Machine learning models based on residue interaction network for ABCG2 transportable compounds recognition.

As the one of the most important protein of placental transport of environmental substances, the identification of ABCG2 transport molecules is the key step for assessing the risk of placental exposure to environmental chemicals. Here, residue interaction network (RIN) was used to explore the difference of ABCG2 binding conformations between transportable and non-transportable compounds. The RIN were treated as a kind of special quantitative data of protein conformation, which not only reflected the changes of single amino acid conformation in protein, but also indicated the changes of distance and action type between amino acids. Based on the quantitative RIN, four machine learning algorithms were applied to establish the classification and recognition model for 1100 compounds with transported by ABCG2 potential. The random forest (RF) models constructed with RIN presented the best and satisfied predictive ability with an accuracy of training set of 0.97 and the test set of 0.96 respectively. In conclusion, the construction of residue interaction network provided a new perspective for the quantitative characterization of protein conformation and the establishment of prediction models for transporter molecular recognition. The ABCG2 transport molecular recognition model based on residue interaction network provides a possible way for screening environmental chemistry transported through placenta.

Percutaneous absorption and exposure risk assessment of organophosphate esters in children's toys.

The percutaneous penetration and exposure risk of organophosphate esters (OPEs) from children's toys remains largely unknown. Percutaneous penetration of OPEs was evaluated by EPISkin™ model. Chlorinated OPEs (Cl-OPEs) and alkyl OPEs, except tris(2-ethylhexyl) phosphate, exhibited a fast absorption rate and good dermal penetration ability with cumulative absorptions of 57.6-127 % of dosed OPEs. Cumulative absorptions of OPEs through skin cells were inversely associated with their molecular weight and log octanol-water partition coefficient. Additionally, a quantitative structure-activity relationship model indicated that topological charge and steric features of OPEs were closely related to the transdermal permeability of these chemicals. With the clarification of the factors affecting the transdermal penetration of OPEs, the level and exposure risk of OPEs in actual toys were studied. The summation of 18 OPE concentrations in 199 toy samples collected from China ranged from 6.82 to 228,254 ng/g, of which Cl-OPEs presented the highest concentration. Concentrations of OPEs in toys exhibited clear type differences. Daily exposure to OPEs via dermal, hand-to-mouth contact, and mouthing was evaluated, and dermal contact was a significant route for children's exposure to OPEs. Hazard quotients for noncarcinogenic risk assessment were below 1, indicating that the health risk of OPEs via toys was relatively low.

Identification of molecular initiating events and key events leading to endocrine disrupting effects of PFOA: Integrated molecular dynamic, transcriptomic, and proteomic analyses.

Perfluorooctanoic acid (PFOA) can rapidly activate signaling pathways independent of nuclear hormone receptors through membrane receptor regulation, which leads to endocrine disrupting effects. In the present work, the molecular initiating event (MIE) and the key events (KEs) which cause the endocrine disrupting effects of PFOA have been explored and determined based on molecular dynamics simulation (MD), fluorescence analysis, transcriptomics, and proteomics. MD modeling and fluorescence analysis proved that, on binding to the G protein-coupled estrogen receptor-1 (GPER), PFOA could induce a conformational change in the receptor, turning it into an active state. The results also indicated that the binding to GPER was the MIE that led to the adverse outcome (AO) of PFOA. In addition, the downstream signal transduction pathways of GPER, as regulated by PFOA, were further investigated through genomics and proteomics to identify the KEs leading to thr endocrine disrupting effects. Two pathways (Endocrine resistance, ERP and Estrogen signaling pathway, ESP) containing GPER were regulated by different concentration of PFOA and identified as the KEs. The knowledge of MIE, KEs, and AO of PFOA is necessary to understand the links between PFOA and the possible pathways that lead to its negative effects.

Assessment of perfluorohexane sulfonic acid (PFHxS)-related compounds degradation potential: Computational and experimental approaches.

Perfluorohexane sulfonic acid (PFHxS) and PFHxS-related compounds are listed in Annex A of the Stockholm Convention without specific exemptions. Substances that potentially degrade to PFHxS are considered as their related compounds. Unfortunately, the degradation behavior of PFHxS precursors, an important basis for the corresponding chemical regulation, remains unclear. Herein, based on the hypothesis that bond dissociation enthalpy (BDE) is the determining factor for the degradation of PFHxS precursors, the BDE of PFHxS-related precursors to produceC6F13SO2-groups was calculated. In addition, quantitative structure-activity relationship models based on partial least squares, partial least squares discrimination analysis, and support vector machine algorithms were developed to predict the BDE of 48 PFHxS precursors and distinguish the precursors with different degradation potential. Subsequent photodegradation experiments demonstrated that the order of degradation rates was consistent with that predicted by theoretical models. Importantly, perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid, and not PFHxS, were detected as the degradation products of potential PFHxS precursors. Sulfonamides, phenyl unit, and other radicals in the non-nucleus part of PFHxS precursors were identified as the critical molecular segments that affect their degradation potential. Ultimately, by comparing BDE values, it was theoretically speculated that PFHxS related compounds exhibit a greater potential to generate PFHxA than PFHxS. Results in this study indicated for the first time that not all the compounds containing C6F13SO2- groups were guaranteed to degrade into PFHxS under natural conditions.

