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Advances in the Research of Endocrine Disrupting Chemicals 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 16201

Special Issue Editor

1. Environmental Health and Drug Department, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka, Yokohama 2450066, Japan
2. National Institute for Environmental Studies, Center for Health and Environmental Risk Research, 16-2 Onogawa, Tsukuba 3058506, Ibraki, Japan
Interests: health and disease in humans and animals; risk assessment of cancer; reproduction; child development; objective methods for epidemiology; in vivo, in vitro and in silico; mechanism sciences; exposure sciences for food and drinking; use and application of stem cells in toxicology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Knowledge is progressively building up related to the potential harm of chemical products to human health, and some agents have been shown to be able to alter endocrine functions, affecting the timing of puberty, fertility, adipose and glucose metabolism, thyroid function, and the control of appetite. Behavior and neurodevelopment are also affected. In order to proceed on the understanding and to be able to plan actions, the contribution of a multidisciplinary approach is of utmost importance.

This Special Issue will focus on basic knowledge, on animal and human studies, and on studies focusing on how to further investigate the effects (ex. epigenetics, omics in general) in order to obtain a full picture. Innovations and plans are welcome. Original papers, reviews, commentaries, and papers focusing on methods and methodology are all also welcome.

Prof. Dr. Hideko Sone
Guest Editor

Manuscript Submission Information

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Keywords

  • endocrine disruptors
  • epigenetics
  • chemicals
  • human health
  • omics
  • growth
  • puberty
  • metabolism
  • neurodeveloment
  • prevention
  • oncogenesis

Published Papers (8 papers)

