Huayta Javier, Seay Sarah, Laster Joseph, Rivera Nelson A, Joyce Abigail S, Ferguson P Lee, Hsu-Kim Heileen, Meyer Joel N
Nicholas School of the Environment, Duke University, Durham, NC, USA.
Pratt School of Engineering, Duke University, Durham, NC, USA.
ALTEX. 2025 Apr 23. doi: 10.14573/altex.2501151.
Few of the many chemicals that regulatory agencies are charged with assessing for risk have been carefully tested for developmental neurotoxicity (DNT). To speed up assessment, and to reduce the use of vertebrate animals, great effort is being devoted to alternative laboratory models for DNT. A major DNT mechanism is altered neuronal architecture resulting from chemical exposure during neurodevelopment. Caenorhabditis elegans is a nematode that has been extensively studied by neurobiologists and developmental biologists, and to a lesser extent by neurotoxicologists. The development of the nervous system in C. elegans is easily visualized, entirely invariant, and fully mapped. We hypothesized that C. elegans could be a powerful in vivo model to test chemicals for their potential to alter neuronal architecture during development. We developed a novel C. elegans DNT testing paradigm that includes developmental exposure, examines major neurotransmitter neuronal types for architectural alterations, and tests neuron-specific behaviors. We characterized the effects of exposures to the developmental neurotoxicants lead, cadmium, and benzo(a)pyrene on neuronal architecture and specification. We identified no cases in which the apparent neurotransmitter type of the neurons we examined changed, but many in which neuronal morphology was altered. We found that neuron-specific behaviors were altered during C. elegans mid-adulthood for populations with measured morphological neurodegeneration in earlier stages. The functional changes were consistent with the morphological changes in terms of the type of neuron affected. Finally, we identified changes consistent with those reported in the mammalian DNT literature, strengthening the case for C. elegans as a DNT model.
监管机构负责评估风险的众多化学物质中，很少有经过发育神经毒性（DNT）的仔细测试。为了加快评估速度并减少脊椎动物的使用，人们正在大力致力于开发用于DNT的替代实验室模型。一个主要的DNT机制是神经发育过程中化学物质暴露导致神经元结构改变。秀丽隐杆线虫是一种线虫，神经生物学家和发育生物学家对其进行了广泛研究，神经毒理学家对其研究较少。秀丽隐杆线虫的神经系统发育易于观察，完全不变且已被完整绘制。我们假设秀丽隐杆线虫可能是一种强大的体内模型，用于测试化学物质在发育过程中改变神经元结构的潜力。我们开发了一种新颖的秀丽隐杆线虫DNT测试范式，包括发育暴露、检查主要神经递质神经元类型的结构改变以及测试神经元特异性行为。我们描述了发育神经毒物铅、镉和苯并[a]芘暴露对神经元结构和特化的影响。我们没有发现所检查神经元的明显神经递质类型发生变化的情况，但发现许多神经元形态发生了改变。我们发现，对于早期有形态学神经退行性变测量结果的群体，秀丽隐杆线虫成年中期的神经元特异性行为发生了改变。功能变化与受影响神经元类型的形态学变化一致。最后，我们确定了与哺乳动物DNT文献中报道的变化一致的变化，从而加强了秀丽隐杆线虫作为DNT模型的论据。
