Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

The production of plastic products, which requires phthalate plasticizers, has resulted in the problems for human health, especially that of reproductive health. Phthalate exposure can induce reproductive disorders at various regulatory levels. The aim of this review was to compile the evidence concerning the association between phthalates and reproductive diseases, phthalates-induced reproductive disorders, and their possible endocrine and intracellular mechanisms. Phthalates may induce alterations in puberty, the development of testicular dysgenesis syndrome, cancer, and fertility disorders in both males and females. At the hormonal level, phthalates can modify the release of hypothalamic, pituitary, and peripheral hormones. At the intracellular level, phthalates can interfere with nuclear receptors, membrane receptors, intracellular signaling pathways, and modulate gene expression associated with reproduction. To understand and to treat the adverse effects of phthalates on human health, it is essential to expand the current knowledge concerning their mechanism of action in the organism.

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The Multiple Actions of Amygdalin on Cellular Processes with an Emphasis on Female Reproduction

Pharmaceuticals ◽

10.3390/ph14090881 ◽

2021 ◽

Vol 14 (9) ◽

pp. 881

Author(s):

Adriana Kolesarova ◽

Simona Baldovska ◽

Shubhadeep Roychoudhury

Keyword(s):

Intracellular Signaling ◽

Current Knowledge ◽

Health Hazard ◽

Secretory Activity ◽

The Body ◽

Female Reproduction ◽

Promising Tool ◽

Physiological Processes ◽

Potential Applicability ◽

Reproductive Processes

The present review summarizes the current knowledge on the provenance and properties, metabolism and toxicity, mechanism of action, physiological, and therapeutic roles of amygdalin—a molecule present in the seeds of apricot and other plants—with an emphasis on the action of amygdalin on reproductive processes, particularly in the female. Amygdalin influences physiological processes including female reproduction at various regulatory levels via extra- and intracellular signaling pathways regulating secretory activity, cell viability, steroidogenesis, proliferation, and apoptosis. On the other hand, while being metabolized in the body, amygdalin releases significant amounts of cyanide, which may lead to acute health hazard in those individuals who may be at risk. Despite some contradictions in the available data about benefits and toxic effects of amygdalin, its potential applicability at low doses may present a promising tool for regulation of various reproductive and other physiological processes including disease management primarily in cancer phytotherapy, animal production, medicine, and biotechnology. However, further research involving carefully designed dose–response studies is required to overcome the possible side effects of amygdalin and assure its safety as a therapeutic agent.

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Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

Archives of Toxicology ◽

10.1007/s00204-020-02834-y ◽

2020 ◽

Vol 94 (10) ◽

pp. 3359-3379 ◽

Cited By ~ 1

Author(s):

Hanna K. L. Johansson ◽

Pauliina Damdimopoulou ◽

Majorie B. M. van Duursen ◽

Julie Boberg ◽

Delphine Franssen ◽

...

Keyword(s):

Reproductive Health ◽

Adverse Outcome ◽

Current Knowledge ◽

Chemical Exposure ◽

Reproductive Hormones ◽

Test Method ◽

Adverse Outcome Pathway ◽

Continuous Exposure ◽

Reproductive Disorders ◽

Female Reproductive Health

Abstract Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause–effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman’s reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause–effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.

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Lactobacillus Reuteri DSM 17938 (Limosilactobacillus reuteri) in Diarrhea and Constipation: Two Sides of the Same Coin?

Medicina ◽

10.3390/medicina57070643 ◽

2021 ◽

Vol 57 (7) ◽

pp. 643

Author(s):

Angela Saviano ◽

Mattia Brigida ◽

Alessio Migneco ◽

Gayani Gunawardena ◽

Christian Zanza ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Emergency Department ◽

