin proteins may play a role.

Especially in a developing body, methylmercury is an insidious toxicant. It masquerades so well as a useful biological molecule that the body accepts it and allows it to go where other foreign molecules are not allowed. Its very familiarity leads to its toxicity.