三苯磷酸酯（TPhP）是一种广泛分布于环境中的有机磷阻燃剂。TPhP的神经发育毒性在动物和人类中已被观察到。之前，我们发现产前接触TPhP会干扰胎盘色氨酸代谢，损害雄性后代的神经发育，并引发异常的神经行为；然而，其潜在机制尚不明确。在本研究中，使用滋养层细胞系JEG-3，我们发现TPhP会改变色氨酸代谢通路中的基因和蛋白表达，抑制色氨酸-5-羟色胺通路，并激活色氨酸-酪氨酸通路。同时，TPhP通过激活单胺氧化酶A（MAOA）引发氧化应激，促进包括核因子κB（NFκB）、白细胞介素-6和肿瘤坏死因子α在内的炎症因子的释放。NFκB抑制剂磺胺嘧啶能够缓解TPhP对色氨酸代谢干扰的影响。MAOA抑制剂瑞格林或抗氧化剂N-乙酰半胱氨酸能够减轻氧化应激，消除TPhP引起的炎症因子和色氨酸代谢干扰。上述数据表明，TPhP通过MAOA诱导的氧化应激激活NFκB，干扰色氨酸代谢。最后，利用小鼠子宫内暴露模型，结果证实TPhP能够在妊娠第二个三分之一期间引起氧化应激、激活炎症因子，干扰色氨酸代谢，并增加胎盘中色氨酸代谢产物5-羟色胺、酪氨酸、3-羟基酪氨酸和3-羟基蒽醌酸的水平。总体而言，TPhP通过激活炎症因子NFκB来干扰胎盘色氨酸代谢，这是由MAOA引起的氧化应激所诱导的。本研究的结果证实了早期生命阶段对外源性化合物的间接暴露可能损害后代发育，并提供了对TPhP神经发育毒性的新视角。 版权所有 © 2023. 由Elsevier B.V.出版。

Triphenyl phosphate (TPhP) is an organophosphate flame retardant widely distributed in the environment. The neurodevelopmental toxicity of TPhP has been observed in animals and humans. Previously, we found that prenatal TPhP exposure disturbed placental tryptophan metabolism, impaired neurodevelopment in male offspring, and induced abnormal neurobehavior; however, the underlying mechanisms are unknown. In this study, using the trophoblast cell line JEG-3, we found that TPhP altered gene and protein expression in the tryptophan metabolism pathway, inhibited the tryptophan-serotonin pathway, and activated the tryptophan-kynurenine pathway. Meanwhile, TPhP induced oxidative stress by activating monoamine oxidase A (MAOA), promoting inflammatory factors including nuclear factor kappa-B (NFκB), interleukin-6, and tumor necrosis factor α. The NFκB inhibitor sulfasalazine could alleviate the effects of TPhP on tryptophan metabolism disturbance. The MAOA inhibitor clorgyline or the antioxidant N-acetylcysteine can mitigate oxidative stress and eliminate TPhP-induced inflammatory factors and tryptophan metabolism disturbances. The data above suggest that TPhP disturbed tryptophan metabolism by activating NFκB through MAOA-mediated oxidative stress. Finally, using the mouse intrauterine exposure model, the results confirmed that TPhP induced oxidative stress, activated inflammatory factors, disturbed tryptophan metabolism, and increased the levels of the tryptophan metabolites serotonin, kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid in the placenta during the second trimester of pregnancy. Overall, TPhP can disturb placental tryptophan metabolism by activating the inflammatory factor NFkB, which was induced by MAOA-induced oxidative stress. The results of this study confirm that indirect exposure to xenobiotic compounds at an early life stage can impair offspring development and provide a novel perspective on the neurodevelopmental toxicity of TPhP.Copyright © 2023. Published by Elsevier B.V.