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Molecular Research on Reproductive Toxicity

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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 (31 August 2022) | Viewed by 20299

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Prof. Dr. Rosaria Scudiero

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Department of Biology, University of Naples, Federico II, 80126 Naples, Italy
Interests: cytotoxicology; environmental toxicology; metals toxicity; oviparous vertebrates development; reproductive toxicology
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Special Issue Information

Dear Colleagues,

In recent years, environmental contamination has strongly affected the reproductive system at all levels, from gametogenesis to embryonic development. This may represent a risk for the survival of Humans and Animals, especially in areas where environmental pollution is higher concentrated. Understanding the molecular mechanisms of the toxic effects induced by various physical and chemical insults on reproduction and development would help the knowledge of basic reproductive processes, as well as improve and increase the strategies to be implemented in defense of humans and animals' reproductive success.

This special issue focuses on all aspects of reproductive toxicology induced by different insults. Potential topics include, but are not limited to, physical and chemical insults and their effects on the endocrine system, gametogenesis, sexual function, embryogenesis, and offspring survival. This special issue focuses on molecular biology and experimental studies in vitro and in vivo. Typical endpoints include infertility, sexual dysfunction, endocrine disruption, embryonic malformations and teratogenesis, behavioral abnormalities and perinatal mortality. This special issue will publish original research articles and comprehensive reviews. The introduction of new techniques to protect and mitigate the impact of insults and improve reproductive fitness is also welcome.

Prof. Dr. Rosaria Scudiero
Guest Editor

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Keywords

cell toxicology
embryogenesis
embryonic gene regulation
endocrine disruption
environmental stressors
gametogenesis
gene expression
larval development
reproductive toxicology
teratogenesis

Published Papers (11 papers)

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Editorial

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4 pages, 184 KiB

Open AccessEditorial

Molecular Research on Reproductive Toxicity

by Rosaria Scudiero

Int. J. Mol. Sci. 2023, 24(4), 3538; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043538 - 10 Feb 2023

Viewed by 1066

Abstract

Fertility rates in animals have shown a progressive decrease in recent decades, and reproductive toxicity is considered an important regulatory endpoint in health hazard assessment [...] Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

Research

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10 pages, 741 KiB

Open AccessArticle

In Vitro Combination of Ascorbic and Ellagic Acids in Sperm Oxidative Damage Inhibition

by Filomena Mottola, Concetta Iovine, Maria Carannante, Marianna Santonastaso and Lucia Rocco

Int. J. Mol. Sci. 2022, 23(23), 14751; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314751 - 25 Nov 2022

Cited by 5 | Viewed by 1285

Abstract

It is known that an altered redox balance interferes with normal spermatic functions. Exposure to genotoxic substances capable of producing oxidative stress (OS) can cause infertility in humans. The use of antioxidants to reduce oxidative stress contributes to the improvement in reproductive function. This study focused on an antigenotoxic evaluation of ellagic acid (EA) and ascorbic acid (AA) in combination against benzene genotoxic action on human spermatozoa in vitro. In addition to the evaluation of sperm parameters, damage in sperm genetic material and intracellular ROS quantification were assessed after AA, EA and benzene co-exposure using the TUNEL technique and DCF assay. The results showed that the combination of the two antioxidants generates a greater time-dependent antigenotoxic action, reducing both the sperm DNA fragmentation index and the oxidative stress. The genoprotective effect of AA and EA association in sperm cells lays the foundations for a more in-depth clinical study on the use of antioxidants as a therapy for male infertility. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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15 pages, 1326 KiB

Open AccessArticle

Candesartan Does Not Activate PPARγ and Its Target Genes in Early Gestation Trophoblasts

by Lena Neuper, Daniel Kummer, Désirée Forstner, Jacqueline Guettler, Nassim Ghaffari-Tabrizi-Wizsy, Cornelius Fischer, Herbert Juch, Olivia Nonn and Martin Gauster

Int. J. Mol. Sci. 2022, 23(20), 12326; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012326 - 14 Oct 2022

