Bisphenol A induces otolith malformations during vertebrate embryogenesis

<p>Abstract</p> <p>Background</p> <p>The plastic monomer and plasticizer bisphenol A (BPA), used for manufacturing polycarbonate plastic and epoxy resins, is produced at over 2.5 million metric tons per year. Concerns have been raised that BPA acts as an endocrine disruptor on both developmental and reproductive processes and a large body of evidence suggests that BPA interferes with estrogen and thyroid hormone signaling. Here, we investigated BPA effects during embryonic development using the zebrafish and <it>Xenopus </it>models.</p> <p>Results</p> <p>We report that BPA exposure leads to severe malformations of the otic vesicle. In zebrafish and in <it>Xenopus </it>embryos, exposure to BPA during the first developmental day resulted in dose-dependent defects in otolith formation. Defects included aggregation, multiplication and occasionally failure to form otoliths. As no effects on otolith development were seen with exposure to micromolar concentrations of thyroid hormone, 17-ß-estradiol or of the estrogen receptor antagonist ICI 182,780 we conclude that the effects of BPA are independent of estrogen receptors or thyroid-hormone receptors. Na⁺/K⁺ATPases are crucial for otolith formation in zebrafish. Pharmacological inhibition of the major Na⁺/K⁺ATPase with ouabain can rescue the BPA-induced otolith phenotype.</p> <p>Conclusions</p> <p>The data suggest that the spectrum of BPA action is wider than previously expected and argue for a systematic survey of the developmental effects of this endocrine disruptor.</p

Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos.

Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure. As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis. We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses. Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers. Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size. Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility. In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development

Implementation of effect biomarkers in human biomonitoring studies: A systematic approach synergizing toxicological and epidemiological knowledge

ReviewHuman biomonitoring (HBM) studies have highlighted widespread daily exposure to environmental chemicals. Some of these are suspected to contribute to adverse health outcomes such as reproductive, neurological, and metabolic disorders, among other developmental and chronic impairments. One of the objectives of the H2020 European Human Biomonitoring Initiative (HBM4EU) was the development of informative effect biomarkers for application in a more systematic and harmonized way in large-scale European HBM studies. The inclusion of effect biomarkers would complement exposure data with mechanistically-based information on early and late adverse effects. For this purpose, a stepwise strategy was developed to identify and implement a panel of validated effect biomarkers in European HBM studies. This work offers an overview of the complete procedure followed, from comprehensive literature search strategies, selection of criteria for effect biomarkers and their classification and prioritization, based on toxicological data and adverse outcomes, to pilot studies for their analytical, physiological, and epidemiological validation. We present the example of one study that demonstrated the mediating role of the effect biomarker status of brain-derived neurotrophic factor BDNF in the longitudinal association between infant bisphenol A (BPA) exposure and behavioral function in adolescence. A panel of effect biomarkers has been implemented in the HBM4EU Aligned Studies as main outcomes, including traditional oxidative stress, reproductive, and thyroid hormone biomarkers. Novel biomarkers of effect, such as DNA methylation status of BDNF and kisspeptin (KISS) genes were also evaluated as molecular markers of neurological and reproductive health, respectively. A panel of effect biomarkers has also been applied in HBM4EU occupational studies, such as micronucleus analysis in lymphocytes and reticulocytes, whole blood comet assay, and malondialdehyde, 8-oxo-2′-deoxyguanosine and untargeted metabolomic profile in urine, to investigate, for example, biological changes in response to hexavalent chromium Cr(VI) exposure. The use of effect biomarkers in HBM4EU has demonstrated their ability to detect early biological effects of chemical exposure and to identify subgroups that are at higher risk. The roadmap developed in HBM4EU confirms the utility of effect biomarkers, and support one of the main objectives of HBM research, which is to link exposure biomarkers to mechanistically validated effect and susceptibility biomarkers in order to better understand the public health implications of human exposure to environmental chemicals.Supported by the European Union's Horizon 2020 research and innovation program projects HBM4EU [grant number 733032]info:eu-repo/semantics/publishedVersio

