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Abstract Diisodecyl phthalate (DIDP) is a new type of phthalate used in the coating of pharmaceutical pills and in plastic food wrappers. This research was conducted to investigate whether DIDP could cause learning and memory impairment in mice, using formaldehyde (FA) to construct a positive control. Behavioral analysis showed that oral administration of 15 mg kg−1·d−1 DIDP combined with inhalation of 1 mg m−3 FA led to learning and memory impairment in mice. Histopathological observations of the brain showed that the pathological alterations in the hippocampi. Detection of testosterone (T) and estradiol (E2) levels in the brain and serum showed that E2 levels were associated with learning and memory disorders. Reactive oxygen species (ROS), reduced glutathione (GSH), malondialdehyde (MDA), and 8-hydroxy-2-deoxyguanosine (8-OH-dG) revealed the increased oxidative stress levels. Detection of caspase-3, NF-κB, the phosphorylated cAMP response-element binding protein (p-CREB) and the brain derived neurotrophic factor (BDNF) showed that the protective effect mediated by BDNF, is reduced. However, some of these effects were blocked by the administration of Vitmin E (VitE, 100 mg kg−1·d−1) or 17β-estradiol (17β-E2, 100 μg kg−1). These data suggest that DIDP may aggravate the FA-exposure-induced learning and memory impairment in mice, and that 17β-E2 could be utilized to avoid these adverse effects. Graphical abstract Image 1 Highlights • DIDP aggravates the FA-exposure-impaired learning and memory via oxidative stress. • DIDP causes learning and memory disabilities in mice by abnormal estradiol levels. • 17β-E2 could be utilized to avoid DIDP-induced learning and memory impairment. [ABSTRACT FROM AUTHOR]