PM10 Mechanisms of Toxic Action
Exhibit Hall
8:00 AM - Monday
(PM153) The developmental toxicity of dithiocarbamates and isothiocyanates in zebrafish.
Tilton, Fred1, 2, Tanguay, Robert1, 2, 1 Oregon State University, Corvallis, OR, USA2 Marine & Freshwater Biomedical Sciences Center, Corvallis, OR, USA
ABSTRACT- We previously determined that the dithiocarbamate pesticide, sodium metam (NaM), and its active ingredient, methylisothiocyanate (MITC) cause notochord malformations in developing zebrafish exposed from 4 to 24 hours post fertilization (hpf). We have also established that the most sensitive developmental window to NaM is between 4 to 14 hpf which is 10 hours before the visual manifestation of the malformed notochord. In this study, a group of isothiocyanates and dithiocarbamates were investigated to determine the structural and teratogenic relationships in the developing zebrafish. Three isothiocyanates (ITC) and eleven dithiocarbamates (DTC) ranging from natural and synthetic pesticides, cancer chemoprevention agents, pharmaceuticals, and environmental degradation products were exposed to the developing embryo from 4 to 24 hpf. Among other observations, notochord morphology, hatching success, and survival were monitored at 24, 48, and 120 hours. All of the dithiocarbamates tested elicited notochord malformations similar to those previously observed with NaM and MITC with EC50s ranging from 4.0 to 400 ppb and NOELs from <4.0 to 40 ppb. The LC50s ranged from 40 ppb to 4 ppm. Of the ITCs tested, only MITC exposures led to notochord malformations. The potential mechanistic involvement of cellular oxidative stress underlying the effects of DTCs and MITC was also investigated. Reduced glutathione (GSH) suppressed DTC induced notochord malformation with toxicant co-exposures; however, hatching was still impaired. When embryos were exposed to DTC between 4 and 14 hpf followed by GSH exposure alone, notochord morphology and hatching success were completely normal. Surprisingly, GSH exposures failed to diminish MITC-mediated malformations. The explanations for the differential MITC and DTC responses and the contributions of DTC metabolism or aqueous degradation products is under investigation. In conclusion, the mechanism of developmental notochord malformation from DTC exposure appears to require in vivo glutathione depletion prior to DTC-target interaction. Supported by NIEHS #ES00210, and #ES03850.
Key words: dithiocarbamates, zebrafish, development, notochord