| ObjectivesCurrently,studies on the effects of low-dose fenvalerate exposure on neurobehavioral development and its mechanism are rarely.Here,we aimed to further investigate the effects of pubertal exposure to low-dose fenvalerate on cognitive and behavioral development by building behavioral models through animal experiments,and explore the role of hippocampal thyroid hormone signal.MethodsFirstly,80 mice(40 males and 40 females)were randomly divided into four groups(10 males and 10 females each group,males and females were separated).Our previous studies showed that no signs of toxicity were observed in mice treated with7.5 mg/kg or a higher dose of fenvalerate.Thus,the dose of 5.0 mg/kg,about 1/40LD50 of the fenvalerate,was chosen as high dose in the present study to explore the effects of low-dose exposure.The experimental mice were daily administered with fenvalerate(0.2,1.0,and 5.0 mg/kg,dissolved in corn oil)by gavage from PND28 to PND56.The control mice were orally administered with corn oil by gavage from PND28 to PND56.Open field test was performed on PND57.Elevated plus-maze was performed on PND59.Morris water maze was performed from PND61 to PND66.Another 80 mice(40 males and 40 females,)were randomly divided into four groups(10 males and 10 females each group,males and females were separated).The experimental mice were daily administered with fenvalerate(0.2,1.0,and 5.0 mg/kg,dissolved in corn oil)by gavage from PND28 to PND56.The control mice were orally administered with corn oil by gavage from PND28 to PND56.All mice were sacrificed on PND57.Collected serum samples to measure total thyroxine(TT4)andtotal triiodothyronine(TT3)by Electrochemiluminescence immunoassay(ECLIA).For each dose group,three entire brains separated from three mice were collected for hippocampal CA1 region histopathology by H&E staining.For each dose group,three pairs of entire hippocampi separated from another three mice were collected to evaluate the protein level of hippocampal TRs by immunoblots.ResultsIn the open field test,the duration in center was significantly decreased in female mice exposed to 5.0 mg/kg compared with controls(F=2.965,P<0.05).Correspondingly,the duration in peripheral was significantly increased in female mice exposed to 5.0 mg/kg(F=2.965,P<0.05).In the elevated plus-maze,times in open arms were significantly decreased in females exposed to fenvalerate(F=5.973,P<0.05).In addition,total times in arms were significantly reduced in females treated with 1.0 mg/kg and 5.0 mg/kg fenvalerate(F=3.007,P<0.05).On the contrary,total times entering arms was significantly increased in males exposed to 5.0 mg/kg fenvalerate(F=3.141,P<0.05).In the Morris water maze,escape latency was significantly reduced on the fifth day in fenvalerate-treated female groups(F=3.019,P<0.05).Repeated measurements indicated that escape latency was significantly increased in females exposed to fenvalerate in a dose-dependent manner,and a significant decrease was observed in 5.0 mg/kg fenvalerate.No difference on escaping latency was observed in males(F=0.330,P>0.05).In spatial probe trail on the sixth day,the times of crossing in objective quadrant were markedly reduced in 1.0 mg/kg and 5.0 mg/kg fenvalerate-treated females(F=4.956,P<0.05).Similarly,the time proportion of objective quadrant was significantly decreased in 1.0 mg/kg and 5.0mg/kg fenvalerate-treated females(F=4.781,P<0.05).Histopathology showed that neuronal density was reduced in fenvalerate-exposed mice,accompanying with elevation of scattered shrinking neurons and nuclear pyknosis in hippocampal CA1 region among fenvalerate-treated males and females.Further quantitative analysis showed that the number of neurons was decreased significantly in a dose-dependent manner in all fenvalerate-treated females(F=14.339,P<0.01).In addition,the numberof neurons was significantly reduced only in males exposed to 5.0 mg/kg fenvalerate(F=6.604,P<0.01).To further investigate the effects of pubertal exposure to low-dose fenvalerate on hippocampal thyroid hormone receptor signaling,we found that there was no significant difference on the levels of serum TT4 and TT3 in both males and females(P>0.05).The level of TRα1 protein was significantly downregulated in females exposed to 5.0 mg/kg fenvalerate(P<0.05),which was not different among male groups(P>0.05).Interestingly,the level of TRβ1 protein was downregulated significantly in females exposed to fenvalerate in a dose-dependent manner(P<0.05),while TRβ1 protein level was signifecantly reduced in males exposed to 1.0 mg/kg and 5.0 mg/kg fenvalerate(P<0.05).ConclusionsPubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development in a gender-dependent manner.In addition,pubertal exposure to low-dose fenvalerate causes neuronal damage.The present study shows that pubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development partially through downregulating hippocampal TR signaling. |
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