Cited by 1 | Viewed by 1674

Abstract

Angiotensin II receptor 1 blockers are commonly used to treat hypertension in women of childbearing age. While the fetotoxic effects of these drugs in the second and third trimesters of pregnancy are well documented, their possible impacts on placenta development in early gestation are unknown. Candesartan, a member of this group, also acts as a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, a key regulator shown to be important for placental development. We have previously shown that trophoblasts do not express the candesartan target–receptor angiotensin II type 1 receptor AGTR1. This study investigated the possible role of candesartan on trophoblastic PPARγ and its hallmark target genes in early gestation. Candesartan did not affect the PPARγ protein expression or nuclear translocation of PPARγ. To mimic extravillous trophoblasts (EVTs) and cytotrophoblast/syncytiotrophoblast (CTB/SCT) responses to candesartan, we used trophoblast cell models BeWo (for CTB/SCT) and SGHPL-4 (EVT) cells as well as placental explants. In vitro, the RT-qPCR analysis showed no effect of candesartan treatment on PPARγ target genes in BeWo or SGHPL-4 cells. Treatment with positive control rosiglitazone, another PPARγ agonist, led to decreased expressions of LEP and PPARG1 in BeWo cells and an increased expression of PPARG1 in SGHPL-4 cells. Our previous data showed early gestation–placental AGTR1 expression in fetal myofibroblasts only. In a CAM assay, AGTR1 was stimulated with angiotensin II and showed increased on-plant vessel outgrowth. These results suggest candesartan does not negatively affect PPARγ or its target genes in human trophoblasts. More likely, candesartan from maternal serum may first act on fetal-placental AGTR1 and influence angiogenesis in the placenta, warranting further research. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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23 pages, 3115 KiB

Open AccessArticle

Unbalanced Expression of Glutathione Peroxidase 4 and Arachidonate 15-Lipoxygenase Affects Acrosome Reaction and In Vitro Fertilization

by Mariana Soria-Tiedemann, Geert Michel, Iris Urban, Maceler Aldrovandi, Valerie B. O’Donnell, Sabine Stehling, Hartmut Kuhn and Astrid Borchert

Int. J. Mol. Sci. 2022, 23(17), 9907; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179907 - 31 Aug 2022

Cited by 4 | Viewed by 1590

Abstract

Glutathione peroxidase 4 (Gpx4) and arachidonic acid 15 lipoxygenase (Alox15) are counterplayers in oxidative lipid metabolism and both enzymes have been implicated in spermatogenesis. However, the roles of the two proteins in acrosomal exocytosis have not been explored in detail. Here we characterized Gpx4 distribution in mouse sperm and detected the enzyme not only in the midpiece of the resting sperm but also at the anterior region of the head, where the acrosome is localized. During sperm capacitation, Gpx4 translocated to the post-acrosomal compartment. Sperm from Gpx4^+/Sec46Ala mice heterozygously expressing a catalytically silent enzyme displayed an increased expression of phosphotyrosyl proteins, impaired acrosomal exocytosis after in vitro capacitation and were not suitable for in vitro fertilization. Alox15-deficient sperm showed normal acrosome reactions but when crossed into a Gpx4-deficient background spontaneous acrosomal exocytosis was observed during capacitation and these cells were even less suitable for in vitro fertilization. Taken together, our data indicate that heterozygous expression of a catalytically silent Gpx4 variant impairs acrosomal exocytosis and in vitro fertilization. Alox15 deficiency hardly impacted the acrosome reaction but when crossed into the Gpx4-deficient background spontaneous acrosomal exocytosis was induced. The detailed molecular mechanisms for the observed effects may be related to the compromised redox homeostasis. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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18 pages, 4159 KiB

Open AccessArticle

Transcriptomic Profiling Revealed Signaling Pathways Associated with the Spawning of Female Zebrafish under Cold Stress

by Guodong Ge, Yong Long, Guili Song, Qing Li, Zongbin Cui and Huawei Yan

Int. J. Mol. Sci. 2022, 23(14), 7494; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147494 - 06 Jul 2022

