Coniine, an
alkaloid from Conium maculatum (poison hemlock), is a known
teratogen in many domestic species with maternal ingestion resulting in
arthrogryposis of the offspring. We have previously shown that rats are not susceptible and rabbits only weakly susceptible to
coniine-induced
arthrogryposis. However, the chick embryo does provide a reproducible laboratory animal model of
coniine-induced
teratogenesis. The reason for this cross-species variation is unknown. The purpose of this study was to evaluate
coniine binding to
nicotinic receptors and to measure
coniine metabolism in vitro between susceptible and non-susceptible species. Using the chick model, neither the peripheral
nicotinic receptor antagonist
d-tubocurarine chloride nor the central
nicotinic receptor antagonist
trimethaphan camsylate blocked the
teratogenesis or lethality of 1.5%
coniine (50 microliters/egg).
Trimethaphan camsylate enhanced
coniine-induced lethality in a dose-dependent manner. Neither
nicotinic receptor blocker prevented
nicotine sulfate-induced malformations but
d-tubocurarine chloride did block lethality in a dose-dependent manner. Competition by
coniine for [125I]-
alpha-bungarotoxin to
nicotinic receptors isolated from adult rat diaphragm and chick thigh muscle and competition by
coniine for [3H]-
cytisine to receptors from rat and chick brain were used to assess
coniine binding to
nicotinic receptors. The IC50 for
coniine in rat diaphragm was 314 microM while that for chick leg muscle was 70 microM. For neuronal
nicotinic receptors, the IC50s of
coniine for maternal rat brain, fetal rat brain, and chick brain were 1100 microM, 820 microM, and 270 microM, respectively. There were no differences in
coniine biotransformation in vitro by microsomes from rat or chick livers. Differences in apparent affinity of
coniine for
nicotinic receptors or differences in the quantity of the
nicotinic receptor between the rat and chick may explain, in part, the differences in susceptibility of
coniine-induced
teratogenesis between these two species.