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Reproductive and Developmental Toxicology 2.0

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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 December 2021) | Viewed by 37732

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Prof. Dr. Louise C. Abbott

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Department of Veterinary Integrative Biosciences (VIBS), School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4458, USA
Interests: toxicology; reproductive toxicology; developmental toxicology
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Special Issue Information

Dear Colleagues,

The fields of reproductive and developmental toxicology are complex areas of considerable importance and intense study, not just for the human population, but also for all animal species. Reproductive systems and developing embryos and fetuses exhibit increased risks of adverse effects due to exposure to a broad range of toxicants, from pharmaceuticals to environmental contaminants. New information concerning risk levels, as well as ways to mitigate risk, are gained using in vitro, in silico, and in vivo toxicity model studies. Research about the effects of toxicants on the process of reproduction and on developing individuals requires investigation at all levels of scientific inquiry—molecular, physiological and anatomical—and the importance of genetic makeup in response to toxicant exposure is just being realized. Individuals may encounter substances that have potentially harmful effects on reproductive health or the developing embryo and fetus anywhere in the environment, through water, air, soil, dust, food, or consumer products. The goal of all toxicology research is to utilize reliable and predictive toxicity testing to understand and prevent exposure to potentially harmful toxicants of reproducing animals and humans, as well as developing individuals. This Special Issue focuses on reproductive and developmental toxicology. We invite authors to submit manuscripts that study the molecular mechanism of any toxicant with adverse effects on male and female reproductive systems or the developing embryo or fetus.

Prof. Dr. Louise Abbott
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

reproductive toxicity
reproductive toxicology
developmental toxicology
embryo toxicity
fetal toxicity
environmental exposures

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

2 pages, 158 KiB

Open AccessEditorial

Exposure to Toxicants Affects Everyone, Especially the Very Young

by Louise C. Abbott

Int. J. Mol. Sci. 2022, 23(13), 7232; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137232 - 29 Jun 2022

Cited by 3 | Viewed by 1025

Abstract

Toxicology is an incredibly complex and diverse area of biomedical science that includes numerous areas of specialization [...] Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

Research

Jump to: Editorial, Review

30 pages, 10546 KiB

Open AccessArticle

The Human Induced Pluripotent Stem Cell Test as an Alternative Method for Embryotoxicity Testing

by Saskia Galanjuk, Etta Zühr, Arif Dönmez, Deniz Bartsch, Leo Kurian, Julia Tigges and Ellen Fritsche

Int. J. Mol. Sci. 2022, 23(6), 3295; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063295 - 18 Mar 2022

Cited by 5 | Viewed by 3126

Abstract

The evaluation of substances for their potency to induce embryotoxicity is controlled by safety regulations. Test guidelines for reproductive and developmental toxicity rely mainly on animal studies, which make up the majority of animal usage in regulatory toxicology. Therefore, there is an urgent need for alternative in vitro methods to follow the 3R principles. To improve human safety, cell models based on human cells are of great interest to overcome species differences. Here, human induced pluripotent stem cells (hiPSCs) are an ideal cell source as they largely recapitulate embryonic stem cells without bearing ethical concerns and they are able to differentiate into most cell types of the human body. Here, we set up and characterized a fetal bovine serum (FBS)-free hiPSC-based in vitro test method, called the human induced pluripotent stem cell test (hiPS Test), to evaluate the embryotoxic potential of substances. After 10 days in culture, hiPSCs develop into beating cardiomyocytes. As terminal endpoint evaluations, cell viability, qPCR analyses as well as beating frequency and area of beating cardiomyocytes by video analyses are measured. The embryotoxic positive and non-embryotoxic negative controls, 5-Fluorouracil (5-FU) and Penicillin G (PenG), respectively, were correctly assessed in the hiPS Test. More compounds need to be screened in the future for defining the assay’s applicability domain, which will inform us of the suitability of the hiPS Test for detecting adverse effects of substances on embryonic development. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

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15 pages, 2311 KiB

Open AccessArticle

PAHs and PCBs Affect Functionally Intercorrelated Genes in the Sea Urchin Paracentrotus lividus Embryos

by Luisa Albarano, Valerio Zupo, Marco Guida, Giovanni Libralato, Davide Caramiello, Nadia Ruocco and Maria Costantini

