Perturbation of serum metabolome in relation to type 2 diabetes mellitus and urinary levels of phthalate metabolites and bisphenols.

BACKGROUND: Emerging evidence has proved the associations between exposure to phthalates (PAEs) and bisphenols and type 2 diabetes mellitus (T2DM), but the underlying mechanisms for these associations are poorly understood. Metabolomics is a powerful tool to identify differential metabolites and metabolic pathways related to diseases and chemical exposure, which may reveal underlying mechanisms. However, little is known about the roles of metabolism in the associations for PAE and bisphenol exposure with T2DM. OBJECTIVES: The purpose of the study was to investigate the roles of metabolism in the associations for exposure to PAEs and bisphenols with T2DM. METHODS: In this study, 60 T2DM cases and 60 controls, who were matched in age, sex, and body mass index (BMI), were selected from the total study population in our previous studies. Fasting blood and spot urine samples of the volunteers were used for non-targeted metabolomics analysis and determination of phthalate metabolites (mPAEs) and bisphenols, respectively. The associations of urinary mPAEs and bisphenols with screened metabolic biomarkers in metabolomics analysis were analyzed using multiple linear regression models. RESULTS: Based on non-targeted metabolomics, 19 serum metabolic biomarkers were screened between T2DM cases and controls, mostly related to galactose metabolism, amino acid metabolism, and pyrimidine metabolism. More than half of mPAEs were mostly positively associated with up-regulated metabolic biomarkers and negatively associated with down-regulated biomarkers. Different from PAEs, no evident results suggested the roles of metabolism in the associations between bisphenol exposure and T2DM. CONCLUSIONS: Combined with the positive associations between most urinary mPAEs and T2DM in our previous study, our findings indicated that PAE exposure may contribute to T2DM risk through disturbing galactose metabolism, amino acid metabolism (especially arginine biosynthesis and alanine, aspartate and glutamate metabolism), and pyrimidine metabolism.

Serum concentrations of per-/polyfluoroalkyl substances and risk of type 2 diabetes: A case-control study.

Per-/polyfluoroalkyl substances (PFASs), as a group of synthetic chemicals, have been extensively detected in human samples. Recently, epidemiological investigations have reported relationships between exposure to PFASs with risk of type 2 diabetes mellitus (T2DM), but with contradictory results. In this study, a case-control study was conducted to explore associations between serum PFASs and T2DM risk among 252 T2DM cases and 252 controls, who were both diagnosed according to fasting glucose and glycosylated hemoglobin levels. Besides, dose-response relationships were analyzed to clarify effects of PFAS exposure on T2DM risk at different exposure levels. Multivariable logistic regression models showed that compared to the lowest tertiles, elevated odds of T2DM risk were observed in the middle tertiles of perfluorohexane sulfonic acid (PFHxS) [odds ratio (OR): 4.09; 95% confidence interval (CI): 2.23, 7.50; p < 0.01] and perfluorohexane sulfonic acid (PFHpA) (OR: 1.87; 95% CI: 1.06, 3.29; p = 0.03), but not in the highest tertiles, and the restricted cubic spline regression models presented inverted U-shaped dose-response relationships for exposure to PFHxS and PFHpA with T2DM risk, indicating non-monotonic dose-response effect and low-dose effect. Most other PFASs were inversely associated with risk of T2DM, especially at higher exposure levels. Our findings suggested that there are associations between exposure to PFASs and risk of T2DM. Further mechanism research is worthy to be conducted to elucidate the mode of action of different PFASs on T2DM at different exposure levels.

Exposure to organophosphate ester flame retardants and plasticizers during pregnancy: Thyroid endocrine disruption and mediation role of oxidative stress.

Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers in consumer and industrial products. Human exposure to OPEs raises concerns due to their endocrine disruptive potentials. Till now, the effects of OPEs on thyroid hormones (THs) and the mediating role of oxidative stress in pregnant women have not been studied. In this study, prenatal urinary concentrations of OPE metabolites (mOPEs), levels of free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and oxidative stress levels of 8-hydroxy-2-deoxy guanosine (8-OHdG) and malondialdehyde (MDA) were measured in pregnant women (n = 360) from a coastal urbanized region and moderate socioeconomic status. Neonatal TSH in heel blood was also measured in newborns (n = 309). Dibutyl phosphate (DBP) and diphenyl phosphate (DPHP) were extensively detected with a median creatinine-adjusted level of 0.19 µg/g and 0.66 µg/g, respectively, and the median of ∑mOPEs was 1.82 µg/g. DBP and DPHP were included in the analysis. The concentrations of DBP and DPHP were positively associated with either maternal or neonatal TSH levels, while not for maternal FT3 and FT4 levels. Positive associations for maternal and neonatal TSH were particularly observed in girls as stratified by newborn sex suggesting a sex-selective difference. Furthermore, 8-OHdG, the biomarker of DNA damage, was found to be a major mediator (>60%) for the association between neonatal TSH and DPHP, suggesting that DNA damage is involved in fetal thyroid function disruption. On the other hand, MDA showed a partially suppressing effect (<40%) for the associations between mOPEs and neonatal TSH, which needs further clarification. For maternal TSH, both 8-OHdG and MDA showed moderate mediating effects while the direct effects of mOPEs on maternal TSH also contributed. These results suggest thyroid disrupting effects of OPE exposure on mothers and fetuses during pregnancy and the potential influence mediated by the oxidative stresses of DNA damage and lipid peroxidation.

Association between urinary organophosphate flame retardant diesters and steroid hormones: A metabolomic study on type 2 diabetes mellitus cases and controls.

Metabolomic analysis was conducted by collecting urine samples from 128 participants in diagnose of type 2 diabetes mellitus (T2DM) and 105 volunteers in healthy condition, in order to identify biomarkers of experimental populations. The urinary concentrations of organophosphate flame retardant (OPFR) diesters were determined and linear regression model was used to find associations between OPFR diesters and the identified biomarkers. The urinary concentrations of OPFR diesters ranged from 0.17-779 µg/g creatinine. Diphenyl phosphate (DPHP) was detected with the highest frequency of 97% at a median level of 1.21 µg/g, and bis(1-chloro-2-propyl) phosphate (BCIPP) dominated the highest median level at 4.24 µg/g with a detection frequency of 94.4%. As compared with the control, the urinary median concentrations of bis(2-butoxyethyl) phosphate (BBOEP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and DPHP were 2.76, 2.48, and 1.46 times higher in people with T2DM, respectively. Urinary metabolomic data revealed that steroid synthesis was the most significantly altered metabolic pathway between the case and control population. Two biomarkers of cortisol and cortisone that play an important role in steroid hormone regulation were quantified. The linear regression model indicated that per-quartile range increase in the concentrations of each OPFR diester was associated 18%-41% increase in the concentrations of cortisol and cortisone, which may impact energy metabolism linked with T2DM. To our knowledge, this study for the first time reported the altered levels of steroid hormones associated with urinary OPFR diesters.

Phthalate exposure and semen quality in infertile male population from Tianjin, China: Associations and potential mediation by reproductive hormones.

Global decline in male fertility and their associations with ubiquitous exposure of phthalates (PAEs) have raised public concerns. However, the current epidemiological data are limited and controversial. Hence, we investigated possible associations between PAE exposure and male infertility. Eleven phthalate metabolites (mPAEs) were determined in urine and serum samples collected from eighty-eight males diagnosed with infertility from Tianjin, China. The median serum levels of mPAE were n.d. -3.63 ng/mL, which were 1-2 orders of magnitude lower than the urinary levels of n.d. -192 ng/mL. Negative associations were identified between urinary follicle-stimulating hormone (FSH) and MiBP and serum MCMHP, as well as testosterone (T) and luteinizing hormone (LH) and the molar concentrations of ∑mPAE, while positive association was found between T and the serum molar concentrations of ∑mDEHP. Positive associations were found between the molar concentrations of serum ∑mPAE and sperm concentration, sperm motility rate, and progressive motility, between mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) and semen volume and total sperm number, and between MCMHP and progressive motility, while negative association was found between mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) and progressive motility. Moreover, FSH was found to mediate the association between serum concentrations of MCMHP and progressive motility (mediation ratio = 41.6%), and LH to mediate the associations between serum concentrations of ∑mPAE and sperm concentration (mediation ratio = 45.7%) and sperm motility rate (mediation ratio = 29.0%). These results also suggested that serum levels of mPAE are a good predictor for male infertility. Further efforts need to be made on toxicological studies to systematically elaborate the internal mechanisms.

