Estrogen Receptor Signaling Is Involved In Lambda-cyhalothrin-induced Neurodevelopmental Toxicity

Interruptions of the neurodevelopmental process may cause serious and lasting structure and function impairments that result in the neurodevelopmental disorders(NNDs),such as autism spectrum disorder(ASD).The global prevalence of ASD is 1/160,which accounts for 0.3 percent of the global disease burden.Identification of environmental risk factors and the mechanisms affecting neurodevelopment are still the primary task of effective prevention and control of NDDs.Lambda-cyhalothrin(LCT)is a type ? pyrethroid insecticide.It is widely used in the prevention and control of agroforestry pests and public health vectors.Human widely exposed to LCT through multiple routes.LCT is an endocrine disruptor of estrogen and has neurodevelopmental toxicity.However,it is still not clear what molecular mechanisms could be involved in the neurodevelopmental toxicity of LCT.What's role of its estrogen-like activity in the neurodevelopmental toxicity,and how it acts remains to be further explored too.In the present study,mice at postnatal day 5(PND5)were selected.During PND5—PND 13 of the critical period of postnatal brain development,LCT(10 mg/kg,1 mg/kg,and 0.1 mg/kg)was fed by oral gavage once every other day.Results of physiological and behavioral development tests revealed that high dose LCT significantly retarded forelimb grasping and reflexes of rooting(forelimb grasping was delayed by 1 day,rooting by 0.5 day).The study also found that LCT affected the levels of synaptic associated proteins.LCT dose-dependent increased growth-associated protein GAP43 level,and reduced postsynaptic density protein PSD95.This phenomenon of the unbalance changes of synaptic associated proteins was significantly in low dose LCT group of female mice,but only in high dose LCT group of male mice.Then the adolescent OVX mouse model was adopted.After one week of recovery,the circulating estrogen was depleted and LCT was exposed twice.LCT showed obvious estrogen-like activity that significantly reduced the first square time which delayed by OVX,increased the total number of squares crossed which reduced by OVX in the open-field test,and reduced the escape latencies which increased by OVX,increased percent time in correct quadrant which reduced by OVX in Morris water maze tests.However,LCT can disrupt the effect of supplemental circulating estrogen.The immunofluorescence histochemical analysis of the hippocampal PSD95 also revealed consistent results.Finally,the mouse hippocampal neuron HT22 cell line was used to investigate the molecular mechanism of LCT affecting PSD95 expression.In addition to confirming the estrogen-like activity of LCT,the findings indicated that LCT affected the translation of PSD95 via the ERa—PI3K/Akt—4E-BP1 pathway,and affected the synaptic development by disrupting the same pathway activated by estrogen.In conclusion,this study demonstrated the estrogen-like activity and neurodevelopmental toxicity of LCT from animal behavioral function,tissue to cell molecular level.The findings firstly suggested that LCT affected PSD95 protein synthesis through disrupting the ERa—PI3K/Akt—4E-BP1 pathway of estrogen,to affect synaptic development.This study has pioneered a research paradigm that from rapid endocrine disruptive pathways to explore neurodevelopmental toxicity of endocrine disruptors.