Int. J. Mol. Sci. 2021, 22(22), 12498; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212498 - 19 Nov 2021

Cited by 11 | Viewed by 1873

Abstract

Polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) represent the most common pollutants in the marine sediments. Previous investigations demonstrated short-term sublethal effects of sediments polluted with both contaminants on the sea urchin Paracentrotus lividus after 2 months of exposure in mesocosms. In particular, morphological malformations observed in P. lividus embryos deriving from adults exposed to PAHs and PCBs were explained at molecular levels by de novo transcriptome assembly and real-time qPCR, leading to the identification of several differentially expressed genes involved in key physiological processes. Here, we extensively explored the genes involved in the response of the sea urchin P. lividus to PAHs and PCBs. Firstly, 25 new genes were identified and interactomic analysis revealed that they were functionally connected among them and to several genes previously defined as molecular targets of response to the two pollutants under analysis. The expression levels of these 25 genes were followed by Real Time qPCR, showing that almost all genes analyzed were affected by PAHs and PCBs. These findings represent an important further step in defining the impacts of slight concentrations of such contaminants on sea urchins and, more in general, on marine biota, increasing our knowledge of molecular targets involved in responses to environmental stressors. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

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15 pages, 3759 KiB

Open AccessArticle

Developmental Toxicology of Metal Mixtures in Drosophila: Unique Properties of Potency and Interactions of Mercury Isoforms

by Catherine R. Beamish, Tanzy M. Love and Matthew D. Rand

Int. J. Mol. Sci. 2021, 22(22), 12131; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212131 - 09 Nov 2021

Cited by 10 | Viewed by 2072

Abstract

Mercury ranks third on the U.S. Agency of Toxic Substances and Disease Registry priority list of hazardous substances, behind only arsenic and lead. We have undertaken uncovering the mechanisms underlying the developmental toxicity of methylmercury (MeHg), inorganic mercury (HgCl₂), lead acetate (Pb), and sodium arsenite (As). To probe these differences, we used the Drosophila model, taking advantage of three developmental transitions—pupariation, metamorphosis, and eclosion—to differentiate potentially unique windows of toxicity. We elaborated dose response profiles for each individual metal administered in food and accounted for internal body burden, also extending analyses to evaluate combinatorial metal mixture effects. We observed all four metals producing larval lethality and delayed pupariation, with MeHg being most potent. Compared to other metals, MeHg’s potency is caused by a higher body burden with respect to dose. MeHg uniquely caused dose-dependent failure in eclosion that was unexpectedly rescued by titrating in HgCl₂. Our results highlight a unique developmental window and toxicokinetic properties where MeHg acts with specificity relative to HgCl₂, Pb, and As. These findings will serve to refine future studies aimed at revealing tissue morphogenesis events and cell signaling pathways, potentially conserved in higher organisms, that selectively mediate MeHg toxicity and its antagonism by HgCl₂. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

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25 pages, 2035 KiB

Open AccessArticle

GSH and Zinc Supplementation Attenuate Cadmium-Induced Cellular Stress and Stimulation of Choline Uptake in Cultured Neonatal Rat Choroid Plexus Epithelia

by Samantha D. Francis Stuart and Alice R. Villalobos

Int. J. Mol. Sci. 2021, 22(16), 8857; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168857 - 17 Aug 2021

Cited by 4 | Viewed by 2223

Abstract

Choroid plexus (CP) sequesters cadmium and other metals, protecting the brain from these neurotoxins. These metals can induce cellular stress and modulate homeostatic functions of CP, such as solute transport. We previously showed in primary cultured neonatal rat CP epithelial cells (CPECs) that cadmium induced cellular stress and stimulated choline uptake at the apical membrane, which interfaces with cerebrospinal fluid in situ. Here, in CPECs, we characterized the roles of glutathione (GSH) and Zinc supplementation in the adaptive stress response to cadmium. Cadmium increased GSH and decreased the reduced GSH-to-oxidized GSH (GSSG) ratio. Heat shock protein-70 (Hsp70), heme oxygenase (HO-1), and metallothionein (Mt-1) were induced along with the catalytic and modifier subunits of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH synthesis. Inhibition of GCL by l-buthionine sulfoximine (BSO) enhanced stress protein induction and stimulation of choline uptake by cadmium. Zinc alone did not induce Hsp70, HO-1, or GCL subunits, or modulate choline uptake. Zinc supplementation during cadmium exposure attenuated stress protein induction and stimulation of choline uptake; this effect persisted despite inhibition of GSH synthesis. These data indicated up-regulation of GSH synthesis promotes adaptation to cadmium-induced cellular stress in CP, but Zinc may confer cytoprotection independent of GSH. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