Distribution of novel and legacy per-/polyfluoroalkyl substances in serum and its associations with two glycemic biomarkers among Chinese adult men and women with normal blood glucose levels.

In recent years, the occurrence of novel per-/polyfluoroalkyl substances (PFASs) such as polyfluoroalkyl ether sulfonates (PFAESs) in human samples have aroused attention due to the change in PFASs production profile, however, the data are still lacking. Furthermore, epidemiological studies have examined the associations of PFAS exposure with glucose homeostasis, but with inconsistent results. Therefore, in this study, fasting serum samples from 252 participants with an age range from 19 to 87 years old were collected in Tianjin, China. A total of 21 target PFASs were determined to analyze the levels and distribution of novel and legacy PFASs in serum and to further evaluate the cross-sectional associations of serum PFAS concentrations with two glycemic biomarkers (i.e., fasting glucose and glycated hemoglobin (HbA1c)). 6:2 chlorinated PFAES (6:2 Cl-PFAES) and trifluoroacetic acid (TFA) were widely detected novel PFASs (greater than90%) with relatively high median concentrations (8.64 ng/mL and 8.46 ng/mL, respectively), which were second only to the two dominant legacy PFASs, i.e., perfluorooctanoic acid (PFOA, 14.83 ng/mL) and perfluorooctane sulfonic acid (14.24 ng/mL). The percentage contributions to the total known PFASs were separately 17.6% and 17.2% for 6:2 Cl-PFAES and TFA. The levels of 6:2 Cl-PFAES were significantly correlated with age and BMI, and the concentrations of TFA were also significantly correlated with age. Furthermore, 1% increase in serum PFOA and perfluorononanoic acid (PFNA) was separately significantly associated with 0.018% [95% confidence interval (CI): 0.004%, 0.033%] and 0.022% (95% CI: 0.007%, 0.037%) increment in fasting glucose levels. Similarly, 1% increase in serum perfluorohexanoic acid, PFNA, and perfluorohexane sulfonic acid was significantly associated with 0.030% (95% CI: 0.010%, 0.051%), 0.018% (95% CI: 0.003%, 0.033%), 0.007% (95% CI: 0.003%, 0.011%) increment in HbA1c levels, respectively. These findings suggested that 6:2 Cl-PFAES and TFA showed greater contributions to PFASs in serum and supported an association of exposure to PFASs with fasting glucose and HbA1c.

Human exposure levels of PAEs in an e-waste recycling area: Get insight into impacts of spatial variation and manipulation mode.

Phthalic acid esters (PAEs) are one important category of additives in plastics, which are ubiquitous products of e-waste recycling areas, where PAEs are released to the environment intensively and higher exposure level is expected for the employees. This study investigated human exposure levels of PAEs in an e-waste recycling area (Ziya Circular Economy Park (ZCEP) in Tianjin, China) with intending to explore the impacts of residence spatial variation and dismantling manipulation mode. We collected 157 urine samples from three sites around ZCEP with different distances from the core dismantling site and urinary phthalate metabolites (mPAEs) concentrations were measured and were compared among these three sites. The exposure levels of PAEs exhibited spatial variation according to the distance from the core dismantling site, and urinary median ∑mPAEs concentrations (389 ng/mL) of the employees in ZCEP were significantly higher than those of residents in Ziya town (285 ng/mL) and the downtown of Jinghai district (207 ng/mL) (p < 0.05). Moreover, PAEs exposure levels were significantly affected by the manipulation modes in the e-waste recycling area and the urinary median ∑mPAEs concentrations in the employees of family workshops (401 ng/mL) were significantly higher than those in plants with centralized management (298 ng/mL). There were obvious differences on the urinary median mPAEs concentrations between subgroups based on age, BMI, and sex; however, no significant statistical associations were found between PAEs exposure levels and these socio-demographic indices (p > 0.05). Besides, there was no correlation between exposure levels of different PAEs and their physicochemical parameters like the logKow (p > 0.05).

Promoting differentiation and lipid metabolism are the primary effects for DINP exposure on 3T3-L1 preadipocytes.

