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Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Reproductive Cells and Development".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 34911

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Prof. Dr. Silvia Garagna

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Laboratory of Developmental Biology, Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia-Via A. Ferrata, 9-27100 Pavia, Italy
Interests: mammalian spermatogenesis and oogenesis; meiosis; 3D tissue imaging; embryonic stem cells
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Prof. Dr. Maurizio Zuccotti

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Laboratory of Developmental Biology, Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Via A. Ferrata, 9-27100 Pavia, Italy
Interests: ovary; oocyte maturation; oocyte developmental competence; folliculogenesis; preimplantation
Special Issues, Collections and Topics in MDPI journals

Dr. Danilo Cimadomo

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GeneraLife, Via G. De Notaris, 1F, 00197 Roma, Italy
Interests: folliculogenesis; oocyte and embryo developmental competence; in vitro fertilization; human fertility

Special Issue Information

Dear Colleagues,

Living organisms are inescapably exposed to endocrine disrupting chemicals (EDCs) of both industrial or natural production, which, by interfering with hormonal and metabolic processes, disrupt the development/homeostasis of tissues and organs at any time of an individual’s life.

A wealth of experimental and epidemiological studies demonstrated reproductive defects in both males and females, leading to infertility. EDCs have genotoxic effects and impair gene expression through epigenetic modifications (i.e., methylation of CpG sites, histone modifications and production of non-coding RNA). Besides direct effects on exposed organisms, trans-generational impairment of the reproductive ability in both sexes has been reported when the offspring is presented to EDCs during fetal and neonatal periods.

With this Special Issue, we aim to provide an important resource for understanding the cellular and molecular mechanisms underlying the EDCs’ observed effects on vertebrate germ cells, gonads and embryos.

We welcome original research articles, reviews, commentary, perspectives and technical notes that, at the molecular, cellular and tissue hierarchical levels, describe the effects of EDCs on primordial germ cells, ovarian and testis function, folliculogenesis and spermatogenesis, oocyte and sperm quality, embryonic development either in vivo or in vitro. Also, welcome are articles describing the effects of EDCs in experimental models using cell lines, stem cells or organoids.

We look forward to your contributions.

Prof. Silvia Garagna
Prof. Dr. Maurizio Zuccotti
Dr. Danilo Cimadomo
Guest Editors

Manuscript Submission Information

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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. Cells is an international peer-reviewed open access semimonthly 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 2700 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

endocrine disruptors
gonadal steroid hormones
ovary
oogenesis and folliculogenesis
oocyte
testis
spermatogenesis and sperm
embryo development
epigenetics
omics
cells lines
stem cells
organoids

Related Special Issue

Effects and Mechanisms of Environmental Toxicants on Germ Cells, Gonads, Embryos and Stem Cells —Series 2 in Cells

Published Papers (10 papers)

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Research

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15 pages, 4015 KiB

Open AccessArticle

Short-Term Exposure to Bisphenol A Does Not Impact Gonadal Cell Steroidogenesis In Vitro

by Neena Roy, Clara Lazzaretti, Elia Paradiso, Chiara Capponi, Tommaso Ferrari, Francesca Reggianini, Samantha Sperduti, Lara Baschieri, Elisa Mascolo, Carmela Perri, Manuela Varani, Giulia Canu, Tommaso Trenti, Alessia Nicoli, Daria Morini, Francesca Iannotti, Maria Teresa Villani, Elena Vicini, Manuela Simoni and Livio Casarini

Cells 2023, 12(11), 1537; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12111537 - 02 Jun 2023

