Inhibition of Toxoplasma gondii replication by dinitroaniline herbicides. Exp. Parasitol

herbicides have been found to specifically inhibit intracellular replication of the protozoan parasite Toxoplasma gondii. IC50 concentrations for T. gondii survival were ∼100 nM for ethalfluralin and oryzalin and ∼300 nM for trifluralin. Primary human fibroblasts employed as host cells for parasite culture were unaffected at>100-fold higher concentrations. Extracellular parasites were unaffected by these drugs, but within 8 hr after treatment of infected cell cultures, intracellular tachyzoites formed large amorphous bodies containing distorted nuclei. Parasite cytokinesis was completely blocked by drug treatment; nucleic acid synthesis, however, continued at near-normal levels for several days in the continuous presence of drug. All dinitroanilines appear to block nuclear division by inhibition of intranuclear spindle formation, but other cytoskeletal components were differentially affected by the various drugs tested. Subpellicular microtubules were absent in oryzalin-treated parasites, and large fragments of the inner membrane complex were observed throughout the parasite cytoplasm. In contrast, subpellicular microtubules and the inner membrane complex remained intact in ethalfluralin-treated parasites, but the endoplasmic reticulum and nuclear envelope were highly distended. Cytoskeletal elements associated with the conoid were not affected by any of the dini-troanilines tested, and treatment with the Ca2+ ionophore A23187 failed to trigger release of drug