Diisononyl phthalate (DINP) is a high-molecular-weight phthalate, and has been recently introduced as di-(2-ethyl hexyl) phthalate (DEHP) substitute and commonly used in a large variety of plastic items. The fat tissue is an important target for DINP exposure, however, very little is understood about its toxicity and mechanism(s) in adipocyte cells. Therefore, the present work aimed to investigate the role of DINP in adipogenesis using 3T3-L1 preadipocytes. DINP exposure for 10 days extensively induced adipogenesis in 3T3-L1 preadipocytes to adipocytes as assessed by lipid accumulation and gene expression of adipogenic markers. The RT-qPCR results showed that DINP could upregulate the expression of peroxisome proliferator-activated receptor-gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα) and C/EBPß, while the expression of sterol regulatory element binding transcription factor 1 (SREBF1) and C/EBPδ was not affected. The DINP-induced adipogenesis could be inhibited by using the selective PPARγ antagonist GW9662. The RNA-seq analysis was used to study the systemic toxicities of DINP on preadipocytes. A total of 1181 differently expressed genes (DEGs) (640 genes were up-regulated, 541 genes were down-regulated) were detected in 3T3-L1 preadipocytes under 50 µM DINP. The GO enrichment showed the GO term of "fat cell differentiation" was the most significantly affected metabolic functions, and the KEGG pathway enrichment showed the PPAR pathway was the top affected pathway. The interactive pathway (iPath) analysis showed that the changed metabolic pathways were focus on the lipid metabolism.

Association between phthalate exposure and glycosylated hemoglobin, fasting glucose, and type 2 diabetes mellitus: A case-control study in China.

Epidemiological studies have shown that exposure to phthalates (PAEs) is associated with type 2 diabetes mellitus (T2DM) and related markers, but limited evidence has been found in Chinese people. Given that China has the highest number of people with DM and Chinese people show relatively higher exposure levels of PAEs, a case-control study was conducted in China to explore the associations of PAE exposure with T2DM and two glycemic indicators, including fasting glucose and glycosylated hemoglobin (HbA1c). Two hundred fifty people with T2DM and 250 controls were recruited in this study. Multivariable logistic regression analyses showed significant positive associations between urinary concentrations of most studied PAE metabolites (mPAEs) and T2DM, with odd ratios comparing extreme mPAEs quartiles ranging from 2.09 to 40.53, whereas two secondary metabolites, mono (2-ethyl-5-carboxypentyl) phthalate and mono [(2-carboxymethyl) hexyl] phthalate showed significant inverse relationships with T2DM. In addition, multivariable linear regression analyses showed that urinary concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate were positively associated with HbA1c levels in controls (ß = 0.013; 95% CI: 0.003, 0.023). A significant positive association was also observed for urinary mono (2-ethylhexyl) phthalate and fasting glucose (ß = 0.009; 95% CI: 0.002, 0.016). In the stratified analyses, the significant associations of mPAEs with T2DM were more likely to be observed in the younger people, compared to the older people. The significant positive associations between urinary mPAEs and HbA1c levels were more likely to be found in the lower body mass index (BMI) subgroup. Additionally, urinary specific mPAEs were found to be significantly positively related to fasting glucose in males and the older people. The findings suggest that exposure to PAEs is associated with T2DM, fasting glucose, and HbA1c levels in Chinese people and the associations of exposure to PAEs with T2DM, fasting glucose, and HbA1c may differ between sexes, BMIs, or ages.

Serum concentrations of bisphenol A and its alternatives in elderly population living around e-waste recycling facilities in China: Associations with fasting blood glucose.

In the present study, concentrations of bisphenol A (BPA) and its six alternatives were quantified in serum samples collected from elder population living around an e-waste recycling facilities as well as an reference area in China. BPA, bisphenol AF (BPAF), and bisphenol F (BPF) were frequently detected (detection rates: > 65%) in serum samples collected from residents living near e-waste dismantling facilities, with geometric mean (GM) concentrations of 3.2, 0.0074, and 0.062 ng/mL, respectively. The detection frequencies of other four bisphenols (BPs) in serum samples were lower than 25%, regardless of the sampling areas. Significant difference (Mann-Whitney U-test, p < 0.05) was observed in the serum concentration of BPA, but not BPAF and BPF, between the e-waste recycling and reference areas. This finding indicated e-waste dismantling activities are correlated with human BPA exposure. Significant higher (p < 0.05) detection rates of donors who had abnormal fasting blood glucose (FBG) levels were found in e-waste recycling areas (45%) than those found in reference area. Our results suggested BPA and BPAF exposure might associated with abnormal FBG in participants living in e-waste sites. To our knowledge, this study is first determination of BPs in serum samples and assessment of health risk of elderly people from BPs exposure in e-waste dismantling area.

