| Objective: As an environmental endocrine disrupter,bisphenol A(BPA)can early initiate pubertal development and promote the gonadal maturation,eventually leading to precocious puberty(PP).There are significantly high levels of BPA in the urine of idiopathic central precocity individuals.However,the precise mechanisms of BPA promoting pubertal development are not clear.Makorin ring finger protein 3(Mkrn3),a key repressor of pubertal initiation,keeps a high expression in the hypothalamus during the prepubertal period,which suppresses KISS 1 and retains the low levels of Gn RH.During the transition of prepuberty to puberty,there is a "cliff-like" decline on the expression of MKRN 3,followed with an obvious upregulation of KISS1,causally the increase of Gn RH and the activation of HPG axis,eventually the onset of puberty.Consequently,MKRN 3 functions as a‘brake’ during the pubertal onset.Nonetheless,which factors,including external and internal,regulate the functions of this brake are ill-defined.Previous studies have proved that BPA could change the hypothalamic Gn RH to initiate puberty via regulating the upstream element of HPG axis,KISS 1.So,it would be an interesting question to ask whether BPA could activate the HPG axis through regulating MKRN 3 to finally onset puberty.This research is going to study the effects of neonatal exposure(PND 1～10)of BPA with different concentrations on the pubertal development and preliminarily explore the underlying mechanisms.Methods: Neonatal SD rats were subcutaneously injected with different concentrations of BPA(solvent,50 μg/kg,500 μg/kg,5mg/kg,50 mg/kg)for 10 consecutive days(one time each day)(PND1,12 hours <injection time < 24 hours),respectively.Then,recorded the opening time of vagina,weight of the whole body,gonads and uterine.In addition,the classical paraffin sectioning technique and HE staining were used to observe the histological structure of ovary and uterine,ELISA was applied to check peripheral serum levels of Gn RH.Furthermore,the hypothalamic MKRN 3 expression were identified with RT-q PCR and Western blotting.Results: Compared with the control group: 1)the hypothalamic m RNA expression of Mkrn 3 were extremely downregulated after BPA administration;2)the MKRN 3 level also decreased correspondingly;3)BPA significantly improved the opening time of vaginal;4)BPA administration obviously promoted the presentation of first oestrus;5)there were no apparent significance of hormone Gn RH between BPA-treated groups and control group;6)The comparison of gonad and uterus weight to body weight ratio in rats showed that early BPA treatment had little effect on female gonad weight to body weight ratio,and only a few groups of ovary and uterus values changed,but the male gonad was significantly affected.Compared with the solvent group and the control group,male testicular body weight after BPA treatment showed a decreased ratio.HE staining section results showed that there was no significant difference in the histological structure of uterus and ovary in females treated with BPA compared with the control group;7)BPA administration decreased the neonatal weight,especially in high concentration groups.Interestingly,obvious sexual bias was found that there were significant decline in male rats,but not in female individuals.Conclusions: 1)Early BPA exposure in newborn SD rats down-regulated the expression of MKRN 3 in hypothalamus;2)Early BPA exposure in newborn SD rats resulted in earlier vaginal opening time and first estrous cycle,with a certain concentration trend.3)Early BPA exposure in newborn SD rats mainly affected the development of reproductive organs at PND 18 and the weight of rats before they leave their mother,and the weight of male rats was more affected than that of female rats. |
PDF Full Text Request