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Research

10 pages, 3248 KiB  
Article
Developmental Exposure to Endocrine Disrupter DDT Interferes with Age-Related Involution of Thymus
Int. J. Mol. Sci. 2022, 23(12), 6678; https://doi.org/10.3390/ijms23126678 - 15 Jun 2022
Cited by 3 | Viewed by 1366
Abstract
The impact of endocrine-disrupting chemicals on the development and involution of the immune system is a possible reason for the increased incidence of disorders associated with inappropriate immune function. The thymus is a lymphoid and also an endocrine organ, and, accordingly, its development [...] Read more.
The impact of endocrine-disrupting chemicals on the development and involution of the immune system is a possible reason for the increased incidence of disorders associated with inappropriate immune function. The thymus is a lymphoid and also an endocrine organ, and, accordingly, its development and functioning may be impaired by endocrine disruptors. The aim was to evaluate age-related thymus involution in mature rats exposed to the endocrine disruptor DDT during prenatal and postnatal ontogeny. Methodology included in vivo experiment on male Wistar rats exposed to low doses of DDT during prenatal and postnatal development and morphological assessment of thymic involution, including the immunohistochemical detection of proliferating thymocytes. The study was carried out at the early stage of involution. Results: DDT-exposed rats exhibited a normal anatomy, and the relative weight of the thymus was within the control ranges. Histological and immunohistochemical examinations revealed increased cellularity of the cortex and the medulla, higher content of lymphoblasts, and more intensive proliferation rate of thymocytes compared to the control. Evaluation of thymic epithelial cells revealed a higher rate of thymic corpuscles formation. Conclusion: The data obtained indicate that endocrine disrupter DDT disturbs postnatal development of the thymus. Low-dose exposure to DDT during ontogeny does not suppress growth rate but violates the developmental program of the thymus by slowing down the onset of age-related involution and maintaining high cell proliferation rate. It may result in excessive formation of thymus-dependent areas in peripheral lymphoid organs and altered immune response. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals 3.0)
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11 pages, 2292 KiB  
Article
Repercussions of Bisphenol A on the Physiology of Human Osteoblasts
Int. J. Mol. Sci. 2022, 23(10), 5349; https://doi.org/10.3390/ijms23105349 - 11 May 2022
Cited by 4 | Viewed by 1548
Abstract
(1) Background: Bisphenol A (BPA) is an endocrine disruptor that is widely present in the environment and exerts adverse effects on various body tissues. The objective of this study was to determine its repercussions on bone tissue by examining its impact on selected [...] Read more.
(1) Background: Bisphenol A (BPA) is an endocrine disruptor that is widely present in the environment and exerts adverse effects on various body tissues. The objective of this study was to determine its repercussions on bone tissue by examining its impact on selected functional parameters of human osteoblasts. (2) Methods: Three human osteoblast lines were treated with BPA at doses of 10−5, 10−6, or 10−7 M. At 24 h post-treatment, a dose-dependent inhibition of cell growth, alkaline phosphatase activity, and mineralization was observed. (4) Results: The expression of CD54 and CD80 antigens was increased at doses of 10−5 and 10−6 M, while the phagocytic capacity and the expression of osteogenic genes (ALP, COL-1, OSC, RUNX2, OSX, BMP-2, and BMP-7) were significantly and dose-dependently reduced in the presence of BPA. (5) Conclusions: According to these findings, BPA exerts adverse effects on osteoblasts by altering their differentiation/maturation and their proliferative and functional capacity, potentially affecting bone health. Given the widespread exposure to this contaminant, further human studies are warranted to determine the long-term risk to bone health posed by BPA. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals 3.0)
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17 pages, 4253 KiB  
Article
Transcriptomic and Physiological Responses of Chlorella pyrenoidosa during Exposure to 17α-Ethinylestradiol
Int. J. Mol. Sci. 2022, 23(7), 3583; https://doi.org/10.3390/ijms23073583 - 25 Mar 2022
Cited by 7 | Viewed by 1717
Abstract
17α-ethinylestradiol (17α-EE2) is frequently detected in water bodies due to its use being widespread in the treatment of prostate and breast cancer and in the control of alopecia, posing a threat to humans and aquatic organisms. However, studies on its toxicity [...] Read more.
17α-ethinylestradiol (17α-EE2) is frequently detected in water bodies due to its use being widespread in the treatment of prostate and breast cancer and in the control of alopecia, posing a threat to humans and aquatic organisms. However, studies on its toxicity to Chlorella pyrenoidosa have been limited to date. This study investigated the effects of 17α-EE2 on the growth, photosynthetic activity, and antioxidant system of C. pyrenoidosa and revealed related molecular changes using transcriptomic analysis. The cell density of algae was inhibited in the presence of 17α-EE2, and cell morphology was also altered. Photosynthetics were damaged, while reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) content increased. Further transcriptomic analysis revealed that the pathways of photosynthesis and DNA replication were affected at three concentrations of 17α-EE2, but several specific pathways exhibited various behaviors at different concentrations. Significant changes in differentially expressed genes and their enrichment pathways showed that the low-concentration group was predominantly impaired in photosynthesis, while the higher-concentration groups were biased towards oxidative and DNA damage. This study provides a better understanding of the cellular and molecular variations of microalgae under 17α-EE2 exposure, contributing to the environmental risk assessment of such hazardous pollutants on aquatic organisms. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals 3.0)