Human exposure to phthalate esters associated with e-waste dismantling: Exposure levels, sources, and risk assessment.

Phthalate esters (PAEs) can be released into the environment during the dismantling of electronic waste (e-waste), but urinary levels of PAE metabolites (mPAEs) in humans living in e-waste sites have not been documented. In this study, 11 mPAEs were determined in urine samples collected from participants living in e-waste dismantling sites and a reference area in Southern China. The total urinary concentrations of the 11 mPAEs (∑mPAEs) in the e-waste sites (range: 11.1 ng/mL to 3380 ng/mL) were dominated by mono-(2-isobutyl) phthalate and mono-n-butyl phthalate. Participants living in the e-waste sites had significantly higher (p < 0.05) urinary concentrations of ∑mPAEs (and 5 individual mPAEs) than those in the reference area. Hence, e-waste dismantling activities contributed to human exposure to PAEs. The exposure doses of di-n-butyl phthalate, di(2-ethylhexyl)phthalate, di-iso-butyl phthalate, dimethyl phthalate, and diethyl phthalate were 3.41, 3.04, 1.37, 0.25, and 0.20 µg/kg bw/day, respectively. Furthermore, the health risk assessment in terms of hazard quotient and hazard index showed that approximately 22% of the participants living in the e-waste sites had HI values exceeding 1; importantly, 68% of them were non-adults (i.e., 0-18 years old). In the e-waste sites, 8 of the 11 mPAEs in urine samples had significantly positively associations (r = 0.185-0.358, p < 0.05) with the urinary concentration of 8-hydroxy-2'-deoxyguanosine, a marker of DNA oxidative stress. Therefore, people living in e-waste dismantling areas may have a potential health risk caused by PAE exposure. To the best of our knowledge, this study is the first to measure urinary mPAE levels in people living in e-waste dismantling areas.

Association of urinary concentrations of bisphenols with type 2 diabetes mellitus: A case-control study.

Bisphenols, as synthetic chemicals, have been widely detected in environmental and human samples. Epidemiological studies have reported relationships between bisphenol A (BPA) and type 2 diabetes mellitus (T2DM), but results are inconsistent. Additionally, the associations between other bisphenols (i.e., the substitutes of BPA) with T2DM have been scarcely reported. A case-control study was conducted to examine the associations of urinary bisphenols with T2DM by investigating 8 bisphenols in urine samples of 251 T2DM cases and 251 controls and using different statistic models. Urinary bisphenol AF (BPAF) and bisphenol S (BPS) concentrations were significantly positively associated with T2DM in the log-transformed statistical models and adjusted odd ratios (ORs) were separately 4.95 [95% confidence interval (CI): 3.15, 7.79] and 1.73 (95% CI: 1.37, 2.18), which was consistent with the results in categorical models (OR = 2.03; 95% CI: 1.31, 3.15; p = 0.001 for BPAF; OR = 3.83; 95% CI: 2.37, 6.20; p < 0.001 for BPS). In addition, in the categorical models, elevated odds of T2DM were observed in the second BPA quartile (OR = 2.58; 95% CI: 1.38, 4.80) and the third quartile (OR = 1.89; 95% CI: 1.03, 3.46), but not in the fourth quartile, which reflected a nonlinear association between urinary BPA and T2DM. Similarly, only significant positive association with T2DM was found in the second quartile of the sum of bisphenols (OR = 2.07; 95% CI: 1.12, 3.82). In the sensitivity analyses, the associations of bisphenols with T2DM remained consistent except for BPAF in the categorical model. Our study suggested that several urinary bisphenols were positively associated with T2DM.

Co-delivery of paclitaxel and gemcitabine by methoxy poly(ethylene glycol)-poly(lactide-coglycolide)-polypeptide nanoparticles for effective breast cancer therapy.

