An invertebrate model of the developmental neurotoxicity of insecticides: Effects of chlorpyrifos and dieldrin in sea urchin embryos and larvae

Chlorpyrifos targets mammalian bra-in development through a combination of effects directed at cholinergic receptors and intracellular signaling casca des that are involved in cell differentiation. We used sea urchin embryos a s an invertebrate model system to explore the cellular mechanisms underlyin g the actions of chlorpyrifos and to delineate the critical period of devel opmental vulnerability. Sea urchin embryos and larvae were exposed to chlor pyrifos at different stages of development ranging from early cell cleavage s through the prism stage. Although early cleavages were unaffected even at high chlorpyrifos concentrations, micromolar concentrations added at the m idblastula stage evoked a prominent change in cell phenotype and overall la rval structure, with appearance of pigmented cells followed by their accumu lation in an extralarval cap that was extruded from the animal pole. At hig her concentrations (20-40 muM), these abnormal cells constituted over 90% o f the total cell number. Studies with cholinergic receptor blocking agents and protein kinase C inhibitors indicated two distinct types of effects, on e mediated through stimulation of nicotinic cholinergic receptors and the o ther targeting intracellular signaling. The effects of chlorpyrifos were no t mimicked by chlorpyrifos oxon, the active metabolite that inhibits cholin esterase, nor by nonorganophosphate cholinesterase inhibitors. Dieldrin, an organochlorine that targets GABAA receptors, was similarly ineffective. Th e effects of chlorpyrifos and its underlying cholinergic and signaling-rela ted mechanisms parallel prior findings in mammalian embryonic central nervo us system. Invertebrate test systems may thus provide both a screening proc edure for potential neuroteratogenesis by organophosphate-related compounds , as well as a system with which to uncover novel mechanisms underlying dev elopmental vulnerability.