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20 pages, 8324 KiB

Open AccessArticle

Co-Treatment of Copper Oxide Nanoparticle and Carbofuran Enhances Cardiotoxicity in Zebrafish Embryos

by Ferry Saputra, Boontida Uapipatanakul, Jiann-Shing Lee, Shih-Min Hung, Jong-Chin Huang, Yun-Chieh Pang, John Emmanuel R. Muñoz, Allan Patrick G. Macabeo, Kelvin H.-C. Chen and Chung-Der Hsiao

Int. J. Mol. Sci. 2021, 22(15), 8259; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158259 - 31 Jul 2021

Cited by 16 | Viewed by 2963

Abstract

The use of chemicals to boost food production increases as human consumption also increases. The insectidal, nematicidal and acaricidal chemical carbofuran (CAF), is among the highly toxic carbamate pesticide used today. Alongside, copper oxide nanoparticles (CuO) are also used as pesticides due to their broad-spectrum antimicrobial activity. The overuse of these pesticides may lead to leaching into the aquatic environments and could potentially cause adverse effects to aquatic animals. The aim of this study is to assess the effects of carbofuran and copper oxide nanoparticles into the cardiovascular system of zebrafish and unveil the mechanism behind them. We found that a combination of copper oxide nanoparticle and carbofuran increases cardiac edema in zebrafish larvae and disturbs cardiac rhythm of zebrafish. Furthermore, molecular docking data show that carbofuran inhibits acetylcholinesterase (AChE) activity in silico, thus leading to impair cardiac rhythms. Overall, our data suggest that copper oxide nanoparticle and carbofuran combinations work synergistically to enhance toxicity on the cardiovascular performance of zebrafish larvae. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

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Review

Jump to: Editorial, Research

16 pages, 633 KiB

Open AccessReview

Looking at Developmental Neurotoxicity Testing from the Perspective of an Invertebrate Embryo

by Gerd Bicker

Int. J. Mol. Sci. 2022, 23(3), 1871; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031871 - 07 Feb 2022

Cited by 3 | Viewed by 1683

Abstract

Developmental neurotoxicity (DNT) of chemical compounds disrupts the formation of a normal brain. There is impressive progress in the development of alternative testing methods for DNT potential in chemicals, some of which also incorporate invertebrate animals. This review briefly touches upon studies on the genetically tractable model organisms of Caenorhabditis elegans and Drosophila melanogaster about the action of specific developmental neurotoxicants. The formation of a functional nervous system requires precisely timed axonal pathfinding to the correct cellular targets. To address this complex key event, our lab developed an alternative assay using a serum-free culture of intact locust embryos. The first neural pathways in the leg of embryonic locusts are established by a pair of afferent pioneer neurons which use guidance cues from membrane-bound and diffusible semaphorin proteins. In a systematic approach according to recommendations for alternative testing, the embryo assay quantifies defects in pioneer navigation after exposure to a panel of recognized test compounds for DNT. The outcome indicates a high predictability for test-compound classification. Since the pyramidal neurons of the mammalian cortex also use a semaphorin gradient for neurite guidance, the assay is based on evolutionary conserved cellular mechanisms, supporting its relevance for cortical development. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

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15 pages, 956 KiB

Open AccessReview

Effects of Aluminium Contamination on the Nervous System of Freshwater Aquatic Vertebrates: A Review

by Marie Closset, Katia Cailliau, Sylvain Slaby and Matthieu Marin

Int. J. Mol. Sci. 2022, 23(1), 31; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010031 - 21 Dec 2021

