scholarly journals A putative adverse outcome pathway network for disrupted female pubertal onset to improve testing and regulation of endocrine disrupting chemicals

2021 ◽  
Author(s):  
Delphine Franssen ◽  
Terje Svingen ◽  
David Lopez Rodriguez ◽  
Majorie Van Duursen ◽  
Julie Boberg ◽  
...  
Keyword(s):  
Method Development ◽  
Adverse Outcome ◽  
Pubertal Timing ◽  
Endocrine Disrupting Chemicals ◽  
Experimental Studies ◽  
Test Method ◽  
Adverse Outcome Pathway ◽  
Pubertal Onset ◽  
Endocrine Disrupting ◽  
Alternative Test

The average age for pubertal onset in girls has declined over recent decades. Epidemiological studies in humans and experimental studies in animals suggest a causal role for Endocrine Disrupting Chemicals (EDCs) that are present in our environment. Of concern, current testing and screening regimens are inadequate in identifying EDCs that may affect pubertal maturation, not least because they do not consider early-life exposure. Also, the causal relationship between EDC exposure and pubertal timing is still a matter of debate. To address this issue, we have used current knowledge to elaborate a network of putative Adverse Outcome Pathways (pAOPs) to identify how chemicals can affect pubertal onset. By using the AOP framework, we highlight current gaps in mechanistic understanding that needs to be addressed and simultaneously point towards events causative of pubertal disturbance that could be exploited for alternative test methods. We propose six pAOPs that could explain the disruption of pubertal timing by interfering with the central hypothalamic trigger of puberty, GnRH neurons, and by so doing highlight specific modes of action that could be targeted for alternative test method development.

scholarly journals In Silico Molecular Docking and In Vivo Validation with Caenorhabditis elegans to Discover Molecular Initiating Events in Adverse Outcome Pathway Framework: Case Study on Endocrine-Disrupting Chemicals with Estrogen and Androgen Receptors

2019 ◽  
Vol 20 (5) ◽  
pp. 1209 ◽  
Author(s):  
Jaeseong Jeong ◽  
Hunbeen Kim ◽  
Jinhee Choi
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Adverse Outcome ◽  
Endocrine Disrupting Chemicals ◽  
Reproductive Toxicity ◽  
Adverse Outcome Pathway ◽  
C Elegans ◽  
Endocrine Disrupting ◽  
Mutant Strains

Molecular docking is used to analyze structural complexes of a target with its ligand for understanding the chemical and structural basis of target specificity. This method has the potential to be applied for discovering molecular initiating events (MIEs) in the Adverse Outcome Pathway framework. In this study, we aimed to develop in silico–in vivo combined approach as a tool for identifying potential MIEs. We used environmental chemicals from Tox21 database to identify potential endocrine-disrupting chemicals (EDCs) through molecular docking simulation, using estrogen receptor (ER), androgen receptor (AR) and their homology models in the nematode Caenorhabditis elegans (NHR-14 and NHR-69, respectively). In vivo validation was conducted on the selected EDCs with C. elegans reproductive toxicity assay using wildtype N2, nhr-14, and nhr-69 loss-of-function mutant strains. The chemicals showed high binding affinity to tested receptors and showed the high in vivo reproductive toxicity, and this was further confirmed using the mutant strains. The present study demonstrates that the binding affinity from the molecular docking potentially correlates with in vivo toxicity. These results prove that our in silico–in vivo combined approach has the potential to be applied for identifying MIEs. This study also suggests the potential of C. elegans as useful in the in vivo model for validating the in silico approach.

scholarly journals Endocrine-Disrupting Chemicals and Early Puberty in Girls

Children ◽  
2021 ◽  
Vol 8 (6) ◽  
pp. 492
Author(s):  
Anastasios Papadimitriou ◽  
Dimitrios T Papadimitriou
Keyword(s):  
Growth Pattern ◽  
Secular Trend ◽  
Pubertal Timing ◽  
Endocrine Disrupting Chemicals ◽  
The Other ◽  
Minor Effect ◽  
Early Puberty ◽  
Pubertal Onset ◽  
Endocrine Disrupting ◽  
A Minor

In recent decades, pubertal onset in girls has been considered to occur at an earlier age than previously. Exposure to endocrine-disrupting chemicals (EDCs) has been associated with alterations in pubertal timing, with several reports suggesting that EDCs may have a role in the secular trend in pubertal maturation, at least in girls. However, relevant studies give inconsistent results. On the other hand, the majority of girls with idiopathic precocious or early puberty present the growth pattern of constitutional advancement of growth (CAG), i.e., growth acceleration soon after birth. Herein, we show that the growth pattern of CAG is unrelated to exposure to endocrine-disrupting chemicals and is the major determinant of precocious or early puberty. Presented data suggest that EDCs, at most, have a minor effect on the timing of pubertal onset in girls.

scholarly journals Endocrine-Disrupting Chemicals and Insulin Resistance in Children

Biomedicines ◽  
2020 ◽  
Vol 8 (6) ◽  
pp. 137 ◽  
Author(s):  
Eleonora Rotondo ◽  
Francesco Chiarelli
Keyword(s):  
Insulin Resistance ◽  
Bisphenol A ◽  
Prospective Studies ◽  
Endocrine Disrupting Chemicals ◽  
Experimental Studies ◽  
Epidemiological Studies ◽  
Cross Sectional ◽  
Obesity And Diabetes ◽  
Endocrine Disrupting ◽  
Background Exposure

The purpose of this article is to review the evidence linking background exposure to endocrine-disrupting chemicals (EDCs) with insulin resistance in children. Although evidence in children is scarce since very few prospective studies exist even in adults, evidence that EDCs might be involved in the development of insulin resistance and related diseases such as obesity and diabetes is accumulating. We reviewed the literature on both cross-sectional and prospective studies in humans and experimental studies. Epidemiological studies show a statistical link between exposure to pesticides, polychlorinated bisphenyls, bisphenol A, phthalates, aromatic polycyclic hydrocarbides, or dioxins and insulin resistance.

