Association Between Urinary Phthalate Metabolites And Hyperuricemia In US Adults

Background:Phthalates are a class of environmental endocrine disruptors,comprising numerous compounds,and are among the most widely used plasticizers.It has been reported that metabolites of phthalates can be detected in the urine of 89%to 98%of the US population.The main impact of phthalates on human health is chronic toxicity,primarily affecting the reproductive systems of both males and females,as well as embryonic development and the endocrine system.Research on the effects of phthalates on the reproductive systems and embryonic development is more extensive,while studies on their association with endocrine disorders are relatively limited.Hyperuricemia,as an endocrine disorder,can lead to various serious complications,such as gout,chronic arthritis,joint deformities,chronic interstitial nephritis,and uric acid nephrolithiasis.It may also contribute to insulin resistance,atherosclerosis,hypertension,myocardial infarction,and other diseases.Animal studies have shown that mice fed a diet containing phthalates exhibited significantly higher levels of serum uric acid compared to the control group.However,to date,no epidemiological study has confirmed a direct correlation between metabolites of phthalates and hyperuricemia,emphasizing the need for a more profound understanding of their relationship.Objective:To analyze the levels of phthalate metabolites in the urine of adults from the general population in the United States,as well as the prevalence of hyperuricemia.Additionally,to examine the linear and non-linear associations between phthalate metabolites in urine and hyperuricemia in adults,providing a scientific basis for further investigating the link between phthalates and hyperuricemia.Methods:The National Health and Nutrition Examination Survey（NHANES）is an ongoing cross-sectional survey conducted by the Centers for Disease Control and Prevention（CDC）in the United States.It aims to gather information on the health and nutrition of the U.S.population.Since 1999,NHANES has been conducted every two years,utilizing a stratified,multistage sampling design to represent the general population.For our study,we utilized data from seven survey cycles:2005-2006,2007-2008,2009-2010,2011-2012,2013-2014,2015-2016,and 2017-2018.A total of 8,816 adults were included in the study after applying inclusion and exclusion criteria.In our study,the independent variable of interest was phthalate metabolites.We categorized the creatinine-adjusted phthalate metabolites into quartiles(Q1:<P₂₅,Q2:P₂₅≤Q2<P₅₀,Q3:P₅₀≤Q3<P₇₅,Q4:≥P₇₅)as ordinal variables.The outcome variable,hyperuricemia,was defined using serum uric acid levels.Hyperuricemia was defined as serum uric acid concentration≥7.0 mg/d L（416 umol/L）for males and≥6.0 mg/d L（357 umol/L）for females.The association between phthalate metabolites in urine and hyperuricemia was analyzed using unconditional logistic regression.Stratified analyses were performed based on gender（males and females）and age（<45 years and≥45 years）.To account for the potential influence of kidney function impairment on elevated uric acid levels,sensitivity analyses were conducted after excluding individuals with kidney function impairment.Furthermore,it is known that uric acid levels above 6.8mg/d L can lead to the formation and aggregation of uric acid crystals in vitro at 37°C and p H7.4.Therefore,sensitivity analyses were also performed by modifying the diagnostic criteria to 6.8 mg/d L.The number of knots for restricted cubic spline（RCS）analysis,which assessed the dose-response relationship between phthalate metabolites and hyperuricemia,was determined using the Akaike information criterion（AIC）after excluding samples beyond the median±1.5 times the interquartile range.Finally,the contribution of each phthalate metabolite to the overall effect was evaluated using weighted quantile sum（WQS）regression.Results:1.The study included a total of 8,816 participants,comprising 4,353 males（49.38%）and4,463 females（50.62%）.The mean age was 49.17±17.49 years.Among the entire population,1,794 individuals were diagnosed with hyperuricemia,resulting in a prevalence rate of20.35%.Significant differences（P<0.05）were observed between the hyperuricemia and non-hyperuricemia groups regarding gender,age,race,waist circumference,diabetes,hypertension,dyslipidemia,smoking status,physical activity,estimated glomerular filtration rate（e GFR）,total cholesterol（TC）,high-density lipoprotein cholesterol（HDL-C）,total calcium,and renal damage.2.After adjusting for gender,age,race/ethnicity,poverty-income ratio,waist circumference,smoking,alcohol consumption,seafood intake,physical activity,e GFR,TC,HDL-C,phosphorus,total calcium,urinary creatinine,diabetes,hypertension,and dyslipidemia,the odds ratios（ORs）with 95%confidence intervals（CIs）for the second quartile（Q2）of phthalate metabolites Mi BP,MEHP,MCOP,ΣBBP,andΣhigh MWP,compared to the lowest quartile（Q1）,were 1.34（1.13-1.58）,1.34（1.13-1.58）,1.12（0.94-1.32）,1.22（1.05-1.43）,and 1.08（0.94-1.25）,respectively（P<0.05）.For MCOP,the highest quartile（Q4）compared to Q1 showed a positive correlation with hyperuricemia,with an OR of 1.21（95%CI:1.01-1.46,P<0.05）.Moreover,the OR and 95%CI forΣhigh MWP（Q3 vs Q1）were 1.43（1.22-1.66）.Except for MEHP,all other factors showed a positive correlation with uric acidemia.3.In gender-stratified analysis,the associations between Mi BP,MEHP,MCOP,Σhigh MWP,and hyperuricemia were statistically significant in males,while the associations between MEHP,ΣBBP,Σhigh MWP,and hyperuricemia were statistically significant in females.Among individuals below the age of 45,Mi BP,MEHP,MCOP,ΣBBP,andΣhigh MWP showed significant associations with hyperuricemia,whereas among individuals aged 45 and above,only MCOP,MCNP,MEHP,andΣHigh MWP had statistically significant ORs.4.Sensitivity analysis showed consistent associations between Mi BP,MEHP,MCOP,ΣBBP,Σhigh MWP,and hyperuricemia compared to the general population.5.The results of restricted cubic spline analysis indicated a positive non-linear dose-response relationship between Mi BP,MCOP,ΣBBP,Σhigh MWP,and hyperuricemia(P_nonlinear<0.05),while MEHP showed a negative non-linear dose-response relationship with hyperuricemia(P_nonlinear<0.05).6.The results of weighted quantile sum regression showed that the top five phthalate metabolites ranked by weight were 0.259（Mi BP）,0.169（MBz P）,0.149（Σhigh MWP）,0.128（MCOP）,and 0.090（ΣBBP）,with a total weight close to 0.8.Except for MBz P,all others were identified as risk factors in our study.Conclusion:There is a non-linear positive correlation between urinary Mi BP,MCOP,ΣBBP,andΣhigh MWP levels and hyperuricemia in the adult population of the United States.On the other hand,urinary MEHP levels show a non-linear negative correlation with hyperuricemia.Among phthalate metabolites,Mi BP,Σhigh MWP,MCOP,andΣBBP contribute the most to the development of hyperuricemia.