Cited by 1 | Viewed by 1492

Abstract

Bisphenol A (BPA) is a ubiquitous, synthetic chemical proven to induce reproductive disorders in both men and women. The available studies investigated the effects of BPA on male and female steroidogenesis following long-term exposure to the compound at relatively high environmental concentrations. However, the impact of short-term exposure to BPA on reproduction is poorly studied. We evaluated if 8 and 24 h exposure to 1 nM and 1 µM BPA perturbs luteinizing hormone/choriogonadotropin (LH/hCG)-mediated signalling in two steroidogenic cell models, i.e., the mouse tumour Leydig cell line mLTC1, and human primary granulosa lutein cells (hGLC). Cell signalling studies were performed using a homogeneous time-resolved fluorescence (HTRF) assay and Western blotting, while gene expression analysis was carried out using real-time PCR. Immunostainings and an immunoassay were used for intracellular protein expression and steroidogenesis analyses, respectively. The presence of BPA leads to no significant changes in gonadotropin-induced cAMP accumulation, alongside phosphorylation of downstream molecules, such as ERK1/2, CREB and p38 MAPK, in both the cell models. BPA did not impact STARD1, CYP11A1 and CYP19A1 gene expression in hGLC, nor Stard1 and Cyp17a1 expression in mLTC1 treated with LH/hCG. Additionally, the StAR protein expression was unchanged upon exposure to BPA. Progesterone and oestradiol levels in the culture medium, measured by hGLC, as well as the testosterone and progesterone levels in the culture medium, measured by mLTC1, did not change in the presence of BPA combined with LH/hCG. These data suggest that short-term exposure to environmental concentrations of BPA does not compromise the LH/hCG-induced steroidogenic potential of either human granulosa or mouse Leydig cells. Full article

(This article belongs to the Special Issue Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos)

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18 pages, 2165 KiB

Open AccessArticle

Impact of Chronic Multi-Generational Exposure to an Environmentally Relevant Atrazine Concentration on Testicular Development and Function in Mice

by Nicola D. Kolaitis, Bethany J. Finger, D. Jo Merriner, Joseph Nguyen, Brendan J. Houston, Moira K. O’Bryan, Jessica M. Stringer, Nadeen Zerafa, Ngoc Nguyen, Karla J. Hutt, Gerard A. Tarulli and Mark P. Green

Cells 2023, 12(4), 648; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12040648 - 17 Feb 2023

Cited by 1 | Viewed by 1896

Abstract

A common herbicide, atrazine, is associated with poor health. Atrazine acts as an endocrine disruptor at supra-environmental levels. Little research, however, has been conducted regarding chronic exposure to environmental atrazine concentrations across generations. This study utilized comprehensive endpoint measures to investigate the effects of chronic exposure to a conservative atrazine concentration (0.02 ng/mL), measured in Australian waterways, on male mice fertility across two generations. Mice were exposed through the maternal line, from the pre-conception period and through the F1 and F2 generations until three or six months of age. Atrazine did not impact sperm function, testicular morphology nor germ cell parameters but did alter the expression of steroidogenic genes in the F1, down-regulating the expression of Cyp17a1 (Cytochrome P450 family 17, subfamily A member 1; p = 0.0008) and Ddx4 (DEAD-box helicase 4; p = 0.007), and up-regulating the expression of Star (Steroidogenic acute regulatory protein; p = 0.017). In the F2, atrazine induced up-regulation in the expression of Star (p = 0.016). The current study demonstrates that chronic exposure to an environmentally relevant atrazine concentration perturbs testicular steroid-associated gene expression that varies across generations. Future studies through the paternal and combined parental lineages should be undertaken to further elucidate the multigenerational effects of atrazine on male fertility. Full article

(This article belongs to the Special Issue Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos)

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21 pages, 41817 KiB

Open AccessArticle

Bisphenol Exposure Disrupts Cytoskeletal Organization and Development of Pre-Implantation Embryos

by Luhan Yang, Claudia Baumann, Rabindranath De La Fuente and Maria M. Viveiros

Cells 2022, 11(20), 3233; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11203233 - 14 Oct 2022

Cited by 1 | Viewed by 2199

Abstract

The endocrine disrupting activity of bisphenol compounds is well documented, but less is known regarding their impact on cell division and early embryo formation. Here, we tested the effects of acute in vitro exposure to bisphenol A (BPA) and its common substitute, bisphenol F (BPF), during critical stages of mouse pre-implantation embryo development, including the first mitotic division, cell polarization, as well as morula and blastocyst formation. Timing of initial cleavage was determined by live-cell imaging, while subsequent divisions, cytoskeletal organization and lineage marker labeling were assessed by high-resolution fluorescence microscopy. Our analysis reveals that brief culture with BPA or BPF impeded cell division and disrupted embryo development at all stages tested. Surprisingly, BPF was more detrimental to the early embryo than BPA. Notably, poor embryo development was associated with cytoskeletal disruptions of the actomyosin network, apical domain formation during cell polarization, actin ring zippering for embryo sealing and altered cell lineage marker profiles. These results underscore that bisphenols can disrupt cytoskeletal integrity and remodeling that is vital for early embryo development and raise concerns regarding the use of BPF as a ‘safe’ BPA substitute. Full article

