Association Of Bisphenol A And Its Alternatives Exposure With The Risk Of Hypertension

Bisphenol A(BPA),one of the highest volume industrial compounds in the world,is extensively used in the manufacture of polycarbonate plastics and epoxy resins.However,toxicological experiments and epidemiological studies indicated that,BPA exposure was associated with infertility,adverse pregnancy outcomes,abnormal child behavior,neurodevelopmental disorders,obesity,diabetes,cardiovascular and cerebrovascular diseases.Recent studies have suggested a potential association between BPA exposure and hypertension risk,but the association is still inconsistent.Considering these adverse effects of BPA,bisphenol S(BPS)and bisphenol F(BPF)as the main substitutes of BPA,have been widely used in the production of polycarbonate plastics and epoxy resins.However,some literature indicated similar or even greater hormonal activities of BPS and BPF than that of BPA.Moreover,significant associations of BPS and BPF exposure with oxidative stress,glucose and lipid metabolism disorder,and heart rate variability have been found in animal experiments and epidemiologic studies.However,it is not clear whether exposure to BPS and BPF is associated with the risk of hypertension.General population are commonly simultaneously exposed to multiple environmental contaminants,which might have interaction effects.Toxic metals such as cadmium and arsenic not only are related with cardiovascular diseases but have endocrine-disrupting effects.Meanwhile,essential trace elements such as selenium and manganese help to maintain the balance of the redox system and the function of vascular endothelial cells.Therefore,metals exposure might strengthen or alleviate bisphenols’ effects on hypertension.Although the exact mechanism of how bisphenols affect blood pressure levels is unknown,estrogenic effects,oxidative stress,and endothelial dysfunction are presumed to play critical roles.Hence,polymorphisms of estrogen receptors,oxidative stress-related and vascular endothelial-related genes might modify the association of BPA and its alternatives exposure with hypertension risk.Accordingly,we comprehensively analyzed the effects of BPA and its alternatives exposure,metals and bisphenols co-exposure,and gene-environment interation on hypertension risk.Part Ⅰ Association of bisphenol A and its alternatives exposure with the risk of hypertensionObjective: The study aimed to evaluate the association of environmental exposure to BPA and its alternatives with hypertension risk and blood pressure levels.Methods: Using the cross-sectional design,we conducted the study in 1437 eligible participants.Urinary BPA and its alternatives’ concentrations were utilized to reflecte individuals’ environmental exposure levels.Regression models and restricted cubic spline models were applied to assess the potential associations and dose-response relationships.Results: In the multi-covariate adjusted models,compared with the reference group of BPA,individuals in the high exposure group had an adjusted odds ratio(OR)of 1.45(95% CI: 1.07,1.97)for hypertension,and had a 3.12(95% CI: 0.79,5.44)and 1.73(95% CI: 0.34,3.12)mm Hg higher systolic and diastolic blood pressure(SBP and DBP),respectively.Compared with the reference group of BPS,individuals in the high exposure group had an adjusted OR of 1.45(95% CI: 1.07,1.97)for hypertension,and had a 3.65(95% CI: 1.26,6.04)and 1.62(95% CI: 0.19,3.05)mm Hg increased SBP and DBP levels,respectively.No significant associations of BPF exposure with hypertension risk and blood pressure levels were found.Restricted cubic spline models shown that the doseresponse curves of BPA exposure with hypertension risk and blood pressure levels were inverted “U” shaped,while the curves of BPS were monotonic.Furthermore,significant associations of BPA and BPS exposure with hypertension risk were more pronounced in males,while the association of BPF was more remarkable in females.Conclusions: BPA and BPS exposure both were associated with increased hypertension risk and blood pressure levels,but with different dose-response relationships.Part Ⅱ Association of co-exposure to metals,bisphenol A and its alternatives with the risk of hypertensionObjective: The study was conducted to investigate the associations of co-exposure to metals,bisphenol A and its alternatives with hypertension risk and blood pressure levels.Methods: We conducted a cross-sectional study in 1224 eligible participants.Nineteen metals and bisphenols’ concentrations in urine were used as biomarkers to evaluate individuals’ internal exposure levels.Single pollutant and multi-pollutant models were utilized to investigate the potential associations.Results: In single pollutant models,iron,arsenic,BPA and BPS exposure were positively associated with the risk of hypertension and DBP levels.Iron,BPA and BPS exposure were positively associated with SBP levels while selenium exposure was negatively associated with SBP levels.In multi-pollutant models,we found that high selenium exposure strengthened iron and BPA’s adverse effects on SBP levels.Conclusions: Iron,arsenic,BPA and BPS exposure were positively associated with the risk of hypertension.Meanwhile,despite selenium exposure was negatively associated with SBP levels,high selenium exposure strengthened iron and BPA’s adverse effects on SBP levels.Part Ⅲ Association of bisphenol A and its alternatives exposure,candidate gene polymorphisms and their interactions with the risk of hypertensionObjective: The study was conducted to investigate the association of BPA and its alternatives exposure,candidate gene polymorphisms,and their interactions with the risk of hypertension.Methods: We conducted a case-control study in 439 pairs of hypertensive cases and matched healthy controls.The associations between genetic polymorphisms of 31 SNPs in nine genes and hypertension risk were analyzed in logistic regression models.The interaction effects between bisphenols exposure and genetic polymorphsims were investigated in multiplicative and additive interaction models,as well as in multifactor dimensionality reduction models.Results: Among the 31 SNPs,ESR1 rs2234693,CAT rs551929,MMP2 rs243865 and rs243866,gene haplotype of ESR1 and MMP2 were significantly associated with the risk of hypertension.In multiplicative interaction models,the interaction effect between CAT rs4755374 and BPA exposure was significant before correction for multiple tests.In additive interaction models,under BPA exposure,individuals carrying ESR1 rs2234693,VEGFA rs2010963,MMP2 rs243865 and rs243866 dominent genotypes had higher hypertension risk.In multifactor dimensionality reduction model,CAT rs10488736 CC genotype had synergistic effect with BPA exposure.Conclusions: Genetic polymorphisms in ESR1,CAT and MMP2 might modify BPA’s effects on hypertension risk.