Study On The Relationship Between Exposure Level Of Bisphenols And Infertility And Its Effect On Pregnancy Outcome Of IVF-ET

Objective: A woman of childbearing age who has not used any contraception and has been sexually active for more than 12 months without a successful pregnancy is said to be infertile.Worldwide,about 8-12% of couples of childbearing age suffer from infertility.The incidence of infertility in China has been increasing year by year due to factors such as economic level,poor lifestyle and environmental pollution.The causes of female infertility are complex,and the etiology varies with changes in social and environmental factors at different times.The most important factor affecting fertility is a woman’s age at conception,but recent studies have shown that factors such as obesity,smoking,late nights,alcohol consumption,caffeine intake,and even social and work stress can all have adverse effects on the female reproductive system.Research on the etiology and influencing factors of infertility at home and abroad has made great progress,but there are still many mechanisms and pathogenetic factors that have not been clarified,so it is necessary to study the etiological components of infertility and its related risk factors to provide a theoretical basis for the early prevention of infertility.Recent studies suggest that environmental factors play an important role in human reproductive effects,and in particular,the effects of environmental endocrine disruptor exposure on reproductive health have received attention.Bisphenol A(BPA)is the most common environmental endocrine disruptor,mainly used in the production of epoxy resins and polycarbonates,which are used in a large number of household plastic products,including drinking water bottles,baby bottles,and food packaging.The chemical structure of BPA is similar to that of 17β-estradiol(E2),which can exert weak estrogenic effects by binding to estrogen receptors.BPA can affect the synthesis,secretion and metabolism of sex hormones either by affecting hypothalamic-pituitary-ovarian axis function or by directly acting on the ovaries to interfere with key enzymes for steroid synthesis.However,current studies on the reproductive effects of BPA are mainly of laboratory origin,and epidemiological studies on the association between BPA and female sex hormone levels are relatively few and inconsistent.Oxidative stress may be the "initiator" of oocyte phenotypic aging and female reproductive abnormalities,and infertile women usually have elevated levels of oxidative stress.8-hydroxy-2’-deoxyguanosine(8-OHd G)is a major product of oxidative DNA damage and is commonly used as a marker to detect oxidative DNA damage.It is often used as a marker to detect oxidative DNA damage.There is a lack of literature on whether increased oxidative damage in infertile women is associated with bisphenol compound exposure levels.In light of the negative effects of BPA exposure on human health,manufacturers have begun to look for industrial alternatives to its raw materials.Bisphenol F(BPF)and bisphenol S(BPS)are structurally similar to BPA and are considered to be "safe" alternatives to BPA.However,some recent experimenal researches have found that they have similar estrogenic and anti-androgenic effects to BPA,suggesting that BPF and BPS exposure may be associated with reduced fertility in women.However,few relevant population studies have been reported.With infertility rates rising every year,scientists have been working hard to find the right treatment for each infertile couple.Among them,in vitro fertilization and embryo transfer(IVF-ET)is one of the more effective treatments available.However,even with the use of morphologically normal embryos for transfer,the pregnancy success rate after IVF-ET treatment is still relatively low,only about 40%-50%.Numerous experimenal researches suggest that BPA may inhibit the production of mature sinus follicles and affect the morphology and function of the ovaries and uterus,leading to infertility,spontaneous abortion,preterm delivery and other adverse pregnancy outcomes.Several epidemiological investigations have evaluated the association between BPA exposure and IVF outcomes both domestically and internationally,but the findings are inconsistent.According to the developmental origins of health and disease theory(DOHa D theory),disturbances to the external environment during early human development may permanently alter the body’s own structure,with long-term