(This article belongs to the Special Issue Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos)

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14 pages, 2600 KiB

Open AccessArticle

Di-n-Butyl Phthalate and Its Monoester Metabolite Impairs Steroid Hormone Biosynthesis in Human Cells: Mechanistic In Vitro Studies

by Liselott Källsten, Paula Pierozan, Jonathan W. Martin and Oskar Karlsson

Cells 2022, 11(19), 3029; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11193029 - 27 Sep 2022

Cited by 6 | Viewed by 4159

Abstract

The widespread environmental contaminant di-n-butyl phthalate (DBP) has been linked with reduced testosterone levels and adverse reproductive health outcomes in men. However, the underlying mechanisms of these anti-androgenic effects and the potential effects on other classes of steroid hormones remain to be elucidated. Here, we conducted mechanistic studies in human adrenocortical H295R cells exposed to 1–500 µM of DBP or its metabolite, mono-n-butyl phthalate (MBP), for 48 h. Quantification of steroid hormones in the cell medium by liquid chromatography-mass spectrometry revealed that both phthalates significantly decreased testosterone, androstenedione, corticosterone, and progesterone levels, in particular after dibutyryl-cyclic-AMP stimulation of steroidogenesis. Western blot analysis of key steroidogenic proteins showed that DBP induced a dose-dependent decrease of CYP11A1 and HSD3β2 levels, while MBP only significantly decreased CYP17A1 levels, indicating that the compounds affect early steps of the steroidogenesis differently. Both DBP and MBP exposure also lead to a dose-related decrease in HSD17β3, the enzyme which catalyzes the final step in the testosterone biosynthesis pathway, although these effects were not statistically significant. Interestingly, DBP increased the cortisol concentration, which may be due to the non-significant CYP11B1 increase in DBP-exposed cells. In contrast, MBP decreased cortisol concentration. Moreover, the analysis of superoxide generation and quantification of the protein oxidation marker nitrotyrosine demonstrated that DBP induced oxidative stress in H295R cells while MBP reduced protein nitrotyrosine levels. These findings confirm the anti-androgenic effects of DBP and MBP and reveal several differences in their toxicological mechanisms, with possible implications for future research on phthalate toxicity. Full article

(This article belongs to the Special Issue Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos)

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18 pages, 3242 KiB

Open AccessArticle

Impact of In Vitro Long-Term Low-Level DEHP Exposure on Gene Expression Profile in Human Granulosa Cells

by Dragana Samardzija Nenadov, Kristina Pogrmic-Majkic, Biljana Tesic, Dunja Kokai, Svetlana Fa Nedeljkovic, Bojana Stanic and Nebojsa Andric

Cells 2022, 11(15), 2304; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11152304 - 27 Jul 2022

Cited by 5 | Viewed by 1938

Abstract

Here, we applied a model of long-term exposure of human granulosa cells to low environmentally relevant levels of di(2-ethylhexyl) phthalate (DEHP). This approach provides more relevant data regarding the impact of DEHP on the function of human granulosa cells. The immortalized human granulosa cells HGrC1 were exposed to 50 nM and 250 nM DEHP for four weeks. The cells were collected every week to analyze the basal granulosa cells’ functions. A portion of the DEHP-exposed cells was stimulated with forskolin (FOR) for 48 h. Steroidogenesis was investigated using ELISA, whereas DNBQ sequencing and RT-qPCR were used to analyze gene expression. The results show that steroidogenesis was not affected by DEHP exposure. RNAsequencing shows that DEHP caused week- and concentration-specific changes in various genes and functions in HGrC1. Sulfotransferase family 1A member 3 (SULT1A3) and 4 (SULT1A4), which are involved in catecholamine metabolism, were the most prominent genes affected by DEHP under both the basal and FOR-stimulated conditions in all four weeks of exposure. This study showed, for the first time, that SULT1A3 and SULT1A4 are expressed in human granulosa cells, are regulated by FOR, and are affected by low-level DEHP exposure. These data provide new insight into the relationship between DEHP, SULT1A3, and SULT1A4 in human granulosa cells. Full article