The adverse outcome pathway (AOP) of estrogen interference effect induced by triphenyl phosphate (TPP): Integrated multi-omics and molecular dynamics approaches.

Triphenyl phosphate (TPP) has been detected with increasing frequency in various biota and environmental media, and it has been confirmed that G protein-coupled estrogen receptor (GPER) was involved in the estrogenic activity of TPP. Therefore, it is necessary to link the estrogen-interfering effects and possible mechanisms of action of TPP with the molecular initiation event (MIE) to improve its adverse outcome pathway framework. In this study, transcriptomic and proteomic methods were used to analyze the estrogen interference effect of TPP mediated by GPER, and the causal relationship was supplemented by molecular dynamics simulation and fluorescence analysis. The omics results showed that TPP could regulate the response of key GPER signaling factors and the activation of downstream pathways including PI3K-Akt signaling pathway, MAPK signaling pathway, and estrogen signaling pathway. The similar activation effect of TPP and agonist G1 change of GPER was proved by molecular dynamics simulation. After TPP binding, the conformation of GPER will change from the inactive to active state. Therefore, TPP may affect cell proliferation, metastasis, and apoptosis and regulate gene transcription and kinase activity, leading to abnormal immune function and other estrogen-dependent cell processes and cancer through GPER, ultimately causing the estrogen interference effect.

Effects of polyethylene microplastics on cell membranes: A combined study of experiments and molecular dynamics simulations.

Microplastics (MPs), widely distributed within the environment, can be ingested by humans easily and cause various biological reactions such as oxidative stress, immune response and membrane damage, ultimately representing a threat to health. Cell membranes work as first barrier for MPs entering the cell and playing biological effects. For now, the researches on interactions of MPs on cell membranes lack an in-depth and effective theoretical model to understand molecular details and physicochemical behaviors. In present study, observations of calcein leakage established polyethylene plastic nanoparticles (PE PNPs), especially of high concentrations, harming cell membrane integrity. SYTOX green and lactate dehydrogenase (LDH) assays supported the evidence that the exposure of cells to PE PNPs caused significant cell membrane damage in dose-response. Molecular dynamics (MD) simulations were further applied to determine the effects of PE on the properties of dipalmitoyl phosphatidylcholine (DPPC) bilayer. PE permeated into lipid membranes easily resulting in significant variations in DPPC bilayer with lower density, fluidity changes and membrane thickening. Besides, PE aggregates bound were more likely to cause pore formation and serious damage to the DPPC bilayer. The interaction mechanisms between MPS and cell membrane were explored which provided valuable insights into membrane effect of MPs.

Effect of short-chain chlorinated paraffins (SCCPs) on lipid membranes: Combination of molecular dynamics and membrane damage experiments.

In recent years, more attention has been paid to the biological effects of short-chain chlorinated paraffin (SCCP). Studies have shown that SCCPs exposure could cause metabolic damage and lipid metabolic damage. In the present work, based on E. coli membrane damage experiments and molecular dynamics (MD) simulation, the effects of SCCPs on the membrane structure and membrane properties were studied to explore the possible toxic damage effects of SCCPs on cell membrane. Experiments results showed that SCCPs had a significant inhibitory effect on E. coli. The E. coli cell membrane of the bacteria was broken and the macromolecules of the cell flowed out when exposed to SCCPs. SCCPs would lead to the decrease and depolarization of cell membrane potential, and then affect the integrity and permeability of cell membrane. The further molecular dynamic simulation revealed that SCCP molecules can easily enter the lipid DPPC membranes from the aqueous phase and tended to aggregate inside bilayer stably. The bound of SCCPs could lead to significant variations in DPPC bilayer with a less dense, more disorder and rougher layer, which thus made the damage of cell membrane. In a word, although the overall toxicity of SCCPs to cell was relatively weak, the damage to the cell membrane may be one of the mechanisms of its toxicity. MAIN FINDING OF THE WORK: The exposure of SCCPs could cause structural change of cell membrane in E. coli, which verified the damage to the cell membrane may be one of the mechanisms of its toxicity.