Disrupting Effects Of TBBPA And TCBPA On Thyroid Hormone Signaling And Hypothalamic-pituitary-thyroid Axis In Xenopus Laevis

Tetrabromobisphenol A(TBBPA)and tetrachlorobisphenol A(TCBPA)are halogenated derivatives of bisphenol A(BPA),and widely used as flame retardants for electronic industrials,furniture,plastic,synthetic textile materials and so on.Nowadays,its has been detected in enormous biotic and abiotic samples.Because of TBBPA and TCBPA has a similar structure with thyroid hormone,lots of studies concerned its TH signaling disruption in higher dose.However,studies lack of toxic evaluate about TBBPA and TCBPA in lower even environmentally relevance concentrations and rarely studies applied HPT axis and thyroid hormone targeting organ of model animals to integrate evaluate endocrine disrupting effects of TBBPA.In this work,we detected influence of TBBPA and TCBPA to GH3 cells proliferation,TH-response genes and protein expression.Results show that TBBPA and TCBPA alone promotes cell proliferation slightly.Both chemicals exposed with T3,in lower dose(10 or 100 nmol/L),able to promote TH-response genes expression,but in higher dose(1000 nmol/L)exposure,observed inhibitory effects,curves present biphasic concentration relationships.In in vivo experiments,we exposed juvenile Xenopus laevis TBBPA for 14 days with different dose including environmentally relevance concentrations,recorded body weight change,detected changing of genes expression of HPT axis related and TH-response in liver and brain and histopathology situations.We found that treatment with 1-100 nmol/L TBBPA for 14 days caused inhibitory effects to Xenopus laevis growth,two key genes(trh and xtrhr3)expression of hypothalamus were decreased,pituitary development(pit1,prop1 and lhx3)and hormone secretion(pomc)related genes expression were disordered,histology section showed that the stain of pituitary distal was deep(1 nmol/L TBBPA),whole pituitary size diminished(100 nmol/L TBBPA),follicular colloid reduced and follicular cells height shorten in thyroid gland histology section of juvenile frog.In addition,juvenile frog liver cells enlarged and blood sinus increased.Exposed to 10 or 100 nmol/L TBBPA for 2 days,trb and tgm2 were up-regulated in liver,exposed to 1-100 nmol/L TBBPA for 14 days making trb,tgm2,klf9 or dio2 gene were inhibited,those suggested that TBBPA exposure damaged liver tissue to some degree.Expression change of TH-response genes(trb,th/bzip,tgm2,klf9,mmp13 and dio2)of brain may tell us disrupted on TH signaling.Taking results together,TBBPA disrupted TH signaling of GH3 cells,and caused gene expression disorder and histopathology on HPT axis and TH targeting organ of juvenile Xenopus laevis.Due to higher sensitiveness of xenopus laevis to pollutants,those findings pointed out that TBBPA has potential environmental exposure risks to animals even to human,especially to infants,needed to control TBBPA production and usage more strictly in case of excessive pollution created disruption to organism endocrine system.