effects on the health status of children and adults.There are reports in the literature that bisphenol compound exposure may be associated with an increased risk of adverse birth outcomes such as fetal growth restriction and low birth weight.However,previous studies have focused more on the effects of bisphenol compound exposure during pregnancy on neonatal physical development,and the effects of pre-pregnancy bisphenol compound exposure on neonatal physical development have been rarely reported.Therefore,this study will examine the exposure levels of bisphenolic compounds(BPA,BPF,BPS)in infertile women before ART and follow up the effects on successful pregnancy and birth outcomes to identify the critical window for the effects of bisphenolic compound exposure on IVF-ET outcomes and to provide new ideas for further research on interventions to avoid adverse birth outcomes.Therefore,in this study,by collecting infertile women from a fertility center in Shenyang as the study population,we first obtained relevant information in the form of a questionnaire to explore the etiological composition of infertility and its associated risk factors in the region.At the same time,urinary bisphenol compounds(BPA,BPF,BPS)were measured in the infertile population to clarify the concentration of bisphenol compound exposure,the source of exposure,and the relationship with sex hormones and8-OHd G in the infertile population.And further explore the association of bisphenol compound exposure on clinical outcomes of IVF-ET and neonatal birth outcomes in infertile women.Methods: 1.A cross-sectional study was conducted to collect infertile women in the medical department of a fertility center in Shenyang,and information on basic information,lifestyle behavior and meal frequency of the infertile population was collected through a face-to-face questionnaire.According to the diagnostic criteria of infertility,i.e.women of childbearing age without any contraceptive measures and having normal sexual intercourse for more than 12 months without successful pregnancy.The etiological components of infertility and its associated risk factors were studied.2.Mid-stream urine was collected in the fasting state on the day the study subjects came to the hospital to establish their records,and the concentrations of bisphenols were determined by ultra performance liquid chromatography-triple quadrupole mass spectrometry.Urinary 8-hydroxydeoxyguanosine concentrations were measured by enzyme-linked immunosorbent assay.The levels of bisphenol compound exposure and its association with sex hormone levels in infertile women were studied in conjunction with clinically relevant sex hormone test levels.3.The data related to the controlled superovulation process and clinical pregnancy outcomes of the study subjects were collected by reviewing the medical record system.The pregnancy-related test results,pregnancy complications,date of delivery,week of gestation,and mode of delivery of the study subjects were collected by telephone follow-up or access to the medical record system after delivery.To analyze the association between bisphenol compound exposure and clinical outcomes of IVF-ET in infertile women;and further to analyze the association between bisphenol compound exposure and neonatal physical development in singleton live birth women.Results:1.The final 483 infertile women were included in this study.The order of infertility etiology and composition ratio were,tubal factor infertility(43.9%),polycystic ovary syndrome(21.7%),male infertility(15.7%),hypovarian reserve function(10.4%),unexplained infertility(5.0%),mixed factors(1.7%)and endometriosis(1.7%).Independent risk factors for the prevalence of tubal factor infertility were history of tubal surgery(OR=6.648,95% CI: 2.741,16.123).Independent risk factors for polycystic ovary syndrome were passive smoking(OR=2.137,95% CI: 1.124,4.063),high Body Mass Index(BMI)(OR=1.087,95% CI: 1.002,1.180),hypercholesterolemia(OR=1.536,95% CI: 1.016,2.323)and hypertriglyceridemia(OR=1.536,95% CI: 1.016,2.323)and hypertriglycerides(OR=1.583,95% CI: 0.984,2.547,P=0.058).Independent risk factors for diminished ovarian reserve function were history of tubal surgery(OR=6.386,95%CI: 1.703,23.947),age(OR=1.204,95% CI: 1.087,1.335)and low free triiodothyronine(OR=0.508,95% CI: 0.268,0.963).Regular exercise was an protective factor for tubal factor infertility and diminished ovarian reserve function(OR=0.519,95% CI:0.299,0.901,OR=0.136,95% CI: 