Cited by 6 | Viewed by 1822

Abstract

As one of the critical abiotic factors, temperature controls fish development and reproduction. However, the effects of low temperature on the transcriptional regulation of zebrafish reproduction remain largely unclear. In this study, the fecundity of zebrafish was examined after exposure to cold temperatures at 19.5 °C, 19 °C, 18.5 °C, or 18 °C. The temperature at 19 °C showed no significant influence on the fecundity of zebrafish, but temperature at 18.5 °C or 18 °C significantly blocked the spawning of females, suggesting the existence of a low temperature critical point for the spawning of zebrafish females. Based on these observations, the brains of anesthetized fish under cold stress at different cold temperatures were collected for high-throughput RNA-seq assays. Key genes, hub pathways and important biological processes responding to cold temperatures during the spawning of zebrafish were identified through bioinformatic analysis. The number of down-regulated and up-regulated genes during the temperature reduction from egg-spawning temperatures at 19.5 °C and 19 °C to non-spawning temperatures at 18.5 °C and 18 °C were 2588 and 2527 (fold change ≥ 1.5 and p-value ≤ 0.01), respectively. Venn analysis was performed to identify up- and down-regulated key genes. KEGG enrichment analysis indicated that the hub pathways overrepresented among down-regulated key genes included the GnRH signaling pathway, vascular smooth muscle contraction, C-type lectin receptor signaling pathway, phosphatidylinositol signaling system and insulin signaling pathway. GO enrichment analysis of down-regulated key genes revealed the most important biological processes inhibited under non-spawning temperatures at 18.5 °C and 18 °C were photoreceptor cell outer segment organization, circadian regulation of gene expression and photoreceptor cell maintenance. Furthermore, 99 hormone-related genes were found in the brain tissues of non-spawning and spawning groups, and GnRH signaling pathway and insulin signaling pathway were enriched from down-regulated genes related to hormones at 18.5 °C and 18 °C. Thus, these findings uncovered crucial hormone-related genes and signaling pathways controlling the spawning of female zebrafish under cold stress. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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16 pages, 3506 KiB

Open AccessArticle

Effect of Passage Number of Conditioned Medium Collected from Equine Amniotic Fluid Mesenchymal Stem Cells: Porcine Oocyte Maturation and Embryo Development

by Ahyoung Park, Hyun Ju Oh, Kukbin Ji, Eunha Miri Choi, Dongern Kim, Eunyoung Kim and Min Kyu Kim

Int. J. Mol. Sci. 2022, 23(12), 6569; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126569 - 12 Jun 2022

Cited by 7 | Viewed by 2262

Abstract

Oocyte in vitro maturation (IVM) is the most important first step in in vitro embryo production. One prerequisite for the success of IVM in oocytes is to provide a rich culture microenvironment that meets the nutritional needs of developing oocytes. We applied different equine amniotic fluid mesenchymal stem cell conditioned medium (eAFMSC-CM) from passages 7, 18, and 27 to porcine oocytes during IVM to determine its effects on oocyte development and subsequent embryo development, specifically. The eAFMSC-CM from passage 7 (eAFMSC-CMp7) has a considerable impact on 9 genes: BAX, BCL2, SOD2, NRF2, TNFAIP6, PTGS2, HAS2, Cx37, and Cx43, which are associated with cumulus cell mediated oocyte maturation. GSH levels and distribution of mitochondrial and cortical granules were significantly increased in oocytes incubated with eAFMSC-CMp7. In addition, catalase and superoxide dismutase activities were high after IVM 44 h with eAFMSC-CMp7. After in vitro fertilization, blastocyst quality was significantly increased in the eAFMSC-CMp7 group compared to control. Lastly, the antioxidant effect of eAFMSC-CMp7 substantially regulated the expression of apoptosis, pluripotency related genes and decreased autophagy activity in blastocysts. Taken together, this study demonstrated that the eAFMSC-CMp7 enhanced the cytoplasmic maturation of oocytes and subsequent embryonic development by generating high antioxidant activity. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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13 pages, 4281 KiB

