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Toxics
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Cellular, Molecular and Genetic Toxicity of Endocrine Disruptors
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Cellular, Molecular and Genetic Toxicity of Endocrine Disruptors

A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Emerging Contaminants".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 13328

Special Issue Editors

Prof. Dr. Yungang Liu

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Guest Editor
School of Public Health, Southern Medical University, Guangzhou, China
Interests: metabolism-activated genotoxicity; health risk assessment; carcinogenesis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Tao Chen

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Guest Editor
Department of Toxicology, School of Public Health, Soochow University, Suzhou, China
Interests: toxicity of environmental chemicals and their active metabolites
Dr. Xiaoshan Liu

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Guest Editor
Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Guangdong 523808, China
Interests: adverse effects and underlying mechanisms of endocrine disruptors; toxicology; human diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Endocrine disruptors comprise a large spectrum of xenobiotics, ranging from medicinal chemicals to various industrial and environmental compounds, such as polychlorinated (or polychrominated) biphenyls, polychrominated diphenyl ethers, phthalic acid esters, phosphate flame-retardants, etc. To date, the endocrine-disrupting effects of these compounds have been relatively sufficiently studied, but other endpoints, such as cellular, molecular and genetic toxicity via activated nuclear receptors and the modulated expression of biotransformation enzymes are not fully understood. Further investigation is highly required regarding the toxic effects of endocrine disruptors via their interaction with intracellular macromolecule targets (e.g., aryl hydrocarbon receptors, pregnane X receptors, constitutive androstane receptors, estrogen receptors, cytochrome P450 enzymes, and phase II biotransformation enzymes) in various experimental models, including but not limited to cell cultures, intact animal models (preferentially relevant transgenic animals), and human subjects.

This Special Issue focuses on nuclear receptors and their downstream protein-mediated toxic effects in various biologic systems (i.e., experimental models), which will be helpful for comprehensively understanding the toxicity of endocrine disruptors.

In this Special Issue, original research articles, literature reviews, and short communications are all welcome.

Prof. Dr. Yungang Liu
Prof. Dr. Tao Chen
Dr. Xiaoshan Liu
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • endocrinal disruptors
  • nuclear receptors
  • genetic toxicity
  • molecular toxicity
  • cellular toxicity

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Published Papers (7 papers)