(This article belongs to the Special Issue Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos)

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16 pages, 2049 KiB

Open AccessArticle

Bisphenol A Analogues Suppress Spheroid Attachment on Human Endometrial Epithelial Cells through Modulation of Steroid Hormone Receptors Signaling Pathway

by Hongjie Fan, Sudini R. Fernando, Luhan Jiang, Ziyi Wang, Suranga P. Kodithuwakku, Chris K. C. Wong, Ernest H. Y. Ng, William S. B. Yeung and Kai-Fai Lee

Cells 2021, 10(11), 2882; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112882 - 26 Oct 2021

Cited by 8 | Viewed by 3351

Abstract

Bisphenol A (BPA) is a well-known endocrine disruptor, widely used in various consumer products and ubiquitously found in air, water, food, dust, and sewage leachates. Recently, several countries have restricted the use of BPA and replaced them with bisphenol S (BPS) and bisphenol F (BPF), which have a similar chemical structure to BPA. Compared to BPA, both BPS and BPF have weaker estrogenic effects, but their effects on human reproductive function including endometrial receptivity and embryo implantation still remain largely unknown. We used an in vitro spheroid (blastocyst surrogate) co-culture assay to investigate the effects of BPA, BPS, and BPF on spheroid attachment on human endometrial epithelial cells, and further delineated their role on steroid hormone receptor expression. We also used transcriptomics to investigate the effects of BPA, BPS, and BPF on the transcriptome of human endometrial cells. We found that bisphenol treatment in human endometrial Ishikawa cells altered estrogen receptor alpha (ERα) signaling and upregulated progesterone receptors (PR). Bisphenols suppressed spheroid attachment onto Ishikawa cells, which was reversed by the downregulation of PR through PR siRNA. Overall, we found that bisphenol compounds can affect human endometrial epithelial cell receptivity through the modulation of steroid hormone receptor function leading to impaired embryo implantation. Full article

(This article belongs to the Special Issue Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos)

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Review

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24 pages, 1216 KiB

Open AccessReview

Multi- and Transgenerational Effects of Environmental Toxicants on Mammalian Reproduction

by Paola Rebuzzini, Gemma Fabozzi, Danilo Cimadomo, Filippo Maria Ubaldi, Laura Rienzi, Maurizio Zuccotti and Silvia Garagna

Cells 2022, 11(19), 3163; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11193163 - 09 Oct 2022

Cited by 10 | Viewed by 2516

Abstract

Environmental toxicants (ETs) are an exogenous chemical group diffused in the environment that contaminate food, water, air and soil, and through the food chain, they bioaccumulate into the organisms. In mammals, the exposure to ETs can affect both male and female fertility and their reproductive health through complex alterations that impact both gametogeneses, among other processes. In humans, direct exposure to ETs concurs to the declining of fertility, and its transmission across generations has been recently proposed. However, multi- and transgenerational inheritances of ET reprotoxicity have only been demonstrated in animals. Here, we review recent studies performed on laboratory model animals investigating the effects of ETs, such as BPA, phthalates, pesticides and persistent contaminants, on the reproductive system transmitted through generations. This includes multigenerational effects, where exposure to the compounds cannot be excluded, and transgenerational effects in unexposed animals. Additionally, we report on epigenetic mechanisms, such as DNA methylation, histone tails and noncoding RNAs, which may play a mechanistic role in a nongenetic transmission of environmental information exposure through the germline across generations. Full article

(This article belongs to the Special Issue Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos)

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33 pages, 2042 KiB

Open AccessReview

Review: Mechanisms of Glyphosate and Glyphosate-Based Herbicides Action in Female and Male Fertility in Humans and Animal Models

by Loïse Serra, Anthony Estienne, Claudine Vasseur, Pascal Froment and Joëlle Dupont

Cells 2021, 10(11), 3079; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113079 - 08 Nov 2021

