Pre-Term Labor Drug Sensitizes Brain to Pesticide Injury
DURHAM, N.C. -- A drug commonly prescribed to halt pre-term labor and stave off premature birth might leave the brains of children susceptible to other chemicals ubiquitously present in the environment, according to research conducted on laboratory animals by Duke University Medical Center pharmacologists. Their new study found that rats exposed to the pre-term labor drug terbutaline suffer greater brain cell damage than those not given the drug upon secondary exposure to the insecticide chlorpyrifos.
The double exposure caused damage to brain regions known to play a role in learning and memory, the team reported in the March 2004 issue of Toxicology and Applied Pharmacology. The result might therefore help to explain earlier suggestions that children whose mothers are administered terbutaline suffer cognitive deficits. The National Institutes of Health supported the research.
Premature labor occurs in approximately 20 percent of all pregnancies in the United States. Of those, an estimated 1 million women annually are treated with terbutaline or related drugs to halt the early contractions. The drugs administered to pregnant women also penetrate to the fetus where they affect brain development.
The work highlights the synergistic and unpredictable effects that exposure to multiple chemicals can have on the brain, said senior author of the study Theodore Slotkin, Ph.D., professor of pharmacology and cancer biology at Duke. Moreover, just as some gene variants confer heightened disease risk, the study suggests that certain early drug or chemical exposures can predispose people to particular ailments, he added.
"The adverse effects of sequential exposure to the two compounds on certain brain characteristics were more than the sum of the two agents' independent effects," Slotkin said. "Our findings suggest that exposure to drugs like terbutaline early in development can leave individuals set on a hair trigger for further problems when subsequently faced with environmental chemicals."
Sensitive subgroups should be taken into consideration when determining safe levels of the chemicals in the household and the environment, Slotkin said.
Chlorpyrifos was one of the most commonly used insecticides in the United States for both agriculture and household uses prior to the year 2000 when the EPA began restricting the chemical from home use in stages. However, chlorpyrifos is still widely used for agricultural purposes and residues of the insecticide can occur on produce.
The highest exposures to environmental contaminants, including chlorpyrifos, occur in young children due to the fact that they crawl across the ground and other surfaces and put objects in their mouths, Slotkin said. Children also consume a greater volume of food and water -- often containing pesticides -- relative to their body weight compared to adults. Studies of chlorpyrifos levels in school-age children have found that virtually everyone is exposed, he said.
The researchers administered terbutaline alone, chlorpyrifos alone or terbutaline followed by chlorpyrifos to three groups of young rats. Rats received terbutaline at 2 to 4 days old, a time equivalent to the early third trimester of human development. Chlorpyrifos was administered at day 11 to 14. A fourth untreated group served as a control.
Both chemicals independently caused brain injuries not seen in the control rats, including the loss of brain cells and the nerve cell projections critical to communication among neurons. The effects persisted into adulthood.
The combined chemical treatment further aggravated the chemicals' damaging effects on the brain, the team reported. The brains of rats exposed to both chemicals also showed reduced nerve cell activity that the researchers did not observe in rats exposed to either chemical alone.
Furthermore, portions of the brain central to learning and memory, including the hippocampus, suffered significant loss of brain cells and nerve cell projections in rats exposed to both chemicals. Rats administered either chemical alone showed much smaller effects on these regions, the researchers said.
"It is increasingly clear that environmental toxicants target specific human subpopulations," said Slotkin. "This study suggests that early drug or chemical exposures might underlie some of these differences in susceptibility. We need to start looking for such vulnerable groups and considering them when making decisions about legislation. It is not adequate to set the allowable concentrations for certain chemicals at levels that might be unsafe for large segments of the population."
Coauthors on the study included Melissa Rhodes, Ph.D., Frederic Seidler, Ph.D., Dan Qiao, Ph.D., Charlotte Tate and Mandy Cousins, all of Duke.