Effects of Phthalate Esters (PAEs) on Cell Viability and Nrf2 of HepG2 and 3D-QSAR Studies

Abstract

Phthalate esters (PAEs) are a widespread environmental pollutant, and their ecological and environmental health risks have gradually attracted attention. To reveal the toxicity characteristics of these compounds, ten PAEs were selected as research objects to establish a cell model. CCK-8 was used to determine cell viability, Western blots were used to determine the content of Nrf2 in HepG2, and the LD50 collected for the 13 PAEs administered to rats. On this basis, 3D-QSAR models of IC50, LD50 and Nrf2 were established. The experimental results showed that as the time of PAEs exposure increased (24, 48 and 72 h), cell viability gradually decreased. The test concentration (62.5 /125/250 μM) of PAEs exposed for 48 h could significantly increase the content of Nrf2, and the 1000 μM PAEs could inhibit the content of Nrf2. The model is relatively stable and predicts well that the introduction of large and hydrophobic groups may significantly affect the toxic effects of PAEs on cells. The present study provided a potential tool for predicting the LD50 and Nrf2 of new PAEs, and provide a reference for the design of new less toxic PAEs in the future.

Effects of DEHP, DEHT and DINP Alone or in a Mixture on Cell Viability and Mitochondrial Metabolism of Endothelial Cells In Vitro

“…In the literature, comparable conditions of time and concentration resulted in a diminishing cell viability, as reported for vascular endothelial cells exposed to MEHP, the main metabolite of DEHP, in HUVEC (from 12.5 µM) and in EA.hy926 (from 100 µM MEHP) [ 28 , 30 , 32 ]. On the other hand, it is of interest to note that an increasing cell viability trend was reported on a non-endothelial cellular model for DEHP (250 µM) and DINP (62.5 µM), tested separately on a hepatocarcinoma cell line at an exposure time of 24 h [ 51 ]. Overall, the time-dependent decrease observed in our study for DEHP and DINP was in line with this study, with more marked effects at 72 h comparatively to 48 h of exposure [ 51 ].…”

“…On the other hand, it is of interest to note that an increasing cell viability trend was reported on a non-endothelial cellular model for DEHP (250 µM) and DINP (62.5 µM), tested separately on a hepatocarcinoma cell line at an exposure time of 24 h [ 51 ]. Overall, the time-dependent decrease observed in our study for DEHP and DINP was in line with this study, with more marked effects at 72 h comparatively to 48 h of exposure [ 51 ]. Cell viability could be explained by cell proliferation as its decrease was reported for DEHP on human corneal endothelial cells, with tested concentrations higher than those in the current study (from 100 µM) [ 52 ].…”

Molecular Design and Mechanism Analysis of Phthalic Acid Ester Substitutes: Improved Biodegradability in Processes of Sewage Treatment and Soil Remediation

“…In the isophobic diagram of the molecular electrostatic field, the red region overlaps with the blue area. The blue area indicates that an increase in the positive electricity of the substituent group in this region promotes the biodegradability of PAEs [43]. DEHP and DBP molecules were detected in sewage in high concentrations, and these were used as target molecules (Figure 1) [41].…”

“…In the isophobic diagram of the molecu electrostatic field, the red region overlaps with the blue area. The blue area indicates t an increase in the positive electricity of the substituent group in this region promotes biodegradability of PAEs [43]. As can be seen from the model molecular stereo field isopotential diagram (Figure 2), the distribution of yellow areas at the ends of sites 3, 5, and 8 of the DEHP molecule and sites 5, 6, 7, and 8 of the DBP molecule indicate that an increase in the volume of the substituent groups around the substitutions mentioned above facilitates the microbial degradability of the PAE molecules during water treatment.…”

Phthalate Exposure: From Quantification to Risk Assessment

“…This experimental model allowed them to study the toxic effects of phthalates starting from the embryonic stage to different developmental stages, thus obtaining a model that could facilitate risk assessments of DEHP exposure. Closely related to phthalate toxic effects is the paper by Liu and collaborators [20], who developed a 3D-QSAR model based on the investigation of the phthalates effects on nuclear factor erythroid 2 related factor 2 (NRF2), a nuclear transcription factor that regulates oxidative stress and plays a crucial role in liver detoxification. The experiments performed in human hepatocyte (HepG2) cells could help predict the toxicity of new analogues and provide a reference for the design of less toxic phthalates PAEs in the future.…”