EFFECTS OF 2-METHOXYETHANOL ON MOUSE NEURULATION

The potent developmental toxicant, 2-methoxyethanol (2-ME), elicits ex encephaly in near-term mouse fetuses following a single maternal treat ment early on gestation day (gd) 8. Deleterious morphological conseque nces to the neurulating embryo shortly after exposure have not been re ported. The present study was designed to fill this gap and to investi gate the impact of 2-ME treatment on cell death patterns in the embryo nic neural folds. Dams were injected subcutaneously with saline, 250 o r 325 mg 2-ME/kg 2 hr prior to the beginning of gd 8. The effect of 2- ME on gross and microscopic neural development was examined in concept uses on gd 9, 6 hr(9:6), 10:6, and 18:0. Compared to saline, 2-ME trea tment increased the percentage of embryos with open neural tubes (ONTs ) at all gestation days. Although few statistically significant differ ences (P < 0.05) existed among the ONT rates on the 3 observation days , an interesting biological response occurred. Both high and low 2-ME doses appeared to elicit the greatest incidence of neural tube patency on gd 9:6 (affecting similar to 27% of embryos). During the subsequen t 24 hr, recovery occurred and many neural folds apparently closed. Co nsequently, the ONT incidences on gd 10:6 (similar to 11%) were quite similar to the gd 18 exencephaly rates elicited by both chemical treat ments (similar to 15%). A dose response was not seen due to a substant ial increase in resorption rates following the 325 mg/kg dose. Compare d to the other treatment groups, the low 2-ME dose significantly inhib ited embryonic growth as indicated by reduced crown-rump and head leng ths and increased incidence of developmentally delayed brain maturatio n. To evaluate chemically induced changes in cell death, neurulating e mbryos were collected on gd 8:6 and either immersed in the vital dye, Nile blue sulfate (NBS), or processed for histopathology. In 2-ME-expo sed embryos, excessive NBS uptake occurred in neural fold neuroepithel ium at sites of nonclosure. Using histopathology, the extent of cell d eath in the cephalic neural folds was dependent on the 2-ME dose, and the neuroepithelium was more severely affected than the mesenchyme. Th ese observations suggest 1) a trend toward repair and catch-up growth later in gestation which may ameliorate the overt early effects of 2-M E, and 2) an association between enhanced cell death and regions of th e neural tube particularly vulnerable to nonclosure. (C) (C) 1997 Wile y-Liss, Inc.