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Research

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12 pages, 3639 KiB  
Article
Genome-Wide Profiling of Transcriptome and DNA Methylome in Human Embryonic Stem Cells Exposed to Extractable Organic Matter from PM2.5
by Jianming Wang, Tiantian Liu, Jin Wang, Tao Chen and Yan Jiang
Toxics 2023, 11(10), 840; https://doi.org/10.3390/toxics11100840 - 6 Oct 2023
Cited by 1 | Viewed by 1336
Abstract
Increasing evidence indicates that PM2.5 exposure disrupts early embryonic development, but the mechanisms remain unclear. We hypothesized that PM2.5 cause abnormal embryonic development by interfering with DNA methylation and mRNA expression. In this study, we observed that human embryonic stem cells (hESCs) treated [...] Read more.
Increasing evidence indicates that PM2.5 exposure disrupts early embryonic development, but the mechanisms remain unclear. We hypothesized that PM2.5 cause abnormal embryonic development by interfering with DNA methylation and mRNA expression. In this study, we observed that human embryonic stem cells (hESCs) treated with extractable organic matters (EOM) from PM2.5 concentrations above 100 μg/mL exhibited reduced viability. While EOM within non-cytotoxicity concentrations did not affect the expression levels of pluripotency genes, it did enhance cellular proliferation, as indicated by increased Edu incorporation and the upregulation of cell cycle genes (Cdk2, Mdm2). Additionally, EOM significantly influenced the transcriptome patterns in hESCs. Notably, the differentially expressed genes were found to be significantly enriched in processes such as extracellular matrix organization, cell–cell junction organization, chromatin organization, and DNA methylation. Furthermore, we observed whole genomic-wide DNA methylation changes. Through a cross-analysis of changes in DNA methylation and mRNA expression, we identified an enrichment of terms related to the VEGFR signaling pathway and extracellular matrix. The gene signal transduction networks revealed that crucial hubs were implicated in cell growth and division. In conclusion, our findings demonstrate that PM2.5 induce significant alterations in transcriptome and DNA methylome in hESCs, leading to aberrant cell proliferation. This research provides novel insights into the molecular mechanisms underlying the developmental toxicity of PM2.5. Full article
(This article belongs to the Special Issue Cellular, Molecular and Genetic Toxicity of Endocrine Disruptors)
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12 pages, 1744 KiB  
Article
Phenylalanine Residues in the Active Site of CYP2E1 Participate in Determining the Binding Orientation and Metabolism-Dependent Genotoxicity of Aromatic Compounds
by Keqi Hu, Hongwei Tu, Jiayi Xie, Zongying Yang, Zihuan Li, Yijing Chen and Yungang Liu
Toxics 2023, 11(6), 495; https://doi.org/10.3390/toxics11060495 - 31 May 2023
Viewed by 1332
Abstract
The composition of amino acids forming the active site of a CYP enzyme is impactful in its substrate selectivity. For CYP2E1, the role of PHE residues in the formation of effective binding orientations for its aromatic substrates remains unclear. In this study, molecular [...] Read more.
The composition of amino acids forming the active site of a CYP enzyme is impactful in its substrate selectivity. For CYP2E1, the role of PHE residues in the formation of effective binding orientations for its aromatic substrates remains unclear. In this study, molecular docking and molecular dynamics analysis were performed to reflect the interactions between PHEs in the active site of human CYP2E1 and various aromatic compounds known as its substrates. The results indicated that the orientation of 1-methylpyrene (1-MP) in the active site was highly determined by the presence of PHEs, PHE478 contributing to the binding free energy most significantly. Moreover, by building a random forest model the relationship between each of 19 molecular descriptors of polychlorinated biphenyl (PCB) compounds (from molecular docking, quantum mechanics, and physicochemical properties) and their human CYP2E1-dependent mutagenicityas established mostly in our lab, was investigated. The presence of PHEs did not appear to significantly modify the electronic or structural feature of each bound ligand (PCB), instead, the flexibility of the conformation of PHEs contributed substantially to the effective binding energy and orientation. It is supposed that PHE residues adjust their own conformation to permit a suitablly shaped cavity for holding the ligand and forming its orientation as favorable for a biochemical reaction. This study has provided some insights into the role of PHEs in guiding the interactive adaptation of the active site of human CYP2E1 for the binding and metabolism of aromatic substrates. Full article
(This article belongs to the Special Issue Cellular, Molecular and Genetic Toxicity of Endocrine Disruptors)
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17 pages, 5705 KiB  
Article
The Role of G3BP1 Gene Mediates P38 MAPK/JNK Pathway in Testicular Spermatogenic Dysfunction Caused by Cyfluthrin
by Xiao-Yu Li, Jian Sun, Li-Ya Ma, Yong-Xin Xie, Na Zhang, Ji Zhao and Hui-Fang Yang
Toxics 2023, 11(5), 451; https://doi.org/10.3390/toxics11050451 - 10 May 2023
Cited by 4 | Viewed by 2160
Abstract
In recent years, male infertility has received global attention and seriously affected the quality of human fertility, and pyrethroids (type II pyrethroids), as recognized environmental endocrine disruptors, may threaten male reproductive health. Therefore, in this study, we established an in vivo model for [...] Read more.
