Lassiter T Leon, MacKillop Emiko A, Ryde Ian T, Seidler Frederic J, Slotkin Theodore A
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Brain Res Bull. 2009 Mar 30;78(6):313-22. doi: 10.1016/j.brainresbull.2008.09.020. Epub 2008 Oct 31.
Fipronil, a GABA(A) receptor antagonist, is replacing many insecticide uses formerly fulfilled by organophosphates like chlorpyrifos. Few studies have addressed the potential for fipronil to produce developmental neurotoxicity. We compared the neurotoxicity of fipronil and chlorpyrifos in undifferentiated and differentiating neuronotypic PC12 cells, evaluating indices of cell replication, cell number, differentiation, and viability for short- and long-term exposures. Fipronil inhibited DNA and protein synthesis in undifferentiated PC12 cells and evoked oxidative stress to a greater extent than did chlorpyrifos, resulting in reduced cell numbers even though cell viability was maintained. In differentiating cells, fipronil displayed an even lower threshold for disruption of development, reducing cell numbers without impairing cell growth, and promoting emergence of neurotransmitter phenotypes; superimposed on this effect, the phenotypic balance was shifted in favor of dopamine as opposed to acetylcholine. Differentiation also enhanced the susceptibility to fipronil-induced oxidative stress, although antioxidant administration failed to provide protection from cell loss. At low concentrations maintained for prolonged periods, fipronil had a biphasic effect on cell numbers, increasing them slightly at low concentrations, implying interference with apoptosis, while nevertheless reducing cell numbers at higher concentrations. Our results suggest that fipronil is inherently a more potent disruptor of neuronal cell development than is chlorpyrifos. The neurodevelopmental effects are not predicated on GABA(A) antagonist properties, since PC12 cells lack the GABA(A) receptor. If fipronil is intended to provide greater safety than chlorpyrifos, then this will have to entail advantages from factors that are yet unexamined: exposure, persistence, pharmacokinetics.
氟虫腈是一种γ-氨基丁酸A型（GABA(A)）受体拮抗剂，正在取代许多以前由毒死蜱等有机磷酸酯类杀虫剂承担的用途。很少有研究探讨氟虫腈产生发育性神经毒性的可能性。我们比较了氟虫腈和毒死蜱对未分化及分化中的神经元样PC12细胞的神经毒性，评估了短期和长期暴露下的细胞复制、细胞数量、分化及活力指标。氟虫腈抑制未分化PC12细胞中的DNA和蛋白质合成，比毒死蜱更易引发氧化应激，尽管维持了细胞活力，但导致细胞数量减少。在分化细胞中，氟虫腈对发育破坏的阈值更低，减少细胞数量但不损害细胞生长，并促进神经递质表型的出现；叠加在此效应上，表型平衡向多巴胺而非乙酰胆碱方向偏移。分化也增强了对氟虫腈诱导的氧化应激的敏感性，尽管给予抗氧化剂未能保护细胞免于损失。在长时间维持的低浓度下，氟虫腈对细胞数量有双相效应，在低浓度时略有增加，这意味着对细胞凋亡有干扰，而在较高浓度时仍会减少细胞数量。我们的结果表明，氟虫腈本质上比毒死蜱更能有效破坏神经元细胞发育。神经发育效应并非基于GABA(A)拮抗剂特性，因为PC12细胞缺乏GABA(A)受体。如果氟虫腈旨在提供比毒死蜱更高的安全性，那么这将必须来自尚未研究的因素的优势：暴露、持久性、药代动力学。