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14 pages, 1292 KiB  
Article
Overcompensation of CoA Trapping by Di(2-ethylhexyl) Phthalate (DEHP) Metabolites in Livers of Wistar Rats
Int. J. Mol. Sci. 2021, 22(24), 13489; https://doi.org/10.3390/ijms222413489 - 16 Dec 2021
Cited by 2 | Viewed by 1985
Abstract
Di(2-ethylhexyl) phthalate (DEHP) is commonly used as a plasticizer in various industrial and household plastic products, ensuring widespread human exposures. Its routine detection in human bio-fluids and the propensity of its monoester metabolite to activate peroxisome proliferator activated receptor-α (PPARα) and perturb lipid [...] Read more.
Di(2-ethylhexyl) phthalate (DEHP) is commonly used as a plasticizer in various industrial and household plastic products, ensuring widespread human exposures. Its routine detection in human bio-fluids and the propensity of its monoester metabolite to activate peroxisome proliferator activated receptor-α (PPARα) and perturb lipid metabolism implicate it as a metabolic disrupter. In this study we evaluated the effects of DEHP exposure on hepatic levels of free CoA and various CoA esters, while also confirming the metabolic activation to CoA esters and partial β-oxidation of a DEHP metabolite (2-ethyhexanol). Male Wistar rats were exposed via diet to 2% (w/w) DEHP for fourteen-days, following which hepatic levels of free CoA and various CoA esters were identified using liquid chromatography-mass spectrometry. DEHP exposed rats showed significantly elevated free CoA and increased levels of physiological, DEHP-derived and unidentified CoA esters. The physiological CoA ester of malonyl-CoA and DEHP-derived CoA ester of 3-keto-2-ethylhexanoyl-CoA were the most highly elevated, at eighteen- and ninety eight-times respectively. We also detected sixteen unidentified CoA esters which may be derivative of DEHP metabolism or induction of other intermediary metabolism metabolites. Our results demonstrate that DEHP is a metabolic disrupter which affects production and sequestration of CoA, an essential cofactor of oxidative and biosynthetic reactions. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals 3.0)
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13 pages, 3678 KiB  
Article
Alteration of Extracellular Matrix Components in the Anterior Pituitary Gland of Neonatal Rats Induced by a Maternal Bisphenol A Diet during Pregnancy
Int. J. Mol. Sci. 2021, 22(23), 12667; https://doi.org/10.3390/ijms222312667 - 23 Nov 2021
Cited by 1 | Viewed by 1986
Abstract
The extracellular matrix (ECM) plays crucial roles in the anterior pituitary gland via the mechanism of cell–ECM interaction. Since bisphenol A (BPA), a well-known endocrine disruptor, can cross through the placenta from mother to fetus and bind with estrogen receptors, cell populations in [...] Read more.
The extracellular matrix (ECM) plays crucial roles in the anterior pituitary gland via the mechanism of cell–ECM interaction. Since bisphenol A (BPA), a well-known endocrine disruptor, can cross through the placenta from mother to fetus and bind with estrogen receptors, cell populations in the neonatal anterior pituitary gland could be the target cells affected by this chemical. The present study treated maternal rats with 5000 µg/kg body weight of BPA daily throughout the pregnancy period and then investigated the changes in ECM-producing cells, i.e., pericytes and folliculostellate (FS) cells, including their ECM production in the neonatal anterior pituitary at Day 1. We found that pericytes and their collagen synthesis reduced, consistent with the increase in the number of FS cells that expressed several ECM regulators—matrix metalloproteinase (MMP) 9 and the tissue inhibitors of metalloproteinase (TIMP) family. The relative MMP9/TIMP1 ratio was extremely high, indicating that the control of ECM homeostasis was unbalanced. Moreover, transmission electron microscopy showed the unorganized cell cluster in the BPA-treated group. This study revealed that although the mother received BPA at the “no observed adverse effect” level, alterations in ECM-producing cells as well as collagen and the related ECM balancing genes occurred in the neonatal anterior pituitary gland. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals 3.0)
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20 pages, 4441 KiB  
Article
Unexpected Interacting Effects of Physical (Radiation) and Chemical (Bisphenol A) Treatments on Male Reproductive Functions in Mice
Int. J. Mol. Sci. 2021, 22(21), 11808; https://doi.org/10.3390/ijms222111808 - 30 Oct 2021
Cited by 2 | Viewed by 2028
Abstract
For decades, numerous chemical pollutants have been described to interfere with endogenous hormone metabolism/signaling altering reproductive functions. Among these endocrine disrupting substances, Bisphenol A (BPA), a widely used compound, is known to negatively impact germ and somatic cells in the testis. Physical agents, [...] Read more.