In recent years, male infertility has received global attention and seriously affected the quality of human fertility, and pyrethroids (type II pyrethroids), as recognized environmental endocrine disruptors, may threaten male reproductive health. Therefore, in this study, we established an in vivo model for the development of testicular and germ cell toxicity induced by cyfluthrin and explored the role and mechanism of the G3BP1 gene-mediated P38 MAPK/JNK pathway in testicular and germ cell damage caused by cyfluthrin to find early and sensitive indicators and new therapeutic targets for the development of testicular damage. Firstly, 40 male Wistar rats (about 260 g) were divided into a control group (corn oil), low dose group (6.25 mg/kg), middle dose group (12.5 mg/kg) and high dose group (25 mg/kg). The rats were anesthetized and executed after 28 days of poisoning on alternate days. Then, HE staining, transmission electron microscopy, ELISA, q-PCR, Western blot, immunohistochemistry, double-immunofluorescence and TUNEL were used to observe the pathology, androgen levels, oxidative damage and altered expression of the key factors of the G3BP1 and MAPK pathways in rat testes. The results showed that, compared with the control group, the testicular tissue and spermatocytes were superficially damaged with an increasing dose of cyfluthrin; furthermore, it could interfere with the normal secretion of the hypothalamic–pituitary–gonadal axis (serum GnRH, FSH, T and LH levels) and cause hypergonadal dysfunction. A dose-dependent increase in MDA and a dose-dependent decrease in T-AOC indicated that the oxidative–antioxidative homeostatic balance was disrupted. The Western blot and qPCR analysis revealed that G3BP1, p-JNK1/2/3, P38 MAPK, p-ERK, COX1 and COX4 proteins and mRNA expression were decreased, and p-JNK1/2/3, p-P38MAPK, caspase 3/8/9 proteins and mRNA expression were significantly increased. The double-immunofluorescence and immunohistochemistry results showed that the protein expression of G3BP1 decreased with an increasing dose of staining, while the expression of JNK1/2/3 and P38 MAPK were increased significantly. The positive expressions of G3BP1 were mainly located in the testicular germinal epithelium and germ cell layer, and the positive expressions of JNK1/2/3 were mainly located in the testicular germinal epithelium and sperm cells, while the positive expressions of P38 MAPK were located in all levels of the germ cells and spermatozoa. Our results demonstrated that exposure to cyfluthrin caused testicular and spermatocyte damage in rats, which could cause pathomorphology, altered androgen levels and a decreased antioxidant capacity. When the intracellular antioxidant capacity was impaired, G3BP1 expression and activity were inhibited, causing activation of the P38 MAPK/JNK pathway and activation of the intracellular apoptotic pathway, which, in turn, led to germ cell apoptosis. Full article
(This article belongs to the Special Issue Cellular, Molecular and Genetic Toxicity of Endocrine Disruptors)
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14 pages, 2195 KiB  
Article
Mono-(2-ethylhexyl) Phthalate (MEHP)-Induced Telomere Structure and Function Disorder Mediates Cell Cycle Dysregulation and Apoptosis via c-Myc and Its Upstream Transcription Factors in a Mouse Spermatogonia-Derived (GC-1) Cell Line
by Fangji Zhou, Chengwei Guo, Lingqiao Wang, Guowei Zhang, Jia Wang, Weiyan Chen, Ke Cui, Yao Tan and Ziyuan Zhou
Toxics 2023, 11(5), 448; https://doi.org/10.3390/toxics11050448 - 10 May 2023
Cited by 6 | Viewed by 1951
Abstract
As a typical environmental endocrine disrupting chemical (EDC), di-(2-ethylhexyl) phthalate (DEHP) is thought to be related to reproductive disorders, especially in males. Growing evidence suggests that various EDCs may result in an impaired telomere structure and function, which is associated with male infertility. [...] Read more.
As a typical environmental endocrine disrupting chemical (EDC), di-(2-ethylhexyl) phthalate (DEHP) is thought to be related to reproductive disorders, especially in males. Growing evidence suggests that various EDCs may result in an impaired telomere structure and function, which is associated with male infertility. However, the adverse effect of DEHP on telomeres in male reproductive cells has rarely been studied, and the related mechanisms remain unclear. In this study, we tested the effects of mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, on telomere dysfunction in mouse spermatogonia-derived cells (GC-1) and the potential role of TERT and c-Myc in MEHP-induced spermatogenic cell damage. Results showed that MEHP induced cell viability inhibition, G0/G1 phase cell cycle arrest, and apoptosis in GC-1 cells in a dose-dependent manner. Shortened telomeres, reduced telomerase activity, and decreased expression of TERT, c-Myc, and upstream transcription factors of c-Myc were also observed in the MEHP-treated cells. In conclusion, it can be concluded that TERT-mediated telomere dysfunction may contribute to MEHP-induced G0/G1 phase cell cycle arrest and apoptosis in GC-1 cells through the impairment of c-Myc and its upstream transcription factors. Full article
(This article belongs to the Special Issue Cellular, Molecular and Genetic Toxicity of Endocrine Disruptors)
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11 pages, 2350 KiB  
Article
Preliminary Study on the Protective Effects and Molecular Mechanism of Procyanidins against PFOS-Induced Glucose-Stimulated Insulin Secretion Impairment in INS-1 Cells
by Hai-Ming Xu, Meng-Yu Wu, Xin-Chen Shi, Ke-Liang Liu, Ying-Chi Zhang, Yin-Feng Zhang and Hong-Mei Li
Toxics 2023, 11(2), 174; https://doi.org/10.3390/toxics11020174 - 14 Feb 2023
Cited by 1 | Viewed by 1976
Abstract
This study aimed to investigate the effects of perfluorooctanesulfonic acid (PFOS) exposure on glucose-stimulated insulin secretion (GSIS) of rat insulinoma (INS-1) cells and the potential protective effects of procyanidins (PC). The effects of PFOS and/or PC on GSIS of INS-1 cells were investigated [...] Read more.
This study aimed to investigate the effects of perfluorooctanesulfonic acid (PFOS) exposure on glucose-stimulated insulin secretion (GSIS) of rat insulinoma (INS-1) cells and the potential protective effects of procyanidins (PC). The effects of PFOS and/or PC on GSIS of INS-1 cells were investigated after 48 h of exposure (protein level: insulin; gene level: glucose transporter 2 (Glut2), glucokinase (Gck), and insulin). Subsequently, the effects of exposure on the intracellular reactive oxygen species (ROS) activity were measured. Compared to the control group, PFOS exposure (12.5, 25, and 50 μM) for 48 h had no significant effect on the viability of INS-1 cells. PFOS exposure (50 μM) could reduce the level of insulin secretion and reduce the relative mRNA expression levels of Glut2, Gck, and insulin. It is worth noting that PC could partially reverse the damaging effect caused by PFOS. Significantly, there was an increase in ROS after exposure to PFOS and a decline after PC intervention. PFOS could affect the normal physiological function of GSIS in INS-1 cells. PC, a plant natural product, could effectively alleviate the damage caused by PFOS by inhibiting ROS activity. Full article
(This article belongs to the Special Issue Cellular, Molecular and Genetic Toxicity of Endocrine Disruptors)
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Review