scholarly journals The EDCMET Project: Metabolic Effects of Endocrine Disruptors

2020 ◽  
Vol 21 (8) ◽  
pp. 3021
Author(s):  
Jenni Küblbeck ◽  
Taina Vuorio ◽  
Jonna Niskanen ◽  
Vittorio Fortino ◽  
Albert Braeuning ◽  
...  
Keyword(s):  
Endocrine Disruptors ◽  
Molecular Mechanisms ◽  
Adverse Outcome ◽  
Close Association ◽  
Endocrine Disrupting Chemicals ◽  
Metabolic Effects ◽  
Health Concern ◽  
Adverse Outcome Pathway

Endocrine disruptors (EDs) are defined as chemicals that mimic, block, or interfere with hormones in the body’s endocrine systems and have been associated with a diverse array of health issues. The concept of endocrine disruption has recently been extended to metabolic alterations that may result in diseases, such as obesity, diabetes, and fatty liver disease, and constitute an increasing health concern worldwide. However, while epidemiological and experimental data on the close association of EDs and adverse metabolic effects are mounting, predictive methods and models to evaluate the detailed mechanisms and pathways behind these observed effects are lacking, thus restricting the regulatory risk assessment of EDs. The EDCMET (Metabolic effects of Endocrine Disrupting Chemicals: novel testing METhods and adverse outcome pathways) project brings together systems toxicologists; experimental biologists with a thorough understanding of the molecular mechanisms of metabolic disease and comprehensive in vitro and in vivo methodological skills; and, ultimately, epidemiologists linking environmental exposure to adverse metabolic outcomes. During its 5-year journey, EDCMET aims to identify novel ED mechanisms of action, to generate (pre)validated test methods to assess the metabolic effects of Eds, and to predict emergent adverse biological phenotypes by following the adverse outcome pathway (AOP) paradigm.

scholarly journals The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds

2020 ◽  
Vol 21 (10) ◽  
pp. 3480 ◽  
Author(s):  
Juliette Legler ◽  
Daniel Zalko ◽  
Fabien Jourdan ◽  
Miriam Jacobs ◽  
Bernard Fromenty ◽  
...  
Keyword(s):  
Endocrine Disrupting Chemicals ◽  
Real Life ◽  
Integrated Approach ◽  
Test Method ◽  
Adverse Outcome Pathway ◽  
In Vivo Models ◽  
Project Report ◽  
Metabolic Disruption

The purpose of this project report is to introduce the European “GOLIATH” project, a new research project which addresses one of the most urgent regulatory needs in the testing of endocrine-disrupting chemicals (EDCs), namely the lack of methods for testing EDCs that disrupt metabolism and metabolic functions. These chemicals collectively referred to as “metabolism disrupting compounds” (MDCs) are natural and anthropogenic chemicals that can promote metabolic changes that can ultimately result in obesity, diabetes, and/or fatty liver in humans. This project report introduces the main approaches of the project and provides a focused review of the evidence of metabolic disruption for selected EDCs. GOLIATH will generate the world’s first integrated approach to testing and assessment (IATA) specifically tailored to MDCs. GOLIATH will focus on the main cellular targets of metabolic disruption—hepatocytes, pancreatic endocrine cells, myocytes and adipocytes—and using an adverse outcome pathway (AOP) framework will provide key information on MDC-related mode of action by incorporating multi-omic analyses and translating results from in silico, in vitro, and in vivo models and assays to adverse metabolic health outcomes in humans at real-life exposures. Given the importance of international acceptance of the developed test methods for regulatory use, GOLIATH will link with ongoing initiatives of the Organisation for Economic Development (OECD) for test method (pre-)validation, IATA, and AOP development.

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

2020 ◽  
Vol 94 (10) ◽  
pp. 3359-3379 ◽  
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.

Evaluation of reproductivity of medaka (Oryzias latipes) exposed to chemicals using a 2-week reproduction test

2000 ◽  
Vol 42 (7-8) ◽  
pp. 53-60 ◽  
Author(s):  
T. Shioda ◽  
M. Wakabayashi
Keyword(s):  
Endocrine Disrupting Chemicals ◽  
Oryzias Latipes ◽  
Test Method ◽  
Diethylhexyl Phthalate ◽  
Reproductive Ability ◽  
Tributyltin Chloride ◽  
Endocrine Disrupting ◽  
Reproduction Test ◽  
17Β Estradiol ◽  
Estrogenic Chemicals

Effects of endocrine disrupting chemicals on reproductive ability of medaka (Oryzias latipes) were investigated. Exposure of male medaka to estrogenic chemicals such as 17β-estradiol (E2), p-nonylphenol (NP), 4-t-butylphenol (BP) and bisphenol-A (BPA) caused a decrease in the numbers of eggs hatched rather than those of eggs spawned, which seemed to be affected by estrogen-like effects of these chemicals. Exposure of female medaka to E2 and NP reduced the numbers of eggs spawned rather than those of eggs hatched. The concentrations at which reproductivity of female decreased (E2:0.1 nmol/L, NP:0.03 μmu;mol/L) were lower than those of male (E2:3 nmol/L, NP:μ>0.3 μmu;mol/L). Diethylhexyl phthalate, benzophenone and tributyltin chloride did not affect reproductivity. In this study, adverse effects of estrogenic chemicals on reproductivity of medaka could be detected, so the materials and methods used in this study were considered to be able to be applied for a screening test method.

Sign in / Sign up

Export Citation Format

Share Document