For decades, numerous chemical pollutants have been described to interfere with endogenous hormone metabolism/signaling altering reproductive functions. Among these endocrine disrupting substances, Bisphenol A (BPA), a widely used compound, is known to negatively impact germ and somatic cells in the testis. Physical agents, such as ionizing radiation, were also described to perturb spermatogenesis. Despite the fact that we are constantly exposed to numerous environmental chemical and physical compounds, very few studies explore the impact of combined exposure to chemical and physical pollutants on reproductive health. The aim of this study was to describe the impact of fetal co-exposure to BPA and IR on testicular function in mice. We exposed pregnant mice to 10 µM BPA (corresponding to 0.5 mg/kg/day) in drinking water from 10.5 dpc until birth, and we irradiated mice with 0.2 Gy (γ-ray, RAD) at 12.5 days post-conception. Co-exposure to BPA and γ-ray induces DNA damage in fetal germ cells in an additive manner, leading to a long-lasting decrease in germ cell abundance. We also observed significant alteration of adult steroidogenesis by RAD exposure independently of the BPA exposure. This is illustrated by the downregulation of steroidogenic genes and the decrease of the number of adult Leydig cells. As a consequence, courtship behavior is modified, and male ultrasonic vocalizations associated with courtship decreased. In conclusion, this study provides evidence for the importance of broadening the concept of endocrine disruptors to include physical agents, leading to a reevaluation of risk management and regulatory decisions. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals 3.0)
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23 pages, 5024 KiB  
Article
Bisphenol a Induces Autophagy Defects and AIF-Dependent Apoptosis via HO-1 and AMPK to Degenerate N2a Neurons
Int. J. Mol. Sci. 2021, 22(20), 10948; https://doi.org/10.3390/ijms222010948 - 11 Oct 2021
Cited by 9 | Viewed by 2527
Abstract
Bisphenol A (BPA) is an environmental contaminant widely suspected to be a neurological toxicant. Epidemiological studies have demonstrated close links between BPA exposure, pathogenetic brain degeneration, and altered neurobehaviors, considering BPA a risk factor for cognitive dysfunction. However, the mechanisms of BPA resulting [...] Read more.
Bisphenol A (BPA) is an environmental contaminant widely suspected to be a neurological toxicant. Epidemiological studies have demonstrated close links between BPA exposure, pathogenetic brain degeneration, and altered neurobehaviors, considering BPA a risk factor for cognitive dysfunction. However, the mechanisms of BPA resulting in neurodegeneration remain unclear. Herein, cultured N2a neurons were subjected to BPA treatment, and neurotoxicity was assessed using neuronal viability and differentiation assays. Signaling cascades related to cellular self-degradation were also evaluated. BPA decreased cell viability and axon outgrowth (e.g., by down-regulating MAP2 and GAP43), thus confirming its role as a neurotoxicant. BPA induced neurotoxicity by down-regulating Bcl-2 and initiating apoptosis and autophagy flux inhibition (featured by nuclear translocation of apoptosis-inducing factor (AIF), light chain 3B (LC3B) aggregation, and p62 accumulation). Both heme oxygenase (HO)-1 and AMP-activated protein kinase (AMPK) up-regulated/activated by BPA mediated the molecular signalings involved in apoptosis and autophagy. HO-1 inhibition or AIF silencing effectively reduced BPA-induced neuronal death. Although BPA elicited intracellular oxygen free radical production, ROS scavenger NAC exerted no effect against BPA insults. These results suggest that BPA induces N2a neurotoxicity characterized by AIF-dependent apoptosis and p62-related autophagy defects via HO-1 up-regulation and AMPK activation, thereby resulting in neuronal degeneration. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals 3.0)
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10 pages, 10473 KiB  
Article
Impaired Morphogenesis and Function of Rat Adrenal Zona Glomerulosa by Developmental Low-Dose Exposure to DDT Is Associated with Altered Oct4 Expression
Int. J. Mol. Sci. 2021, 22(12), 6324; https://doi.org/10.3390/ijms22126324 - 12 Jun 2021
Cited by 7 | Viewed by 1952
Abstract
Dichlorodiphenyltrichloroethane (DDT) is a persistent organic pollutant and one of the most widespread endocrine disrupting chemicals. The impact of low-dose exposure to DDT on the morphogenesis of the adrenal gland is still poorly understood. The development and function of zona glomerulosa in rats [...] Read more.
Dichlorodiphenyltrichloroethane (DDT) is a persistent organic pollutant and one of the most widespread endocrine disrupting chemicals. The impact of low-dose exposure to DDT on the morphogenesis of the adrenal gland is still poorly understood. The development and function of zona glomerulosa in rats has been found to be associated with changes in the expression of the transcription factor Oct4 (Octamer 4), which is the most important player in cell pluripotency. The aim of the study was to investigate the morphogenesis and function of rat adrenal zona glomerulosa in rats exposed to low doses of DDT during prenatal and postnatal development and to determine the possible role of Oct4 in DDT-mediated structural and functional changes. The DDT-exposed rats demonstrated slower development and lower functional activity of the zona glomerulosa during the pubertal period associated with higher expression of Oct4. Further, accelerated growth and restoration of hormone production was associated with, firstly, a decrease in Oct4 expressing cells and secondly, the loss of the inverse relationship between basal aldosterone levels and the number of Oct4 expressing cells. Thus, the transcriptional factor Oct4 exhibited an altered pattern of expression in the DDT-exposed rats during postnatal development. The results of the study uncover a novel putative mechanism by which low doses of DDT disrupt the development of adrenal zona glomerulosa. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals 3.0)
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