Spatiotemporal role of muscarinic signaling in early chick development: exposure to cholinomimetic agents by a mathematical model,Cell Biology and Toxicology

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Spatiotemporal role of muscarinic signaling in early chick development: exposure to cholinomimetic agents by a mathematical model
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2022-09-13 , DOI: 10.1007/s10565-022-09770-w
Ombretta Paladino ₁ , Arianna Moranda ₁ , Carla Falugi ₂

Affiliation

Awareness 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

1.
Early chick embryos were exposed to muscarinic drugs in a spatial-temporal context.
2.
Effects were stage-(time) dependent, according to distance and position of the source.
3.
Atropine inhibited growth, mainly interfering with the cephalic process formation and heart differentiation; carbachol increased growth reducing differentiation.
4.
Interferences may be exerted by alteration of calcium responses to naturally occurring morphogen-driven mechanisms.

中文翻译：

毒蕈碱信号在早期雏鸡发育中的时空作用：通过数学模型暴露于拟胆碱剂

人们越来越认识到，除了几种神经毒性作用外，能够干扰胆碱能神经递质系统的拟胆碱药物可能会对脊椎动物和无脊椎动物的胚胎发育产生致畸作用。拟胆碱物质通过在AChE活性位点水平和乙酰胆碱受体水平上完全或部分取代ACh分子来抑制胆碱能系统的功能，从而对生物体发挥毒性活性。在这项工作中，我们将注意力集中在毒蕈碱拮抗剂（阿托品）和激动剂（卡巴胆碱）药物在鸡胚胎早期发育和个体发生过程中的作用。开发了药物释放和命运的非稳态数学模型，以使药物浓度梯度的暴露与不同的发育事件同步。由于在不损害胚胎本身的情况下无法采取时间和空间上的浓度测量，因此扩散模型是在每个时间步骤建立胚胎体不同点处药物精确浓度的唯一方法（被认为是二维的50小时阶段）。该浓度取决于胚胎相对于释放源的距离和位置。暴露于卡巴胆碱通常会增加胚胎的尺寸和阶段，而阿托品主要导致发育延迟和胚胎尺寸变小。这两种药物都能引起发育异常，具体取决于发育时刻，以时间和剂量依赖性方式，无论驱动每个事件的基因表达如何。