Abdominal Pain ◽

Human Health ◽

Bowel Disease ◽

Chronic Constipation ◽

Lactobacillus Reuteri ◽

Current Knowledge ◽

Gastrointestinal Symptoms ◽

Inflammatory Bowel

Background and Objectives: Lactobacillus reuteri DSM 17938 (L. reuteri) is a probiotic that can colonize different human body sites, including primarily the gastrointestinal tract, but also the urinary tract, the skin, and breast milk. Literature data showed that the administration of L. reuteri can be beneficial to human health. The aim of this review was to summarize current knowledge on the role of L. reuteri in the management of gastrointestinal symptoms, abdominal pain, diarrhea and constipation, both in adults and children, which are frequent reasons for admission to the emergency department (ED), in order to promote the best selection of probiotic type in the treatment of these uncomfortable and common symptoms. Materials and Methods: We searched articles on PubMed® from January 2011 to January 2021. Results: Numerous clinical studies suggested that L. reuteri may be helpful in modulating gut microbiota, eliminating infections, and attenuating the gastrointestinal symptoms of enteric colitis, antibiotic-associated diarrhea (also related to the treatment of Helicobacter pylori (HP) infection), irritable bowel syndrome, inflammatory bowel disease, and chronic constipation. In both children and in adults, L. reuteri shortens the duration of acute infectious diarrhea and improves abdominal pain in patients with colitis or inflammatory bowel disease. It can ameliorate dyspepsia and symptoms of gastritis in patients with HP infection. Moreover, it improves gut motility and chronic constipation. Conclusion: Currently, probiotics are widely used to prevent and treat numerous gastrointestinal disorders. In our opinion, L. reuteri meets all the requirements to be considered a safe, well-tolerated, and efficacious probiotic that is able to contribute to the beneficial effects on gut-human health, preventing and treating many gastrointestinal symptoms, and speeding up the recovery and discharge of patients accessing the emergency department.

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Liquid–liquid phase separation in human health and diseases

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00678-1 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Bin Wang ◽

Lei Zhang ◽

Tong Dai ◽

Ziran Qin ◽

Huasong Lu ◽

...

Keyword(s):

Phase Separation ◽

Liquid Phase ◽

Human Health ◽

Essential Role ◽

Current Knowledge ◽

Vital Role ◽

Liquid Phase Separation ◽

Eukaryotic Cells ◽

Liquid Liquid Phase Separation

AbstractEmerging evidence suggests that liquid–liquid phase separation (LLPS) represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells (also known as biomolecular condensates or droplets). Recent studies have revealed evidences that indicate that LLPS plays a vital role in human health and diseases. In this review, we describe our current understanding of LLPS and summarize its physiological functions. We further describe the role of LLPS in the development of human diseases. Additionally, we review the recently developed methods for studying LLPS. Although LLPS research is in its infancy—but is fast-growing—it is clear that LLPS plays an essential role in the development of pathophysiological conditions. This highlights the need for an overview of the recent advances in the field to translate our current knowledge regarding LLPS into therapeutic discoveries.

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Microalgae n-3 PUFAs Production and Use in Food and Feed Industries

Marine Drugs ◽

10.3390/md19020113 ◽

2021 ◽

Vol 19 (2) ◽

pp. 113

Author(s):

Marine Remize ◽

Yves Brunel ◽

Joana L. Silva ◽

Jean-Yves Berthon ◽

Edith Filaire

Keyword(s):

Fatty Acids ◽

Global Warming ◽

Docosahexaenoic Acid ◽

Polyunsaturated Fatty Acids ◽

Eicosapentaenoic Acid ◽

Human Health ◽

Current Knowledge ◽

Epa And Dha ◽

Anti Cancer ◽

Food And Feed

N-3 polyunsaturated fatty acids (n-3 PUFAs), and especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential compounds for human health. They have been proven to act positively on a panel of diseases and have interesting anti-oxidative, anti-inflammatory or anti-cancer properties. For these reasons, they are receiving more and more attention in recent years, especially future food or feed development. EPA and DHA come mainly from marine sources like fish or seaweed. Unfortunately, due to global warming, these compounds are becoming scarce for humans because of overfishing and stock reduction. Although increasing in recent years, aquaculture appears insufficient to meet the increasing requirements of these healthy molecules for humans. One alternative resides in the cultivation of microalgae, the initial producers of EPA and DHA. They are also rich in biochemicals with interesting properties. After defining macro and microalgae, this review synthesizes the current knowledge on n-3 PUFAs regarding health benefits and the challenges surrounding their supply within the environmental context. Microalgae n-3 PUFA production is examined and its synthesis pathways are discussed. Finally, the use of EPA and DHA in food and feed is investigated. This work aims to define better the issues surrounding n-3 PUFA production and supply and the potential of microalgae as a sustainable source of compounds to enhance the food and feed of the future.

