A new mechanism for chlorpyrifos? Implicating serotonin.

Organophosphate pesticides kill insects by allowing the neurotransmitter acetylcholine to build up at nerve endings. This short-circuits the cholinergic system, which governs involuntary processes. Low organophosphate doses given to rats in utero are associated with neurodevelopmental effects and impaired behavior in adult animals, and in the past, researchers assumed these adverse effects arose from disruption of the cholinergic system. But recently Justin E. Aldridge and colleagues at Duke University Medical Center found that one organophosphate, chlorpyrifos, appears to affect brain development through other, additional mechanisms, and at doses lower than those that perturb the cholinergic system. Now Aldridge and colleagues report that fetal and newborn rats exposed to chlorpyrifos during particular developmental windows undergo changes in their brain serotonin systems that persist into adulthood, possibly contributing to the neurodevelopmental effects of this particular pesticide [EHP 112:148-155].

Chlorpyrifos was once one of the most widely used pesticides in the United States. Due to concerns about its neurologic effects in children, chlorpyrifos was banned from home and garden use in June 2000 under an agreement between the U.S. Environmental Protection Agency and pesticide manufacturers. But it is still used in the United States to protect commercial fruit and vegetable crops, and worldwide it remains one of the most heavily used pesticides.

Aldridge and colleagues injected pregnant rats daily with 1 or 5 milligrams of chlorpyrifos per kilogram body weight (mg/kg) for 3 days either early (when the brain is first being formed) or late in gestation. These doses bracket the threshold for maternal toxicity and fetal cholinesterase inhibition. They also injected non-previously exposed 1-week-old pups with 1 mg/kg and 2-week-old pups with 5 mg/kg over a 3-day period.

The researchers allowed the young rats and the offspring of the pregnant rats to mature, then harvested the adult aimals and measured biomarkers of serotonin system function in their dissected brains. These biomarkers included a number of serotonin receptors and transporters that the researchers had earlier found to be altered shortly after chlorpyrifos exposure (see EHP 111:1736-1743 [2003]).

Although statistically significant effects were seen at all exposure intervals and for both doses, treatments during the late gestational period and the first week after birth--a stage in the rat that parallels the second trimester of human fetal development--had the maximum effects, with increases in receptors and transporters as great as 30-80% above control values in some brain regions. The greatest of these elevations occurred in male rats in the striatum region, which is generally thought to be involved with motor control.

It appears that later in development, the treatment affects males more than females. Other studies of chlorpyrifos's neurodevelopmental effects also have found that sex differences emerged only when exposure occurred late in gestation or in the neonatal period, but those studies did not follow rats to adulthood, nor did they focus on serotonin disruption by chlorpyrifos.

The authors suggest that perturbations in cell differentiation and brain architecture may be one of the contributors to noncholinergic mechanisms of chlorpyrifos-induced neurobehavioral anomalies. Because serotonin is involved in controlling appetite and modulating depression, these results also lend support to the idea that environmental exposures may increase the risk of these problems, according to the authors. --Rebecca Renner