Student Research: Anne Caughlan

, , 2001
Faculty Advisor: Zhengui Xia

Apoptosis: A Novel Endpoint for Chlorpyrifos-Induced Neurotoxicity


Pesticides are ubiquitous in our environment and exposure is common. However, fetuses, infants and children may be at an increased risk of toxicity. For example, widespread mercury poisoning in Iraq in the 1970's caused nervous system effects in children born to women exposed during pregnancy. However, many of the women showed no over toxicity. To date, there is little data regarding adverse effects of pesticide exposure in utero. However, given the widespread use of pesticides and the fact that most neurodevelopmental deficits arise from unknown causes, it is important to investigate how pesticides might contribute. We are researching mechanisms by which pesticides might interfere with neurodevelopment. A representative pesticide being studied is chlorpyrifos.

Chlorpyrifos is an organophosphate (OP) insecticide in worldwide use. Although its effects on acetylcholinesterase inhibition are well characterized in the adult, there is evidence suggesting the chlorpyrifos may have other effects, particularly during development. For example, immature animals are more sensitive to chlorpyrifos than adults though they recover acetylcholinesterase activity more quickly. The effects of chlorpyrifos on neuronal apoptosis have not been characterized.

Apoptosis is a complex process that is critical to maintaining tissue homeostatis in the adult and to proper development of the CNS. Perturbations in the normal process have been associated with diseases, such as Parkinson's Disease, cancer and HIV. The mitogen activated protein (MAP) kinases are among the most thoroughly studied regulators of apoptosis.

Using an in vitro primary neuron culture system to model two stages of neuronal development, we have shown that chlorpyrifos and its active metabolite, chlorpyrifosoxon, induce apoptosis in postnatal and embryonic rat cortical neurons. Furthermore, we have shown that chlorpyrifos activates several of the MAP kinases known to be involved in the regulation of apoptosis. In addition, we have found that chlorpyrifos, chlorpyrifos-oxon and TCP may impair mitochondrial function. These data suggest that chlorpyrifos may induce neuronal apoptosis and that this cell death may be mediated by these MAP kinases in vivo. In addition, mitochondrial function may be another biomarker of effect. These data provide insight into the possible mechanisms by which chlorpyrifos exposure in utero might adversely affect neurodevelopment.