Evaluation of the developmental toxicity of trichloroethylene and detoxification metabolites using Xenopus

Abstract

Potential mechanisms of trichloroethylene-induced developmental toxicity were evaluated using FETAX (Frog Embryo Teratogenesis Assay--Xenopus). Early Xenopus laevis embryos were exposed to trichloroethylene for 96 h in two separate definitive concentration-response assays with and without an exogenous metabolic activation system (MAS) and inhibited MAS. The MAS was treated with either carbon monoxide or cyclohexene oxide to modulate mixed-function oxidase (MFO) or epoxide hydrolase activity, respectively. Trichloroethylene metabolites: dichloroacetic acid, trichloroacetic acid, trichloroethanol, and oxalic acid were also evaluated in two separate definitive, static renewal tests. Addition of the MAS decreased the 96 h LC50 and EC50 (malformation) of trichloroethylene 1.8-fold and 3.8-fold, respectively. Addition of the carbon monoxide inhibited MAS decreased the developmental toxicity of activated trichloroethylene to levels approximating that of the parent compound. Cyclohexene oxide-inhibited MAS substantially increased the developmental toxicity of trichloroethylene. In addition, each of the metabolites tested were significantly less developmental toxic than the parent compound, trichloroethylene. Results indicate that a highly embryotoxic epoxide intermediate, trichloroethylene oxide, formed as the results of MFO mediated metabolism may play a significant role in the developmental toxicity of trichloroethylene in vitro.

Effects of Putative Hydroxylated Thalidomide Metabolites on Blood Vessel Density in the Chorioallantoic Membrane (CAM) Assay and on Tumor and Endothelial Cell Proliferation.

“…13,[32][33][34][35] Furthermore, in a Xenopus oocyte assay of teratogenesis, activation of thalidomide by a single cytochrome P450 enzyme, CYP2E1, lead to a teratogenic compound whereas unactivated thalidomide was non-teratogenic. 35) Thus metabolism of thalidomide is critical to its anti-angiogenic and teratogenic activity. However, the identity of the active anti-angiogenic and teratogenic moiety or moieties of thalidomide are still unknown.…”

Developmental Toxicity of Drinking Water Disinfection By-Products to Embryos of the African Clawed Frog (Xenopus laevis)

“…Test methods followed the Frog Embryo Teratogenicity Assay -Xenopus (FETAX) (Fort et al, 1993). Embryos were cultured in FETAX solution as described in the ASTM Standard Guide (ASTM, 1998 Assay -Xenopus (FETAX)" (ASTM, 1998) and the "Atlas of Abnormalities" (Bantle et al 1998) Two replicates of 25 embryos per replicate were used for each of the chloroform, DBAA, and sodium chlorate test concentrations.…”

Assessing the predictive validity of frog embryo teratogenesis assay?Xenopus (FETAX)

“…The remaining four compounds were found to have weak teratogenic activity and scored as equivocal. Determination of whether the test materials were teratogens was based on the following criteria: 1) TI value greater than 3.0 [8][9][10][11], 2) MCIG value <30% of the 96-h LC50 value [8][9][10][11], and/or 3) presence of strong characteristic malformations [9][10][11]. Characteristic malformations were those abnormalities that increased in both number of affected organisms and the severity of the abnormality with increasing concentration.…”