Open AccessArticle

Toxicity of Vanadium during Development of Sea Urchin Embryos: Bioaccumulation, Calcium Depletion, ERK Modulation and Cell-Selective Apoptosis

by Roberto Chiarelli, Rosaria Scudiero, Valeria Memoli, Maria Carmela Roccheri and Chiara Martino

Int. J. Mol. Sci. 2022, 23(11), 6239; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116239 - 02 Jun 2022

Cited by 2 | Viewed by 1546

Abstract

Vanadium toxicology is a topic of considerable importance as this metal is widely used in industrial and biomedical fields. However, it represents a potential emerging environmental pollutant because wastewater treatment plants do not adequately remove metal compounds that are subsequently released into the environment. Vanadium applications are limited due to its toxicity, so it is urgent to define this aspect. This metal is associated with sea urchin embryo toxicity as it perturbs embryogenesis and skeletogenesis, triggering several stress responses. Here we investigated its bioaccumulation and the correlation with cellular and molecular developmental pathways. We used cytotoxic concentrations of 1 mM and 500 μM to perform quantitative analyses, showing that vanadium accumulation interferes with calcium uptake during sea urchin development and provokes a disruption in the biomineralization process. At the end of the whole treatment, the accumulation of vanadium was about 14 and 8 μg for embryos treated respectively with 1 mM and 500 μM, showing a dose-dependent response. Then, we monitored the cell signaling perturbation, analyzing key molecular markers of cell survival/cell death mechanisms and the DNA fragmentation associated with apoptosis. This paper clarifies vanadium’s trend to accumulate directly into embryonic cells, interfering with calcium uptake. In addition, our results indicate that vanadium can modulate the ERK pathway and activate a cell-selective apoptosis. These results endorse the sea urchin embryo as an adequate experimental model to study metal-related cellular/molecular responses. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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16 pages, 6555 KiB

Open AccessArticle

Molecular and Histological Effects of Glyphosate on Testicular Tissue of the Lizard Podarcis siculus

by Mariailaria Verderame, Teresa Chianese, Luigi Rosati and Rosaria Scudiero

Int. J. Mol. Sci. 2022, 23(9), 4850; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094850 - 27 Apr 2022

Cited by 11 | Viewed by 1930

Abstract

The expansion of agriculture produces a steady increase in habitat fragmentation and degradation due to the increased use of pesticides and herbicides. Habitat loss and alteration associated with crop production play an important role in reptile decline, among which lizards are particularly endangered. In this study, we evaluated testicular structure, steroidogenesis, and estrogen receptor expression/localization after three weeks of oral exposure to glyphosate at 0.05 and 0.5 μg/kg body weight every other day in the field lizard Podarcis siculus. Our results show that glyphosate affected testicular morphology, reduced spermatogenesis, altered gap junctions and changed the localization of estrogen receptors in germ cells, increasing their expression; the effects were mostly dose-dependent. The result also demonstrates that glyphosate, at least at these concentrations, did not influence steroidogenesis. Overall, the data indicate that this herbicide can disturb the morphophysiology of the male lizard’s reproductive system, with obviously detrimental effects on their reproductive fitness. The effects of glyphosate must be considered biologically relevant and could endanger the reproductive capacity not only of lizards but also of other vertebrates, including humans; a more controlled and less intensive use of glyphosate in areas devoted to crop production would therefore be advisable. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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Review

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14 pages, 3679 KiB

Open AccessReview

The Italian Wall Lizard Podarcis siculus as a Biological Model for Research in Male Reproductive Toxicology

by Luigi Rosati, Teresa Chianese, Palma Simoniello, Chiara Maria Motta and Rosaria Scudiero

Int. J. Mol. Sci. 2022, 23(23), 15220; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315220 - 02 Dec 2022