Traditional chemotherapeutic drugs have shown limited clinical curative effects in antitumor therapy. The application of multidrug combination and adjuvant-drug carriers is a feasible strategy to overcome the limitations while minimizing the dosage of single drug and acquiring the synergistic effects in tumor therapy. However, the systemic toxicity, drug resistance, and tumor recurrence are still unavoidable. Here we develop core-shell nanoparticles (NPs) to encapsulate paclitaxel (PTX) and gemcitabine (GEM) for breast cancer therapy. We find that the NPs could encapsulate PTX and GEM, with an encapsulation efficiency of 96.3 and 95.13%, respectively. Moreover, the drug loading of these NPs is 2.71% (PTX) and 2.64% (GEM). Notably, the co-delivery of GEM and PTX performs enhanced anticancer effect compared with the PTX alone or GEM alone therapy at the same concentration, which indicates a synergistic effect. Moreover, encapsulation of PTX and GEM by methoxy poly(ethylene glycol)-poly(lactide-coglycolide) also shows enhanced anticancer effects (81.5% tumor inhibition) and reduced systemic toxicity in vivo compared with free drugs (65% tumor inhibition). Together with those results, co-delivery of PTX and GEM by methoxy poly(ethylene glycol)-poly(lactide-coglycolide) might have important potencies in clinical applications for breast cancer therapy.

Distribution of Phthalate Metabolites between Paired Maternal-Fetal Samples.

Phthalic acid esters (PAEs) are readily metabolized to phthalate metabolites (mPAEs) in the human body. The occurrence of mPAEs in adult human samples is well documented; however, the maternal-fetal transmission of mPAEs has seldom been studied. In this study, 78 paired maternal-fetal samples, including maternal urine (MU), maternal serum (MS), cord serum (CS), and amniotic fluid (AF), were collected from pregnant women in Tianjin, China. Seven mPAEs were detected in MS, CS, and AF, whereas all 11 investigated mPAEs were found in MU. The median concentration of ∑mPAEs was the highest in MU (128 ng/mL, with a range of 20.2-973 ng/mL), and proceeded in the order of CS (44.9, 13.9-315 ng/mL), MS (24.6, 3.75-156 ng/mL), and AF (10.4, 7.69-79.8 ng/mL). The values of ∑mPAEs and several individual mPAEs were significantly correlated between MU and MS, with generally higher concentrations in MU, which indicated that urinary mPAEs is a good indicator of PAEs' exposure in adults. Notably, the median CS:MS ratios of ∑mPAEs (1.58) were higher than 1, indicating that fetuses were exposed to mPAEs before birth. Significant correlations were also observed between MS and CS, which suggested that mPAEs in MS provide an indication of the fetal exposure. This study presents the first systematic analysis of the distribution and transmission of various mPAEs between mothers and fetuses.

Exposure to phthalates in patients with diabetes and its association with oxidative stress, adiponectin, and inflammatory cytokines.

Epidemiologic studies have revealed higher concentrations of the metabolites of phthalic acid esters (mPAEs) in patients with type 2 diabetes. On the other hand, oxidative stress, adiponectin, and inflammatory cytokines play important roles in the pathogenesis of diabetes and its complications. However, little information is known about the association between exposure to PAEs and these physiological parameters. Hence, paired urine and blood samples were collected from a total of 329 volunteers, and 11 main mPAEs and malondialdehyde (MDA), as a biomarker of oxidative stress, were measured in the urine samples. Serum adiponectin and tumor necrosis factor-α (TNF-α), a biomarker of inflammation, were also measured. Multivariable linear regression was used to assess the association between urinary mPAEs and these physiological parameters in the total subjects and subjects stratified by age, sex, and body mass index (BMI) to elucidate their possible interactions. All 11 mPAEs were detected in the urine with detection rates of 42.9%-100% and geometric means of 0.30-54.52ng/mL (0.44-79.93µg/g creatinine). The mPAEs were all positively associated with MDA levels. There were significant positive associations between monomethyl phthalate (mMP) and TNF-α, and inverse associations between mMP and adiponectin levels. In the stratified analysis, there were age-, sex-, and BMI-specific differences for these associations. The positive associations between mPAEs and MDA were insignificant in some subgroups, especially in the larger age group. However, in the larger BMI group, summed metabolites of di-(2-ethylhexyl) phthalate (∑DEHP) and mono(2-ethylhexyl) phthalate were positively associated with TNF-α, and the concentrations of ∑DEHP were negatively associated with adiponectin. Our findings suggested that PAE exposure is associated with oxidative stress, adiponectin, and inflammatory cytokines in diabetic patients; further studies on toxicology and a comparison with general population are needed.