Lassiter_1998_Toxicol.Appl.Pharmacol_152_56

Previous studies have shown that, in general, young, postnatal animals are more sensitive than adults to the toxic effects of anticholinesterase (antiChE) pesticides. Paradoxically, often fetal brain cholinesterase (ChE) is less inhibited than maternal brain after gestational exposure to an antiChE, presumably due to placental and fetal detoxification of the antiChE. The present investigation was designed to study selected toxicokinetic and toxicodynamic factors surrounding the toxicity of chlorpyrifos (CPF; [O,O'-diethyl O-3,5,6-trichloro-2-pyridyl] phosphorothionate) in pregnant rats dosed repeatedly or singly during late gestation. Dams were dosed daily (po) with CPF in corn oil (0 or 7 mg/kg) on gestational days (GD) 14 to 18. Animals were euthanized at 2 to 120 h after the last dose and tissues were collected for enzyme analysis. Using this dosing regimen, we found that (1) the time of maximal ChE inhibition was the same (i.e., 5-10 h after dosing) for both maternal and fetal brain, (2) the degree of fetal brain ChE inhibition was 4.7 times less than maternal brain inhibition, and (3) the detoxification potential (i.e., carboxylesterase and chlorpyrifos-oxonase) of the fetal tissues was very low compared to the maternal tissues. A separate group of experiments showed that if pregnant dams received only one oral dose of 7 or 10 mg/kg CPF on GD18, the degree of ChE inhibition in the fetal brain was comparable to the maternal brain ChE inhibition. Taking into consideration the net increase (more than fourfold) in fetal brain ChE activity from GD14 to 18 in control animals, and the fact that maternal brain ChE was inhibited more than fetal brain ChE only in a repeated-dosing regimen, we conclude that the fetus is not genuinely protected from the toxic effects of a given dose of CPF. We propose that fetal brain ChE is simply able to recover more fully between each dose as compared to maternal brain ChE, giving the illusion that the fetal compartment is less affected than the maternal compartment.