A commonly used drug for reducing toxicological effects of lead poisoning might alter immune function, a Cornell University study of pregnant rats and their offspring has found.
The drug is Meso-2, 3-dimercaptosuccinic acid (DMSA), also known as succimer. DMSA is currently the only approved oral medication in the United States for children with high levels of lead.
Reporting in the current issue of the journal Toxicology (Vol. 132, No. 1, pages 67-79), the researchers say it is not known if the so-called chelation therapy has the same side effects in humans as was observed in rats. "Our study and previous studies prove that DMSA can do what it's supposed to. It chemically binds with lead in the recipient and gets that poison out of the body," says Rodney R. Dietert, the Cornell professor of immunotoxicology who led the study.
"We knew that lead harms the immune systems of rats, humans and other animals, but no one had ever looked at DMSA's effects on the fetal immune system. This study provides the first evidence suggesting that DMSA chelation therapy could have problematic side effects for the developing immune system."
One cause for the immune system impairment, Dietert said, could be DMSA's effect on the availability of essential minerals in the pregnant rats and fetuses. A candidate mineral could be zinc, which is crucial for both development and maintenance of the immune system.
"This raises the question of whether supplementation (with zinc or other minerals) during DMSA treatment might protect against DMSA-induced immune alteration," the Cornell researchers wrote in their Toxicology report. "The identification of effective strategies to minimize DMSA-induced immunomodulation requires further study."
The Cornell study, conducted through the university's Institute for Comparative and Environmental Toxicology and College of Veterinary Medicine, examined the effects of DMSA on pregnant rats, nursing rats and their offspring through 3 months of age. Fischer 344 rats were chosen because their immune systems are well characterized and they have served as the preferred models to identify cancer-causing chemicals.
DMSA was found effective in reducing the amount of lead reaching the rat embryos (through the placenta) and in young, nursing rats (through mother's milk). The chelation therapy for rats also reversed several harmful effects of lead exposure, such as altered body weight and spleen weight in rat pups and increased levels of tumor necrosis factor (TNF) and interlukin-4
(IL-4). Elevated levels of TNF and IL-4 are generally regarded as signs of a malfunctioning immune system.
But the offspring whose mothers had received chelation treatment during pregnancy displayed other persistent impairments to their immune systems -- including suppressed delayed-type hypersensitivity and increased interlukin-2 levels -- that, as adults, could leave them susceptible to infections or tumors.
Further study, the report said, might help explain some of the immunotoxicological effects of lead. In some cases, lead exposure enhances certain immune responses, such as those associated with allergies and asthma.
"We still have a lot to learn," Dietert says. "Certainly we are not suggesting that a life-saving treatment like DMSA be abandoned. But a more complete understanding of all the factors involved should make this DMSA more beneficial for recipients of this treatment."
Funding support was provided by the National Institute of Environmental Health Science (NIEHS) and the Environmental Protection Agency (EPA). Joining Dietert in the Toxicology report were Suping Chen, a Cornell graduate student; Karen A. Golmemboski, a postdoctoral associate at the time of the study; and Forrest S. Sanders, a laboratory technician.