Association of phthalate exposure with type 2 diabetes and the mediating effect of oxidative stress: A case-control and computational toxicology study.

Phthalic acid esters (PAEs) are widely used as plasticizers and have been suggested to engender adverse effects on glucose metabolism. However, epidemiological data regarding the PAE mixture on type 2 diabetes (T2DM), as well as the mediating role of oxidative stress are scarce. This case-control study enrolled 206 T2DM cases and 206 matched controls in Guangdong Province, southern China. The concentrations of eleven phthalate metabolites (mPAEs) and the oxidative stress biomarker 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine were determined. Additionally, biomarkers of T2DM in paired serum were measured to assess glycemic status and levels of insulin resistance. Significantly positive associations were observed for mono-(2-ethylhexyl) phthalate (MEHP) and Mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) with T2DM (P < 0.001). Restricted cubic spline modeling revealed a non-linear dose-response relationship between MEHHP and T2DM (Pnon-linear = 0.001). The Bayesian kernel machine regression and quantile g-computation analyses demonstrated a significant positive joint effect of PAE exposure on T2DM risk, with MEHHP being the most significant contributor. The mediation analysis revealed marginal evidence that oxidative stress mediated the association between the mPAEs mixture and T2DM, while 8-OHdG respectively mediated 26.88 % and 12.24 % of MEHP and MEHHP on T2DM risk individually (Pmediation < 0.05). Di(2-ethylhexyl) phthalate (DEHP, the parent compound for MEHP and MEHHP) was used to further examine the potential molecular mechanisms by in silico analysis. Oxidative stress may be crucial in the link between DEHP and T2DM, particularly in the reactive oxygen species metabolic process and glucose import/metabolism. Molecular simulation docking experiments further demonstrated the core role of Peroxisome Proliferator Activated Receptor alpha (PPARα) among the DEHP-induced T2DM. These findings suggest that PAE exposure can alter oxidative stress via PPARα, thereby increasing T2DM risk.

Thyroid hormones and oxidative stress moderated the association between urinary phthalate metabolites and cardiovascular risk factors.

While previous studies suggested that phthalate exposure poses a risk to cardiovascular health, the results are mixed and indicated variability based on population characteristics and health outcomes assessed. Research that simultaneously investigates the association between urinary phthalate metabolites and multiple cardiovascular risk factors within a single study is relatively scarce. This study assessed human exposure to phthalates by determining urinary metabolite concentrations, and applied multiple statistical techniques to systematically evaluate the individual dose-response relationships and joint effects of phthalate exposure on blood lipids, blood pressure, and fasting blood glucose. The results revealed significant negative associations between urinary phthalate metabolites and low-density lipoprotein cholesterol, triglycerides, total cholesterol, diastolic blood pressure, systolic blood pressure, and fasting blood glucose. Significant nonlinear associations were obtained between specific individual metabolites and diastolic blood pressure. The oxidative stress biomarker 8-hydroxydeoxyguanosine levels in urine and thyroid hormone levels in paired serum were measured simultaneously. Then, we examined the indirect roles of thyroid hormones and oxidative stress in the association between urinary phthalate metabolites and cardiovascular risk factors by mediation and moderation analysis. While the mediation effect was not statistically significant, the negative associations of urinary phthalate metabolites with fasting blood glucose, triglyceride, and lipoprotein cholesterol were statistically significant at lower levels of thyroid hormones by moderation analysis. The association was also significant under certain levels of oxidative stress. The results demonstrated that phthalate exposure is associated with several cardiovascular risk factors, and maintaining appropriate oxidative stress levels and ensuring sufficient thyroid hormone levels may attenuate these associations.

Unraveling the contribution of dietary intake to human phthalate internal exposure.

Human exposure to phthalates (PAEs) occurs primarily through diet, but the contribution of dietary exposure to the total internal exposure of PAEs has not been well studied. This work investigated the relationship between dietary exposure and human internal exposure to PAEs. Daily food samples were determined to evaluate the health risk of dietary exposure, and phthalate metabolites (mPAEs) were determined from urine samples of 360 volunteers of Guangzhou to assess their internal exposure. The total mPAEs concentration in the urine samples ranged from 8.43 to 1872 ng/mL, with mono-(2-ethylhexyl) phthalate (MEHP), mono-n-butyl phthalate (MnBP), and mono-isobutyl phthalate (MiBP) being the most predominant mPAEs. The concentration of PAEs in food ranged from n.d-40200 µg/kg, and benzyl butyl phthalate (BBzP), di-n-butyl phthalate (DnBP) and di-(2-ethylhexyl) phthalate (DEHP) were the most prevalent. PAE exposure was significantly associated with age, and children exhibited the highest concentration of mPAEs. Using Monte Carlo simulation to estimate PAE exposure's health risk eliminated uncertainties caused by single-point sampling and provided more reliable statistical results. The hazard quotient (HQ) was used to evaluate PAE exposure health risks. The results showed that 37% of the volunteers had HQ levels higher than 1 based on urinary mPAE concentrations, while 24% of the volunteers had HQ levels greater than 1 because of dietary exposure to PAEs. Dietary intake was the predominant exposure route for PAEs, and accounted for approximately 65% (24% out of 37%) of the cases where HQ levels exceeded 1. The work revealed the correlation between dietary external and internal exposure to PAEs, and further studies are needed to better understand the implications.