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The Expression of the Cancer-Associated lncRNA Snhg15 Is Modulated by EphrinA5-Induced Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms22031332 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1332

Author(s):

Daniel Pensold ◽

Julia Gehrmann ◽

Georg Pitschelatow ◽

Asa Walberg ◽

Kai Braunsteffer ◽

...

Keyword(s):

Tyrosine Kinases ◽

Intracellular Signaling ◽

Granule Cells ◽

Cerebellar Granule Cells ◽

Membrane Receptors ◽

In Vitro Assays ◽

Eph Receptor ◽

Medulloblastoma Cell Line ◽

And Migration

The Eph receptor tyrosine kinases and their respective ephrin-ligands are an important family of membrane receptors, being involved in developmental processes such as proliferation, migration, and in the formation of brain cancer such as glioma. Intracellular signaling pathways, which are activated by Eph receptor signaling, are well characterized. In contrast, it is unknown so far whether ephrins modulate the expression of lncRNAs, which would enable the transduction of environmental stimuli into our genome through a great gene regulatory spectrum. Applying a combination of functional in vitro assays, RNA sequencing, and qPCR analysis, we found that the proliferation and migration promoting stimulation of mouse cerebellar granule cells (CB) with ephrinA5 diminishes the expression of the cancer-related lncRNA Snhg15. In a human medulloblastoma cell line (DAOY) ephrinA5 stimulation similarly reduced SNHG15 expression. Computational analysis identified triple-helix-mediated DNA-binding sites of Snhg15 in promoters of genes found up-regulated upon ephrinA5 stimulation and known to be involved in tumorigenic processes. Our findings propose a crucial role of Snhg15 downstream of ephrinA5-induced signaling in regulating gene transcription in the nucleus. These findings could be potentially relevant for the regulation of tumorigenic processes in the context of glioma.

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Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

International Journal of Molecular Sciences ◽

10.3390/ijms22116047 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6047

Author(s):

Mattias F. Lindberg ◽

Laurent Meijer

Keyword(s):

Tyrosine Phosphorylation ◽

Human Disease ◽

Intracellular Signaling ◽

Neuronal Development ◽

Viral Infections ◽

Current Knowledge ◽

Lymphoblastic Leukemia ◽

Cell Cycle Control ◽

Megakaryoblastic Leukemia ◽

Dual Specificity

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.

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Divergent Pathways Regulate Ligand-Independent Activation of ERα in SK-N-BE Neuroblastoma and COS-1 Renal Carcinoma Cells

Molecular Endocrinology ◽

10.1210/mend.12.6.0114 ◽

1998 ◽

Vol 12 (6) ◽

pp. 835-841

Author(s):

Cesare Patrone ◽

Elisabetta Gianazza ◽

Sabrina Santagati ◽

Paola Agrati ◽

Adriana Maggi

Keyword(s):