Cited by 16 | Viewed by 7897

Abstract

Glyphosate (G), also known as N-(phosphonomethyl)glycine is the declared active ingredient of glyphosate-based herbicides (GBHs) such as Roundup largely used in conventional agriculture. It is always used mixed with formulants. G acts in particular on the shikimate pathway, which exists in bacteria, for aromatic amino acids synthesis, but this pathway does not exist in vertebrates. In recent decades, researchers have shown by using various animal models that GBHs are endocrine disruptors that might alter reproductive functions. Our review describes the effects of exposure to G or GBHs on the hypothalamic–pituitary–gonadal (HPG) axis in males and females in terms of endocrine disruption, cell viability, and proliferation. Most of the main regulators of the reproductive axis (GPR54, GnRH, LH, FSH, estradiol, testosterone) are altered at all levels of the HPG axis (hypothalamus, pituitary, ovaries, testis, placenta, uterus) by exposure to GBHs which are considered more toxic than G alone due to the presence of formulants such as polyoxyethylene tallow amine (POEA).” In addition, we report intergenerational impacts of exposure to G or GBHs and, finally, we discuss different strategies to reduce the negative effects of GBHs on fertility. Full article

(This article belongs to the Special Issue Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos)

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20 pages, 2165 KiB

Open AccessReview

NF-κB—An Important Player in Xenoestrogen Signaling in Immune Cells

by Karolina Nowak, Ewa Jabłońska and Wioletta Ratajczak-Wrona

Cells 2021, 10(7), 1799; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071799 - 16 Jul 2021

Cited by 2 | Viewed by 3343

Abstract

The proper functioning of the immune system is critical for an effective defense against pathogenic factors such as bacteria and viruses. All the cellular processes taking place in an organism are strictly regulated by an intracellular network of signaling pathways. In the case of immune cells, the NF-κB pathway is considered the key signaling pathway as it regulates the expression of more than 200 genes. The transcription factor NF-κB is sensitive to exogenous factors, such as xenoestrogens (XEs), which are compounds mimicking the action of endogenous estrogens and are widely distributed in the environment. Moreover, XE-induced modulation of signaling pathways may be crucial for the proper development of the immune system. In this review, we summarize the effects of XEs on the NF-κB signaling pathway. Based on our analysis, we constructed a model of XE-induced signaling in immune cells and found that in most cases XEs activate NF-κB. Our analysis indicated that the indirect impact of XEs on NF-κB in immune cells is related to the modulation of estrogen signaling and other pathways such as MAPK and JAK/STAT. We also summarize the role of these aspects of signaling in the development and further functioning of the immune system in this paper. Full article

(This article belongs to the Special Issue Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos)

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Other

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12 pages, 675 KiB

Open AccessPerspective

Endocrine-Disrupting Chemicals, Gut Microbiota, and Human (In)Fertility—It Is Time to Consider the Triad

by Gemma Fabozzi, Paola Rebuzzini, Danilo Cimadomo, Mariachiara Allori, Marica Franzago, Liborio Stuppia, Silvia Garagna, Filippo Maria Ubaldi, Maurizio Zuccotti and Laura Rienzi

Cells 2022, 11(21), 3335; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11213335 - 22 Oct 2022

Cited by 11 | Viewed by 4132

Abstract

The gut microbiota (GM) is a complex and dynamic population of microorganisms living in the human gastrointestinal tract that play an important role in human health and diseases. Recent evidence suggests a strong direct or indirect correlation between GM and both male and female fertility: on the one hand, GM is involved in the regulation of sex hormone levels and in the preservation of the blood–testis barrier integrity; on the other hand, a dysbiotic GM is linked to the onset of pro-inflammatory conditions such as endometriosis or PCOS, which are often associated with infertility. Exposure to endocrine-disrupting chemicals (EDCs) is one of the main causes of GM dysbiosis, with important consequences to the host health and potential transgenerational effects. This perspective article aims to show that the negative effects of EDCs on reproduction are in part due to a dysbiotic GM. We will highlight (i) the link between GM and male and female fertility; (ii) the mechanisms of interaction between EDCs and GM; and (iii) the importance of the maternal–fetal GM axis for offspring growth and development. Full article

(This article belongs to the Special Issue Effects and Mechanisms of Endocrine Disruptors on Germ Cells, Gonads and Embryos)

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