The ubiquitous contamination of di(2-ethylhexyl)phthalate (DEHP) in the environment, biota, and food poses potential ecological and human health risks. DEHP exposure can adversely affect learning and memory, yet the underlying mechanisms remain unclear. In this study, Caenorhabditis elegans was used to investigate the effect of early-life DEHP exposure on age-related long-term associative memory (LTAM) decline, as well as the associations with the cAMP-responsive element-binding protein (CREB) transcription factor and insulin/IGF-1 signaling (IIS). We showed that early-life exposure to DEHP reduced LTAM in wild-type worms at day-0 adulthood. Chronic exposure to DEHP from the L1 stage to day-5 adulthood worsened the age-dependent decline of LTAM. Moreover, the effect of DEHP on age-related LTAM requires CRH-1, a homolog of CREB. Mutations in daf-2, the sole receptor of C. elegans IIS, ameliorated the inhibition of LTAM by DEHP, and the effect depended on daf-16. In addition, daf-2 mutation restored the CRH-1 level in DEHP-exposed worms, and the effect required daf-16. Our study suggests that early-life chronic exposure to DEHP worsens age-related LTAM decline and the effect is associated with CRH-1 and IIS in C. elegans. The evolutionary conservation of IIS and CREB implies possible adverse effects by DEHP across species.

邻苯二甲酸二（2-乙基己基）酯（DEHP）在环境，生物群和食物中的普遍污染构成潜在的生态和人类健康风险。暴露于DEHP会对学习和记忆产生不利影响，但其潜在机制仍不清楚。在这项研究中，秀丽隐杆线虫用于研究早期DEHP暴露对与年龄相关的长期联想记忆（LTAM）下降以及与cAMP反应元件结合蛋白（CREB）转录因子和胰岛素/IGF-α的关联的影响1个信令（IIS）。我们表明，在成年第0天时，早期暴露于DEHP可以降低野生型蠕虫的LTAM。从L1阶段到成年第5天长期接受DEHP会使年龄依赖性的LTAM下降恶化。此外，DEHP对与年龄有关的LTAM的作用需要CRH-1（CREB的同系物）。秀丽隐杆线虫IIS的唯一受体daf-2的突变改善了DEHP对LTAM的抑制作用，其作用取决于daf-16。另外，daf-2突变恢复了暴露于DEHP的蠕虫中CRH-1的水平，而这种作用需要daf-16。我们的研究表明，生命早期长期暴露于DEHP会加剧与年龄相关的LTAM下降，并且这种影响与秀丽隐杆线虫中的CRH-1和IIS有关。IIS和CREB的进化保守性暗示DEHP可能对物种产生不利影响。