Spatiotemporal role of muscarinic signaling in early chick development: exposure to cholinomimetic agents by a mathematical model

Abstract

AbstractAwareness is growing that, besides several neurotoxic effects, cholinomimetic drugs able to interfere the cholinergic neurotransmitter system may exert a teratogen effect in developing embryos of vertebrate and invertebrate organisms. Cholinomimetic substances exert their toxic activity on organisms as they inhibit the functionality of the cholinergic system by completely or partially replacing the ACh molecule both at the level of the AChE active site and at the level of acetylcholine receptors. In this work, we focused the attention on the effects of muscarinic antagonist (atropine) and agonist (carbachol) drugs during the early development and ontogenesis of chick embryos. An unsteady-state mathematical model of the drug release and fate was developed, to synchronize exposure to a gradient of drug concentrations with the different developmental events. Since concentration measures in time and space cannot be taken without damaging the embryo itself, the diffusion model was the only way to establish at each time-step the exact concentration of drug at the different points of the embryo body (considered two-dimensional up to the 50 h stage). This concentration depends on the distance and position of the embryo with respect to the releasing source. The exposure to carbachol generally enhanced dimensions and stages of the embryos, while atropine mainly caused delay in development and small size of the embryos. Both the drugs were able to cause developmental anomalies, depending on the moment of development, in a time- and dose-dependent way, regardless the expression of genes driving each event. Graphical abstract Early chick embryos were exposed to muscarinic drugs in a spatial-temporal context. Effects were stage-(time) dependent, according to distance and position of the source. Atropine inhibited growth, mainly interfering with the cephalic process formation and heart differentiation; carbachol increased growth reducing differentiation. Interferences may be exerted by alteration of calcium responses to naturally occurring morphogen-driven mechanisms.