Mechanism Of Anxiety Induced By Nonylphenol And Octylphenol Via 5-HT System In Rats

Nonylphenol(NP)and Octylphenol(OP)are typical representatives of alkylphenols,belonging to environmental endocrine disruptors.They are widely found in the environment and can be passed through water sources,food chain via mouth,skin contact,plastic utensils and other ways,entering organisms and has a wide range of adverse effects on organisms,such as reproduction and development,immunotoxicity,and promotion of cancer.The prefrontal cortex(PFC)is the command and control center of the brain,and is mainly involved in advanced functions such as human cognitive and emotional regulation.At present,studies on the toxicity of NP and OP mainly focus on reproductive toxicity and immunotoxicity.There are few reports on the neurotoxicity of NP and OP.Therefore,this study focused on the neurotoxic mechanism of NP and OP and NO(Nonylphenol and Octylphenol,NP,OP combined)on the neurotoxicity of the 5-HT system in the prefrontal cortex.Eighty male Sprague-Dawley rats were randomly divided into 10 groups: negative control group(filling corn oil),low-dose,medium-dose,and high-dose NP groups [30,90,270 mg/(kg·d)],OP groups [40,120,360 mg/(kg·d)],and NO groups [with corresponding NP,OP alone exposures low,medium,or high doses in proportion to the natural environment NP:OP=4: 1 Compounding] The 5-HT metabolic pathways in the prefrontal cortex was studied from the transport,decomposition,and receptor pathways over a 30-day short-term repeated exposure experiment.The biochemical indicators analyzed included 5-HT,Serotonin(5-HT),Monoamine Oxidase A(MAOA),Serotonin Transporter(SERT),Vesicular Monoamine Transporter 2(VAMT2),in prefrontal cortex and Tryptophan hydroxylase-2(TPH-2)in the midbrain of the rats.According the change of biochemical indexes,the mechanism and mechanism of the toxic effects of NP and OP on the 5-HT metabolic network in the prefrontal cortex of the body were explored.The main findings are as follows:(1)General toxic effects of NP,OP,and NO on rats: NP,OP,and NO all produced certain toxic effects on rats,and the abnormal appearance of the rats.At the end of the exposure,the body weight gain of NP and OP exposed to high-dose group was significantly lower(P<0.01),and the NP and OP exposure to high-dose group caused a decrease in food utilization rate(P<0.01);The liver coefficient,kidney coefficient and testis coefficient of rats increased in different degrees after NP all dose exposure(P<0.05,P<0.01,P<0.05).The liver coefficient and kidney coefficient of rats induced by high-dose of OP exposure increased(P<0.05,P<0.05);high-dose of NO group induced rat kidney coefficient increased(P <0.01);(2)The neurobehavioral toxicity of NP,OP and NO in rats: Before exposure,there was no significant difference in the indexes of OFT and EPM between rats in each group(P>0.05).After exposure,the total distances of rats in the NP medium and high dose groups entering the central area were less than those in the control group(P<0.05,P<0.01);the number and time of the high dose group of NP in the central area were significantly less than that of the control group(P<0.05,P<0.05).The time and total distance of central and high-dose group rats were significantly lower in the OP group than in the control group(P<0.05,P<0.05)and he number of times in the central area was significantly less than that of the control group(P<0.05);The time,number,and total distance of rats in the NO high-dose group were significantly less than those in the control group(P<0.05,P<0.05,P<0.05);The time to enter the open arm time(OT),the ratio of time to enter the open arm(OT%),the times to enter the open arm entry(OE)and the ratio of time to enter the open arm(OE%)were also significantly less than the control group(P<0.05 or P<0.01);The NP high dose group entered the closed arm time(CT),the ratio of time to enter the closed arm(CT%)and the ratio of entering the closed arm(CE%)were also significantly more than the control group(P <0.05);The total time entry arms(TNT)of rats in OP medium-dose and high-dose groups were significantly higher than that in the control group(P<0.05);The total number of arms(TNE)OP of highdose group was significantly less than the control group(P<0.05);the OT,OT%,OE and OE% in the high-dose OP group were also significantly less than the control group(P<0.05 or P<0.01);the high-dose OP group CT,CT% and CE% were also significantly higher than those in the control group(P<0.01 or P<0.05).TNT and CT were significantly higher in rats exposed to high-dose NO than in the control group(P<0.05);(3)The toxic effects of NP,OP,and NO on the 5-HT pathway in the prefrontal cortex: The exposure to NP,OP,and NO all caused a significant increase in 5-HT levels(P<0.05 or P<0.01);NP each dose,medium-dose and high-doses of OP and high-doses of NO exposure all caused a significant reduction in the level of MAOA expression(P<0.01);(4)Toxic effects of NP,OP,and NO on the 5-HT decomposition pathway in the prefrontal cortex: NP,OP,and NO doses all caused significant increases in 5-HT expression levels(P<0.05 or P<0.01);NP doses,OP,high doses and high doses of NO exposure all caused a significant decrease in the level of MAOA expression(P<0.01);(5)Toxic effects of NP,OP and NO on 5-HT transport pathway in prefrontal cortex: High doses of NP and OP all caused a decrease in SERT expression(P<0.05 or P<0.01);The highdose and high-dose OP exposures all caused a decrease in VAMT2 expression levels(P<0.05,P<0.01 or P<0.01).The above results showed that NP,OP and NO had different degrees of neurotoxicity in rats;in the prefrontal cortex 5-HT decomposition and translocation pathway,the three doses could reduce the MAOA and SERT,which increased the expression of 5-HT;NP,OP,and NO did not affect TPH-2 levels in the midbrain.In turn,eventually changed the expression level of 5-HT in the prefrontal cortex;thus,it was confirmed that NP,OP and NO could affect 5-HT decomposition,transport,and receptor binding pathways in the prefrontal cortex of the organism,and induced the occurrence of anxiety.