Koff Leandra, Di Re Jessica, Chand Subhash, Avchalumov Yosef, Nguyen Nghi M, Baumgartner Timothy J, Singh Aditya K, Goode Nana A, Marosi Mate, Hallberg Lance M, Ameredes Bill T, Green Thomas A, Yelamanchili Sowmya V, Pendyala Gurudutt, Laezza Fernanda
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA.
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA; NIEHS Environmental Toxicology Training Program, University of Texas Medical Branch, Galveston, Texas, USA.
Mol Cell Proteomics. 2025 Feb;24(2):100902. doi: 10.1016/j.mcpro.2024.100902. Epub 2024 Dec 31.
Pyrethroid pesticides have been associated with neurodevelopmental disorders including attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). While behavioral effects of pyrethroid exposure have been previously reported, the underlying mechanisms remain unclear. Here, we hypothesized that exposure to deltamethrin (DM), a widely used pyrethroid pesticide known for its neurotoxicity during early developmental stages, induces brain dysfunction through alterations in brain-derived extracellular vesicle (BDEV) signaling. Using a well-established rodent model of early life DM exposure within the recommended no observable effect level, we isolated BDEVs from postnatal 30-day-old vehicle-exposed (control) and DM-exposed mice using a differential sucrose density gradient. Following ZetaView nanoparticle tracking and electron microscopy characterization, quantitative mass spectrometry-based proteomics revealed 89 differentially expressed proteins (DEPs) in BDEVs from DM exposed animals compared to control BDEVs. Bioinformatic analysis identified convergence of DEPs on pathways associated with mitochondrial function and synaptic plasticity. PKH67-green conjugated BDEVs derived from either control or DM-exposed mice were bilaterally injected intracerebroventricularly into naive adult mice, and the brain distribution of labeled BDEVs was verified prior to extracellular field recording experiments. Strikingly, long-term potentiation (LTP) at CA3-CA1 hippocampal synapses, a functional correlate of learning and memory, was intact in control BDEVs but absent in naive mice receiving BDEVs from DM exposed mice. Notably, exogenously delivering LRRTM1, one of the DEPs found in DM BDEVs, disrupts synaptic transmission in CA1 neurons consistent with impaired LTP. Thus, differentially regulated signaling in BDEVs represents a novel mechanism of DM neurotoxicity.
拟除虫菊酯类农药与神经发育障碍有关，包括注意力缺陷多动障碍（ADHD）和自闭症谱系障碍（ASD）。虽然先前已报道了拟除虫菊酯暴露的行为影响，但其潜在机制仍不清楚。在此，我们假设，暴露于溴氰菊酯（DM），一种在发育早期阶段以其神经毒性而闻名的广泛使用的拟除虫菊酯类农药，会通过脑源性细胞外囊泡（BDEV）信号的改变诱导脑功能障碍。使用在推荐的无可见效应水平内建立的早期生活DM暴露的啮齿动物模型，我们使用差示蔗糖密度梯度从出生后30天的溶剂暴露（对照）和DM暴露小鼠中分离出BDEV。在进行ZetaView纳米颗粒追踪和电子显微镜表征后，基于定量质谱的蛋白质组学显示，与对照BDEV相比，DM暴露动物的BDEV中有89种差异表达蛋白（DEP）。生物信息学分析确定DEP在与线粒体功能和突触可塑性相关的途径上的汇聚。将来自对照或DM暴露小鼠的PKH67绿色共轭BDEV双侧脑室内注射到未处理的成年小鼠中，并在细胞外场记录实验之前验证标记BDEV的脑部分布。令人惊讶的是，CA3-CA1海马突触处的长时程增强（LTP），一种学习和记忆的功能相关指标，在对照BDEV中是完整的，但在接受来自DM暴露小鼠的BDEV的未处理小鼠中不存在。值得注意的是，外源递送LRRTM1，一种在DM BDEV中发现的DEP，会破坏CA1神经元中的突触传递，这与LTP受损一致。因此，BDEV中差异调节的信号代表了DM神经毒性的一种新机制。