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14 pages, 2825 KiB  
Review
Research Progress on Neurodevelopmental Toxicity in Offspring after Indirect Exposure to PFASs in Early Life
by Huai-Yu Zhuchen, Jie-Yu Wang, Xiao-Shan Liu and Yan-Wei Shi
Toxics 2023, 11(7), 571; https://doi.org/10.3390/toxics11070571 - 30 Jun 2023
Cited by 10 | Viewed by 2173
Abstract
Per- and polyfluoroalkyl substances (PFASs) are widespread environmental pollutants. There is increasing evidence that PFASs have various adverse health effects, including renal toxicity, metabolic dysfunction, endocrine disruption, and developmental toxicity. PFASs have been found to accumulate in the placenta, and some PFASs can [...] Read more.
Per- and polyfluoroalkyl substances (PFASs) are widespread environmental pollutants. There is increasing evidence that PFASs have various adverse health effects, including renal toxicity, metabolic dysfunction, endocrine disruption, and developmental toxicity. PFASs have been found to accumulate in the placenta, and some PFASs can cross the placental barrier and subsequently accumulate in the fetus via the maternal–fetal circulation. An increasing number of studies have shown that early life exposure to PFASs can affect fetal neurodevelopment. This paper reviews the characteristics of indirect exposure to PFASs in early life, the effects on neurodevelopment in offspring, and the possible mechanisms of toxic effects. Full article
(This article belongs to the Special Issue Cellular, Molecular and Genetic Toxicity of Endocrine Disruptors)
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12 pages, 525 KiB  
Review
Effects of Xenobiotic Compounds on Preeclampsia and Potential Mechanisms
by Miaoliang Wu, Fuhui Yan, Qian Liu, Ganzhong Liao, Yilin Shen, Zhi Bai and Xiaoshan Liu
Toxics 2023, 11(6), 492; https://doi.org/10.3390/toxics11060492 - 31 May 2023
Cited by 3 | Viewed by 1698
Abstract
Preeclampsia (PE) refers to a disease with new hypertension and albuminuria or other end-organ damage after 20 weeks of pregnancy. As a major complication of pregnancy, PE can increase the morbidity and mortality of pregnant women and fetuses and cause serious social burden. [...] Read more.
Preeclampsia (PE) refers to a disease with new hypertension and albuminuria or other end-organ damage after 20 weeks of pregnancy. As a major complication of pregnancy, PE can increase the morbidity and mortality of pregnant women and fetuses and cause serious social burden. Recently, it has been found that exposure to xenobiotic compounds, especially endocrine disruptors in the environment, may contribute to the development of PE. However, the underlying mechanism is still unclear. It is generally believed that PE is related to placental dysplasia, spiral artery remodelling failure, oxidative stress, etc. Therefore, in order to better prevent the occurrence of PE and reduce the damage and impact on mother and fetus, this paper reviews the role and potential mechanism of PE induced by exogenous chemicals and provides an outlook on the environmental etiology of PE. Full article
(This article belongs to the Special Issue Cellular, Molecular and Genetic Toxicity of Endocrine Disruptors)
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