Cited by 3 | Viewed by 1488

Abstract

Spermatogenesis is a genetically driven differentiation process that occurs in the testis and leads to the formation of spermatozoa. This process is extensively studied in several experimental models, particularly in vertebrates that share the morphological structure and functionality of the mammalian testis. Although reptiles are not generally considered biological models, the lizard Podarcis siculus has represented a suitable organism for the study of spermatogenesis over the years. In this lizard, the process of spermatogenesis is regulated by the interaction between systemic factors such as gonadotropins and local factors, i.e., molecules produced by the somatic and germinal cells of the testis. Many exogenous substances are able to alter the production of these regulative factors, thus altering the course of spermatogenesis, and P. siculus has proven to be an excellent model for studying the effects of various endogenous or exogenous substances on mechanisms underlying spermatogenesis. This review summarizes the available data on the effects of different substances on the control of spermatogenesis, highlighting the induced morphological and molecular alterations. Overall, the data show that sex hormone levels as well as the final stages of spermatogenesis are most affected by an imbalance of endogenous compounds or contamination by environmental pollutants. This is helpful for the male individual, since the damage, not affecting the spermatogonial stem cells, can be considered transient and not irreversible. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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19 pages, 1077 KiB

Open AccessReview

Effect of Neonicotinoid Pesticides on Japanese Water Systems: Review with Focus on Reproductive Toxicity

by Hayato Terayama, Kou Sakabe, Daisuke Kiyoshima, Ning Qu, Tsutomu Sato, Kaori Suyama, Shogo Hayashi, Kenichi Sakurai, Emiko Todaka and Chisato Mori

Int. J. Mol. Sci. 2022, 23(19), 11567; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911567 - 30 Sep 2022

Cited by 8 | Viewed by 2282

Abstract

Neonicotinoid pesticides (NPs) are neurotoxic substances. They are highly effective as insecticides owing to their water solubility, permeability, and long-lasting activity. These molecules are structurally similar to nicotine and act as nicotinic acetylcholine receptor agonists. The administration of NPs to experimental animals reportedly causes neuromuscular and reproductive disorders. Moreover, recently reported problems caused by NPs include damage to land-dwelling creatures (such as mammals and birds), hydrobiology, and ecosystems. This review summarizes the recent reports on NP concentrations detected in river systems in several Japanese regions. These values were lower than the environmental standard values; however, seasonal variations were observed. Furthermore, reports on NP-induced testicular and ovarian toxicity were examined, revealing that the mechanism of injury is mainly driven by oxidative stress. The use of NPs is declining worldwide, except in Japan; therefore, continuous monitoring remains necessary. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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13 pages, 858 KiB

Open AccessReview

Toxicological Impact of Rare Earth Elements (REEs) on the Reproduction and Development of Aquatic Organisms Using Sea Urchins as Biological Models

by Chiara Martino, Teresa Chianese, Roberto Chiarelli, Maria Carmela Roccheri and Rosaria Scudiero

Int. J. Mol. Sci. 2022, 23(5), 2876; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052876 - 06 Mar 2022

Cited by 8 | Viewed by 2561

Abstract

The growing presence of lanthanides in the environment has drawn the attention of the scientific community on their safety and toxicity. The sources of lanthanides in the environment include diagnostic medicine, electronic devices, permanent magnets, etc. Their exponential use and the poor management of waste disposal raise serious concerns about the quality and safety of the ecosystems at a global level. This review focused on the impact of lanthanides in marine organisms on reproductive fitness, fertilization and embryonic development, using the sea urchin as a biological model system. Scientific evidence shows that exposure to lanthanides triggers a wide variety of toxic insults, including reproductive performance, fertilization, redox metabolism, embryogenesis, and regulation of embryonic gene expression. This was thoroughly demonstrated for gadolinium, the most widely used lanthanide in diagnostic medicine, whose uptake in sea urchin embryos occurs in a time- and concentration-dependent manner, correlates with decreased calcium absorption and primarily affects skeletal growth, with incorrect regulation of the skeletal gene regulatory network. The results collected on sea urchin embryos demonstrate a variable sensitivity of the early life stages of different species, highlighting the importance of testing the effects of pollution in different species. The accumulation of lanthanides and their emerging negative effects make risk assessment and consequent legislative intervention on their disposal mandatory. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Toxicity)

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