Hidayat Alia S, Pitt Jordan A, Fredricks Helen, Hahn Mark E, Aluru Neelakanteswar
Biology Department and Woods Hole Center for Oceans and Human Health, Woods Hole Oceanographic Institution, Woods Hole, MA 02543, USA; Massachusetts Institute of Technology (MIT) - Woods Hole Oceanographic Institution (WHOI) Joint Graduate Program in Oceanography and Oceanographic Engineering, USA; Center for American Progress, WA, DC 20002, USA.
Biology Department and Woods Hole Center for Oceans and Human Health, Woods Hole Oceanographic Institution, Woods Hole, MA 02543, USA; Massachusetts Institute of Technology (MIT) - Woods Hole Oceanographic Institution (WHOI) Joint Graduate Program in Oceanography and Oceanographic Engineering, USA; Exponent Inc, 1075 Worcester Street, Natick, MA, 01760, USA.
Harmful Algae. 2025 Jun;146:102862. doi: 10.1016/j.hal.2025.102862. Epub 2025 Apr 17.
Harmful algal blooms (HABs), driven by warming oceans and increased eutrophication, are negatively affecting aquatic ecosystems as well as human health. Blooms of diatom Pseudo-nitzschia spp. produce a neurotoxin, domoic acid (DA), which can be concentrated by filter feeders, including shellfish. Consumption of DA-contaminated seafood causes amnesic shellfish poisoning. DA causes well-established effects on neurons, inducing neurotoxicity by binding to ionotropic glutamate receptors. However, its effects on non-neuronal cells including microglia, the resident immune cells in the brain, are less well understood. Microglia play critical roles in brain health, and disruptions in microglial activity during development can have long-term impacts on brain function and disease risk. The objective of this study was to examine the effects of developmental DA exposure on microglia using zebrafish (Danio rerio). We characterized effects of DA exposure on microglial abundance and morphology at two developmental stages (2 and 4 days post-fertilization (dpf)). We additionally assessed impacts on cell death, cytokine expression, and startle response behavior. In older larvae (4 dpf), microglial effects occurred only at the highest dose (0.3 ng DA per larvae) and coincided with severe morphological defects. In contrast, 2 dpf exposure to lower doses (0.1 ng DA per embryo) caused transient tremors without gross abnormalities but exposure to either 0.1 or 0.3 ng DA per larvae increased microglial abundance and altered microglial morphology. In contrast, 4 dpf exposure to 0.3 ng DA per larvae reduced microglial numbers. Increases in mRNA levels of il1b, il4, and tgfb were observed after 4 dpf exposure, but no significant cytokine changes were detected at 2 dpf. Overall, the effects of DA are highly developmental stage-specific, with microglial reactivity occurring at doses that do not cause gross morphological changes. These findings suggest that neuroinflammation may arise at lower DA doses, indicating a potential mechanism for subtle toxic effects and emphasizing the need for further research to better understand the consequences of low-dose DA exposure on microglial function.
由海洋变暖及富营养化加剧导致的有害藻华（HABs）正对水生生态系统以及人类健康产生负面影响。硅藻假微型海链藻属（Pseudo-nitzschia spp.）的藻华会产生一种神经毒素——软骨藻酸（DA），这种毒素可在包括贝类在内的滤食性动物体内富集。食用受DA污染的海鲜会导致失忆性贝类中毒。DA对神经元具有确切的影响，它通过与离子型谷氨酸受体结合来诱发神经毒性。然而，其对包括小胶质细胞（大脑中的常驻免疫细胞）在内的非神经元细胞的影响却鲜为人知。小胶质细胞在大脑健康中发挥着关键作用，发育过程中小胶质细胞活性的破坏会对脑功能和疾病风险产生长期影响。本研究的目的是利用斑马鱼（Danio rerio）来研究发育过程中暴露于DA对小胶质细胞的影响。我们在两个发育阶段（受精后2天和4天，即dpf）表征了DA暴露对小胶质细胞丰度和形态的影响。我们还评估了对细胞死亡、细胞因子表达和惊吓反应行为的影响。在较年长的幼虫（4 dpf）中，小胶质细胞的影响仅在最高剂量（每只幼虫0.3 ng DA）时出现，且与严重的形态缺陷同时出现。相比之下，2 dpf暴露于较低剂量（每个胚胎0.1 ng DA）会导致短暂震颤但无明显异常，不过每只幼虫暴露于0.1或0.3 ng DA会增加小胶质细胞丰度并改变小胶质细胞形态。相反，4 dpf暴露于每只幼虫0.3 ng DA会减少小胶质细胞数量。在4 dpf暴露后观察到il1b、il4和tgfb的mRNA水平升高，但在2 dpf未检测到明显的细胞因子变化。总体而言，DA的影响具有高度的发育阶段特异性，小胶质细胞反应性在不会导致明显形态变化的剂量下就会出现。这些发现表明，在较低的DA剂量下可能会引发神经炎症，这表明了一种潜在的微妙毒性效应机制，并强调需要进一步研究以更好地理解低剂量DA暴露对小胶质细胞功能的影响。