Cited by 11 | Viewed by 2660

Abstract

Aluminium (Al) is the most common natural metallic element in the Earth’s crust. It is released into the environment through natural processes and human activities and accumulates in aquatic environments. This review compiles scientific data on the neurotoxicity of aluminium contamination on the nervous system of aquatic organisms. More precisely, it helps identify biomarkers of aluminium exposure for aquatic environment biomonitoring in freshwater aquatic vertebrates. Al is neurotoxic and accumulates in the nervous system of aquatic vertebrates, which is why it could be responsible for oxidative stress. In addition, it activates and inhibits antioxidant enzymes and leads to changes in acetylcholinesterase activity, neurotransmitter levels, and in the expression of several neural genes and nerve cell components. It also causes histological changes in nerve tissue, modifications of organism behaviour, and cognitive deficit. However, impacts of aluminium exposure on the early stages of aquatic vertebrate development are poorly described. Lastly, this review also poses the question of how accurate aquatic vertebrates (fishes and amphibians) could be used as model organisms to complement biological data relating to the developmental aspect. This “challenge” is very relevant since freshwater pollution with heavy metals has increased in the last few decades. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

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15 pages, 846 KiB

Open AccessReview

Overview of Drug Transporters in Human Placenta

by Michiko Yamashita and Udo R. Markert

Int. J. Mol. Sci. 2021, 22(23), 13149; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313149 - 05 Dec 2021

Cited by 11 | Viewed by 3460

Abstract

The transport of drugs across the placenta is a point of great importance in pharmacotherapy during pregnancy. However, the knowledge of drug transport in pregnancy is mostly based on experimental clinical data, and the underlying biological mechanisms are not fully understood. In this review, we summarize the current knowledge of drug transporters in the human placenta. We only refer to human data since the placenta demonstrates great diversity among species. In addition, we describe the experimental models that have been used in human placental transport studies and discuss their availability. A better understanding of placental drug transporters will be beneficial for the health of pregnant women who need drug treatment and their fetuses. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

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22 pages, 1558 KiB

Open AccessReview

Toxic and Teratogenic Effects of Prenatal Alcohol Exposure on Fetal Development, Adolescence, and Adulthood

by Dae D. Chung, Marisa R. Pinson, Lokeshwar S. Bhenderu, Michael S. Lai, Rhea A. Patel and Rajesh C. Miranda

Int. J. Mol. Sci. 2021, 22(16), 8785; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168785 - 16 Aug 2021

Cited by 14 | Viewed by 11536

Abstract

Prenatal alcohol exposure (PAE) can have immediate and long-lasting toxic and teratogenic effects on an individual’s development and health. As a toxicant, alcohol can lead to a variety of physical and neurological anomalies in the fetus that can lead to behavioral and other impairments which may last a lifetime. Recent studies have focused on identifying mechanisms that mediate the immediate teratogenic effects of alcohol on fetal development and mechanisms that facilitate the persistent toxic effects of alcohol on health and predisposition to disease later in life. This review focuses on the contribution of epigenetic modifications and intercellular transporters like extracellular vesicles to the toxicity of PAE and to immediate and long-term consequences on an individual’s health and risk of disease. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

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15 pages, 1587 KiB

Open AccessReview

Mercury Toxicity and Neurogenesis in the Mammalian Brain

by Louise C. Abbott and Fikru Nigussie

Int. J. Mol. Sci. 2021, 22(14), 7520; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147520 - 14 Jul 2021

Cited by 18 | Viewed by 3323

Abstract

The mammalian brain is formed from billions of cells that include a wide array of neuronal and glial subtypes. Neural progenitor cells give rise to the vast majority of these cells during embryonic, fetal, and early postnatal developmental periods. The process of embryonic neurogenesis includes proliferation, differentiation, migration, the programmed death of some newly formed cells, and the final integration of differentiated neurons into neural networks. Adult neurogenesis also occurs in the mammalian brain, but adult neurogenesis is beyond the scope of this review. Developing embryonic neurons are particularly susceptible to neurotoxicants and especially mercury toxicity. This review focused on observations concerning how mercury, and in particular, methylmercury, affects neurogenesis in the developing mammalian brain. We summarized information on models used to study developmental mercury toxicity, theories of pathogenesis, and treatments that could be used to reduce the toxic effects of mercury on developing neurons. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)

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