Diisodecyl Phthalate Aggravated The Learning And Memory Impairment In Mice Induced By Formaldehyde Exposure And The Neuroprotective Effect Of 17?-estradiol

Nowadays,plasticizers have been widely used in many fields,and the safety of plasticizers has been receiving widespread attention.Diisodecyl phthalate?DIDP?,as a new type of plasticizer with low toxicity and excellent performance,is considered to be a suitable substitute for traditional phthalate plasticizers with high toxicity.As it becomes more and more widely used,its potential toxicity and mechanism of action cannot be ignored.In this study,a model of learning and memory impairment in mice was constructed with gaseous formaldehyde?FA?as a positive control.The aim was to investigate whether DIDP could cause learning and memory impairment in mice,and whether the combined exposure of DIDP and FA could induce more severe learning and memory impairment in mice.We assessed the learning and memory ability of mice after DIDP exposure by morris water maze test,and then made hippocampal H&E stained sections and Nissl stained sections for brain histopathological observation.The levels of testosterone?T?and?-estradiol??-E2?,oxidative stress,inflammation and apoptosis,and memory-related protein content in brain tissue homogenate were measured to evaluate the effect of DIDP exposure on learning and memory in mice and the degree of damage to brain tissue.In the Morris water maze test,for the mice exposed to 15 mg·kg^-1·d^-1 DIDP,150mg·kg^-1·d^-1 DIDP,1 mg·m^-3 FA+15 mg·kg^-1·d^-1 DIDP,we find that the escape latency decrease slowly,the residence time in the target quadrant becomes shorter,the swimmers trajectories are chaos and aimless,i.e.,the learning and memory ability decline.The results of pathological observation indicate that the pyramidal neurons in the hippocampal CA1 region of the above three groups of mice are relatively loose and disordered,some neurons show swelling and deformation,shrinkage or vacuolar lesion,and Nissl substance is reduced.Especially,in the FA+DIDP group,a large number of neurons are even lost in the hippocampal CA1 area,and a large number of neurons show cytoplasmic condensation,hyperchromia,and the corresponding Nissl substance is decreased.T and?-E2 detection of brain tissue show a decline in the content of?-E2 for the mice with decline of learning and memory ability,however,for the mice with administration of 17?-estradiol?17?-E2?,the content of?-E2 increases and the learning and memory ability is improved,this indicate that?-E2 is related to learning and memory ability;oxidative stress indicators detection of brain tissue homogenate show that reactive oxygen species?ROS?,malondialdehyde?MDA?and 8-hydroxy-2-deoxyguanosine?8-OH-dG?contents increase significantly,but the content of glutathione?GSH?obviously decrease,these further suggest that the levels of oxidative stress of brain tissue are elevated.Evaluation of brain tissue caspase-3 and NF-?B show an increase in the levels of inflammation and apoptosis.The detection of cAMP response element binding protein?p-CREB?and brain-derived neurotrophic factor?BDNF?phosphorylation in brain tissue indicates decrease of these two indicators,indicates a decrease in BDNF-mediated protection.Vitamin E(100 mg·kg^-1·d^-1)reduces the oxidative damage caused by DIDP and FA in mouse brain by reducing the level of oxidative stress.17?-E2(100?g·kg^-1)promotes the growth of hippocampal neurons through its neuroprotective effect,which further improves the learning and memory ability of mice.The above data shows that:15 mg·kg^-1·d^-1 DIDP,150 mg·kg^-1·d^-1 DIDP,1 mg·m^-3 FA+15 mg·kg^-1·d^-1 DIDP can cause brain damage and decrease learning and memory ability in mice;exposure to DIDP can further increase brain damage and learning and memory impairment in mice which caused by FA;however,Vitamin E or 17?-E2 can be used to reduce these adverse reactions.