0.049,0.373).2.One hundred and thirty-five infertile women were tested for bisphenols,and the detection rates of urinary BPA,BPF,and BPS were 100%,99.25%,and 61.48%,respectively.The median uncorrected and specific gravity-corrected(SG-)BPA concentrations in urine were 4.40 μg/L and 4.83 μg/L,respectively.The median uncorrected and SG-BPF concentrations in urine were 2.83 μg/L and 3.22 μg/L,respectively.The median uncorrected and SG-BPS concentrations in urine were 0.23μg/L and 0.24 μg/L,respectively.When not adjusted for other factors,serum follicle-stimulating hormone(FSH)was reduced by 1.214 m IU/m L(95% CI:-2.334,-0.093)in the urinary BPF medium concentration group compared with the low concentration reference group.Serum testosterone was reduced by 0.080 ng/m L(95% CI:-0.156,-0.004)in the urinary BPS high concentration group,respectively,compared with the low concentration reference group.In the regression model corrected for covariates,serum FSH was reduced by 0.932 m IU/m L(95% CI:-0.989,0.124,P=0.083)in the urinary BPF medium concentration group compared with the low concentration reference group.Compared with the low concentration reference group,serum T was reduced by0.076 ng/m L(95% CI:-0.150,-0.002)in the urinary BPS high concentration group,respectively.Women who consumed plastic buckets of water and regular take-out had a higher risk of BPA exposure;regular consumption of vegetables was a protective factor for BPA exposure.Folic acid supplementation was a protective factor for BPF exposure.Women who regularly used personal care products had a higher risk of BPS exposure.Both BPF exposures were positively associated with 8-hydroxydeoxyguanosine levels(P<0.05).3.There was a 12.7%(95% CI:-0.237,-0.016)reduction in the rate of quality embryos in the urine specific gravity corrected BPA high concentration group compared to the low concentration group.The fertilization rate was reduced by 7.9%(95% CI:-0.147,-0.011)in the BPS high concentration group after urine specific gravity correction compared to the low concentration group.After correction for covariates,the probability of embryo implantation,clinical pregnancy,and obtaining a live birth were significantly lower in the BPA high concentration group than in the low concentration group;the probability of embryo implantation and obtaining a live birth were significantly lower in the BPF high concentration group than in the low concentration group,and all these differences were statistically significant(P<0.05).there was a synergistic effect of BPF exposure and BMI in live birth outcome,compared with the wasted/normal low concentration BPF group.The overweight/obese high concentration BPF group had the largest risk ratio for reduced live birth(OR=0.231,95% CI: 0.055,0.970).The dose-response relationship between both pre-pregnancy urinary BPA and BPF exposure and neonatal birth weight and parity index were both inverted "U" shaped,with statistically significant differences(P<0.05).Conclusion: 1.Tubal factor infertility was the first cause of infertility in this study,followed by polycystic ovary syndrome.Risk factors for the prevalence of tubal factor infertility were history of tubal surgery;risk factors for polycystic ovary syndrome were passive smoking,high BMI,high triglycerides and cholesterolemia;risk factors for ovarian hypoplasia were history of tubal surgery and low free triiodothyronine.Regular exercise is a protective factor for tubal factor infertility and ovarian reserve hypofunction.2.Infertile women can be commonly exposed to BPA,BPF and BPS in this study.Medium or high levels of BPF and BPS exposure are associated with sex hormone abnormalities in infertile women.High levels of BPA,BPF and BPS exposure can increase oxidative damage in the infertile female organism.The high risk factors for BPA exposure were drinking plastic buckets of water and frequent consumption of take-out,while frequent consumption of vegetables was the protective factor;taking folic acid is a protective factor for BPF exposure;and frequent use of personal care products is a risk factor for BPS exposure.3.Both BPA and BPF exposure can affect embryo implantation and the occurrence of clinical pregnancy and live birth in IVF-ET women.there is an interaction between BPF exposure and BMI in the outcome of IVF-ET live birth in infertile women.There was an inverted "U" shaped dose-response relationship between both pre-pregnancy urinary BPA and BPF exposure and neonatal birth weight and neonatal parity index.