Cell Line ◽

Intracellular Signaling ◽

Steroid Receptors ◽

Neuroblastoma Cell ◽

Cross Coupling ◽

Activation Function ◽

Neuroblastoma Cell Line ◽

Membrane Receptors ◽

Insulin Dependent ◽

The Cross

Abstract The α-estrogen receptor (ERα) transcriptional activity can be regulated either by binding to the cognate ligand or by intracellular signaling pathways responsive to a variety of factors acting through cell membrane receptors. Studies carried out in HeLa and COS-1 cells demonstrated that the cross-coupling between estrogen and growth factor receptors is mediated by p21ras and requires phosphorylation of a specific serine residue (Ser 118 in the human ERα and Ser 122 in mouse ERα) located in the ERα N-terminal activation function 1 (AF-1). Likewise, in the SK-N-BE neuroblastoma cell line p21ras is involved in the cross-coupling between insulin and ERα receptors. However, in this cell line Ser 122 is not necessary for insulin-dependent activation of unliganded ERα. In addition, after insulin activation, the electrophoretic mobility associated to serine hyperphosphorylation of ERα in SK-N-BE and in COS-1 cells is different. Our study rules out the possibility of tyrosine phosporylation in unliganded ERα activation by means of transactivation studies of ERα tyrosine mutants and analysis of Tyr phosphorylation immunoreactivity. The two cofactors for steroid receptors RIP 140 and SRC-1 do not seem to be specifically involved in the insulin-induced ERα transactivation. The present study demonstrates the possibility of an alternative, cell-specific pathway of cross-coupling between intracellular and membrane receptors, which might be of importance for the understanding of the physiological significance of this mode of activation in the nervous system.

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Imaging of persistent cAMP signaling by internalized G protein-coupled receptors

Journal of Molecular Endocrinology ◽

10.1677/jme-10-0014 ◽

2010 ◽

Vol 45 (1) ◽

pp. 1-8 ◽

Cited By ~ 47

Author(s):

Davide Calebiro ◽

Viacheslav O Nikolaev ◽

Martin J Lohse

Keyword(s):

G Protein ◽

Intracellular Signaling ◽

Current Model ◽

Living Cells ◽

G Protein Coupled Receptors ◽

Membrane Receptors ◽

Optical Methods ◽

Camp Signaling ◽

Gpcr Signaling ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They mediate the effects of several endogenous cues and serve as important pharmacological targets. Although many biochemical events involved in GPCR signaling have been characterized in great detail, little is known about their spatiotemporal dynamics in living cells. The recent advent of optical methods based on fluorescent resonance energy transfer allows, for the first time, to directly monitor GPCR signaling in living cells. Utilizing these methods, it has been recently possible to show that the receptors for two protein/peptide hormones, the TSH and the parathyroid hormone, continue signaling to cAMP after their internalization into endosomes. This type of intracellular signaling is persistent and apparently triggers specific cellular outcomes. Here, we review these recent data and explain the optical methods used for such studies. Based on these findings, we propose a revision of the current model of the GPCR–cAMP signaling pathway to accommodate receptor signaling at endosomes.

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Endocrine Disrupting Chemicals and Reproductive Health in Boys and Men

Frontiers in Endocrinology ◽

10.3389/fendo.2021.706532 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wiwat Rodprasert ◽

Jorma Toppari ◽

Helena E. Virtanen

Keyword(s):

Reproductive Health ◽

Testicular Cancer ◽

Semen Quality ◽

Endocrine Disrupting Chemicals ◽

Serum Testosterone ◽

Serum Testosterone Level ◽

Sensitive Period ◽

Testicular Development ◽

Reproductive Disorders ◽

Endocrine Disrupting

Male reproductive health has declined as indicated by increasing rates of cryptorchidism, i.e., undescended testis, poor semen quality, low serum testosterone level, and testicular cancer. Exposure to endocrine disrupting chemicals (EDCs) has been proposed to have a role in this finding. In utero exposure to antiandrogenic EDCs, particularly at a sensitive period of fetal testicular development, the so-called ‘masculinization programming window (MPW)’, can disturb testicular development and function. Low androgen effect during the MPW can cause both short- and long-term reproductive disorders. A concurrent exposure to EDCs may also affect testicular function or damage testicular cells. Evidence from animal studies supports the role of endocrine disrupting chemicals in development of male reproductive disorders. However, evidence from epidemiological studies is relatively mixed. In this article, we review the current literature that evaluated relationship between prenatal EDC exposures and anogenital distance, cryptorchidism, and congenital penile abnormality called hypospadias. We review also studies on the association between early life and postnatal EDC exposure and semen quality, hypothalamic-pituitary-gonadal axis hormone levels and testicular cancer.

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