The Effect Of Bisphenol A (bpa) On Male Reproductive Function And Mechanism Is Discussed In This Paper

Bisphenol A(BPA), the environmental estrogen, is an important chemical rawmaterial. Because of its widespread presence, humans exposure to BPA is thought tobe ubiquitous. BPA exhibits both weak estrogenic and strong antiandrogenic effects.BPA has been reported to affect the male reproductive system. However, studies ofthe BPA effect on human male reproductive system and related mechanisms are verylimited. In the present study, we investigated the adverse impacts BPA on human malereproduction, identified the male reproductive toxic effects on wistar rats, exploredthe potential mechanism, provided the epidemiology evidence and scientific evidenceon reproductive toxicity of BPA.OBJECTIVETo investigate the adverse impacts BPA on male reproduction, explore thepotential mechanism, provide the new idea of BPA male reproductive toxicity andmechanism.1.To investigate the effects of BPA on human male reproduction, including theeffects on semen quality, serum sex hormones levels and sexual function.2.To evaluate the toxic effects of BPA on reproduction of male wistar rats,including the effects on the reproductive system, semen quality and the primary malesex hormones testosterone (T) and follicle stimulating hormone(FSH).3.To explore the possible mechanism in BPA effect on male reproduction byinvestigating the impacts of BPA on androgen receptor(AR), follicle stimulatinghormone receptor(FSHR), and signaling pathway related genes including Src,ERK1/2and CREB.METHODSEpidemiological study:543male workers were involved in the present study. Allworkers were investigated with the same structured questionnaire. The questionnaireincluded general demographic characteristics, history of disease and medication history, general lifestyle habits, sexual life history．The urine, semen and peripheralblood samples from all of the objects were collected. The levels of urine BPA weremeasured using high-performance liquid chromatography (HPLC). The semenqualities were analyzed by the Computer Assisted Sperm Anyalysis (CASA) system,while the sperm morphology were examined by Papanicolaou staining. Serum folliclestimulating hormone (FSH), prolactin (PRL), total testosterone (T) and estradiol (E2)were measured by radioimmunoassay. Free testosterone (FT), Inhibin B (INB),Sexhormone binding globulin (SHBG) and androstenedione (AD) were measured byenzyme-linked immunosorbent assay (ELISA). Data analysis was performed usingSPSS version16.0. The main statistical methods included t-test,chi-square test, trendchi-square test, Pearson correlation analysis,Spearman rank correlation analysis,multiple linear regression analysis.Animal experimental study: Male Wistar rats (200±20g) were randomly dividedinto four groups according to body weight. Rats of each group were administratedBPA by gavage at fixed times every day for4weeks, at the dose of0,50,100and200mg/kg body weight, respectively. The reproductive organs and serum samples, spermspecimens from left epididymis were collected after all rats were executed.killed．Morphological changes of rats reproductive organs were observed under lightmicroscope after HE staining, Sperm counts, sperm motility and sperm vitality wereanalyzed by CASA system, sperm malformation rate were examined by Papanicolaoustaining. Serum total testosterone(T) and follicle stimulating hormone(FSH)concentrations were measured by radioimmunoassay. Real-time PCR and westernblot methods were applied to detect AR、FSHR、Src、ERK1/2、CREB gene and proteinexpression levels in rats testis. Data analysis was performed using SPSS version16.0.The main statistical methods included ANOVA, Dunnet-t test and chi-square test.RESULTSEpidemiological study1.Dose-response associations were observed between urine BPA concentrationand sperm concentration, sperm count, sperm total vitality, sperm motility. After adjustment for potential confounders using linear regression, increasing urine BPAconcentration was statistically associated with decreased spermconcentration,decreased total sperm count, decreased sperm vitality and decreasedsperm motility.2. Dose-response associations were observed between urine BPA concentrationand FT, AD, SHBG, PRL, FSH levels. After adjustment for potential confoundersusing linear regression, increasing urine BPA concentration was statisticallyassociated with decreased FT, AD, FSH level and increased SHBG, PRL, E2level.3. Dose-response associations were observed between urine BPA concentrationand all domains of decreased male sexual function. After adjustment for potentialconfounders using linear regression, increasing urine BPA concentration wasstatistically associated with decreased male sexual function in all domains.Animal experimental study1. Significantly differences were observed in body weight gains and bodyweight after BPA treatment in different groups. The body weight gains in200mg/kggroup was significantly lower than that in control group. Significantly differenceswere observed in organ indexes of seminal vesicle, prostate, testis and epididymisamong all groups. The testis index, seminal vesicle index and prostate index in100mg/kg group or200mg/kg group were significantly lower than those in controlgroup. In200mg/kg group, the epididymis index was also lower than that in controlgroup.2. There were significantly differences in sperm concentration, sperm motility,sperm vitality and sperm malformation rate among all groups. The sperm motility andsperm vitality were significantly higher in100mg/kg or200mg/kg groups than thosein control group. The sperm concentration was significantly higher in200mg/kggroup than that in control group.3. There were significantly differences in serum T and FSH levels among allgroups. Compared with control group, the serum T level was significantly decreasedin100mg/kg or200mg/kg groups; while the FSH level was significantly increased in200mg/kg group. There were significantly differences in AR mRNA and protein expression levels among all groups. Compared with control group, the AR mRNAand protein expression levels were significantly decreased in100mg/kg or200mg/kggroups. There were significantly differences in FSHR mRNA and protein expressionlevels among all groups. Compared with control group, the FSHR mRNA and proteinexpression levels were significantly decreased in200mg/kg group.4. No differences were observed in Src mRNA, Src and phosphorylated Srcprotein expression levels among all groups. There were no differences in ERK1/2mRNA and protein expression levels among all groups. But there were significantlydifference in phosphorylated ERK1/2protein expression levels among all groups.Compared with control group, the phosphorylated ERK1/2protein expression levelswere significantly decreased in100mg/kg and200mg/kg groups. There were nodifferences in CREB mRNA and protein expression levels among all groups. Butthere were significantly differences in phosphorylated CREB protein expressionlevels among all groups. Compared with control group, the phosphorylated CREBprotein expression levels were significantly decreased in200mg/kg group.CONCLUSIONS1.Increasing of urine BPA concentration has adverse impacts to malereproduction, may result in male lower semen quality, abnormal sex hormones levelsand reduced sexual function.2.Higher doses of BPA have obviously reproductive toxic effects includingdamage male reproductive organs, decrease semen quality and change the level of sexhormones on male wistar rats,3.BPA decreased the protein phosphorylation levels of ERK1/2and CREB. BPAmay have adverse effects on male reproduction via ERK1/2and CREB signalingpathway. But Src may not act as an upstream regulatory gene.