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, North Carolina, USA.
Pratt School of Engineering, Duke University, Durham, North Carolina, USA.
bioRxiv. 2025 Jan 14:2025.01.11.632560. doi: 10.1101/2025.01.11.632560.
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 testing efforts, as well as to reduce the use of vertebrate animals, great effort is being devoted to alternate laboratory models for testing DNT. A major mechanism of DNT is altered neuronal architecture resulting from chemical exposure during neurodevelopment. is a nematode that has been extensively studied by neurobiologists and developmental biologists, and to a lesser extent by neurotoxicologists. The developmental trajectory of the nervous system in is easily visualized, normally entirely invariant, and fully mapped. Therefore, we hypothesized that could be a powerful model to test chemicals for the potential to alter developmental patterning of neuronal architecture. To test whether this might be true, we developed a novel DNT testing paradigm that includes exposure throughout development, examines all major neurotransmitter neuronal types for architectural alterations, and tests behaviors specific to dopaminergic, cholinergic, and glutamatergic functions. We used this paradigm to characterize the effects of early-life exposures to the developmental neurotoxicants lead, cadmium, and benzo(a)pyrene (BaP) on dopaminergic, cholinergic, and glutamatergic architecture. We also assessed whether exposures would alter neuronal specification as assessed by expression of reporter genes diagnostic of specific neurotransmitters. 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 also found that neuron-specific behaviors were altered during mid-adulthood for populations with measured morphological neurodegeneration in earlier stages. The functional changes were consistent with the morphological changes we observed in terms of type of neuron affected. We identified changes consistent with those reported in the mammalian DNT literature, strengthening the case for as a DNT model, and made novel observations that should be followed up in future studies.
在众多由监管机构负责评估风险的化学物质中，很少有经过仔细的发育神经毒性（DNT）测试。为了加快测试工作，并减少脊椎动物的使用，人们正在大力投入开发用于测试DNT的替代实验室模型。DNT的一个主要机制是神经发育过程中化学物质暴露导致的神经元结构改变。秀丽隐杆线虫已被神经生物学家和发育生物学家广泛研究，神经毒理学家对其研究较少。秀丽隐杆线虫神经系统的发育轨迹易于观察，通常完全不变且已被完整绘制。因此，我们假设秀丽隐杆线虫可能是一种强大的模型，用于测试化学物质改变神经元结构发育模式的潜力。为了验证这是否属实，我们开发了一种新颖的秀丽隐杆线虫DNT测试范式，该范式包括在整个发育过程中进行暴露，检查所有主要神经递质神经元类型的结构改变，并测试多巴胺能、胆碱能和谷氨酸能功能特有的行为。我们使用这个范式来表征生命早期暴露于发育神经毒物铅、镉和苯并[a]芘（BaP）对多巴胺能、胆碱能和谷氨酸能结构的影响。我们还评估了暴露是否会改变通过诊断特定神经递质的报告基因表达评估的神经元特化。我们没有发现所检查的神经元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。我们还发现，对于在早期阶段有形态学神经退行性变测量结果的群体，在成年中期神经元特异性行为发生了改变。功能变化与我们观察到的受影响神经元类型的形态学变化一致。我们确定的变化与哺乳动物DNT文献中报道的变化一致，加强了秀丽隐杆线虫作为DNT模型的证据，并得出了一些新的观察结果，有待未来研究跟进。