A systematic approach synergizing toxicological and epidemiological knowledge

Funding Information: This work was supported by the European Union's Horizon 2020 research and innovation program projects HBM4EU [grant number 733032 ]. Authors acknowledge the editorial assistance of Richard Davies. Publisher Copyright: © 2023 The Author(s)Human biomonitoring (HBM) studies have highlighted widespread daily exposure to environmental chemicals. Some of these are suspected to contribute to adverse health outcomes such as reproductive, neurological, and metabolic disorders, among other developmental and chronic impairments. One of the objectives of the H2020 European Human Biomonitoring Initiative (HBM4EU) was the development of informative effect biomarkers for application in a more systematic and harmonized way in large-scale European HBM studies. The inclusion of effect biomarkers would complement exposure data with mechanistically-based information on early and late adverse effects. For this purpose, a stepwise strategy was developed to identify and implement a panel of validated effect biomarkers in European HBM studies. This work offers an overview of the complete procedure followed, from comprehensive literature search strategies, selection of criteria for effect biomarkers and their classification and prioritization, based on toxicological data and adverse outcomes, to pilot studies for their analytical, physiological, and epidemiological validation. We present the example of one study that demonstrated the mediating role of the effect biomarker status of brain-derived neurotrophic factor BDNF in the longitudinal association between infant bisphenol A (BPA) exposure and behavioral function in adolescence. A panel of effect biomarkers has been implemented in the HBM4EU Aligned Studies as main outcomes, including traditional oxidative stress, reproductive, and thyroid hormone biomarkers. Novel biomarkers of effect, such as DNA methylation status of BDNF and kisspeptin (KISS) genes were also evaluated as molecular markers of neurological and reproductive health, respectively. A panel of effect biomarkers has also been applied in HBM4EU occupational studies, such as micronucleus analysis in lymphocytes and reticulocytes, whole blood comet assay, and malondialdehyde, 8-oxo-2′-deoxyguanosine and untargeted metabolomic profile in urine, to investigate, for example, biological changes in response to hexavalent chromium Cr(VI) exposure. The use of effect biomarkers in HBM4EU has demonstrated their ability to detect early biological effects of chemical exposure and to identify subgroups that are at higher risk. The roadmap developed in HBM4EU confirms the utility of effect biomarkers, and support one of the main objectives of HBM research, which is to link exposure biomarkers to mechanistically validated effect and susceptibility biomarkers in order to better understand the public health implications of human exposure to environmental chemicals.publishersversionpublishe

Removing critical gaps in chemical test methods by developing new assays for the identification of thyroid hormone system-disrupting chemicals—the athena project

The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood–brain and blood–placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation

Bisphenol A and its analogues: A comprehensive review to identify and prioritize effect biomarkers for human biomonitoring

Human biomonitoring (HBM) studies have demonstrated widespread and daily exposure to bisphenol A (BPA). Moreover, BPA structural analogues (e.g. BPS, BPF, BPAF), used as BPA replacements, are being increasingly detected in human biological matrices. BPA and some of its analogues are classified as endocrine disruptors suspected of contributing to adverse health outcomes such as altered reproduction and neurodevelopment, obesity, and metabolic disorders among other developmental and chronic impairments. One of the aims of the H2020 European Human Biomonitoring Initiative (HBM4EU) is the implementation of effect biomarkers at large scales in future HBM studies in a systematic and standardized way, in order to complement exposure data with mechanistically-based biomarkers of early adverse effects. This review aimed to identify and prioritize existing biomarkers of effect for BPA, as well as to provide relevant mechanistic and adverse outcome pathway (AOP) information in order to cover knowledge gaps and better interpret effect biomarker data. A comprehensive literature search was performed in PubMed to identify all the epidemiologic studies published in the last 10 years addressing the potential relationship between bisphenols exposure and alterations in biological parameters. A total of 5716 references were screened, out of which, 119 full-text articles were analyzed and tabulated in detail. This work provides first an overview of all epigenetics, gene transcription, oxidative stress, reproductive, glucocorticoid and thyroid hormones, metabolic and allergy/immune biomarkers previously studied. Then, promising effect biomarkers related to altered neurodevelopmental and reproductive outcomes including brainderived neurotrophic factor (BDNF), kisspeptin (KiSS), and gene expression of nuclear receptors are prioritized, providing mechanistic insights based on in vitro, animal studies and AOP information. Finally, the potential of omics technologies for biomarker discovery and its implications for risk assessment are discussed. To the best of our knowledge, this is the first effort to comprehensively identify bisphenol-related biomarkers of effect for HBM purposes.European Union Commission H2020-EJP-HBM4EU 733032HBM4EU Initiativ

Mixtures measured in human, disrupt thyroid hormone signaling and behavior in Xenopus laevis

International audienceEndocrine disrupting chemicals (EDCs) harm human health both as singlemolecules and as mixtures. Most research on EDCs is done on individualchemicals whereas we are exposed to mixtures of numerous and possiblyinteracting molecules. This discrepancy presents a dilemma for risk assessmentand legislation. Thyroid hormones are essential for normal brain developmentwhere they influence, through specific embryonic and post-natal periods all thesteps of brain development. In adults, TH roles are essential to brain function andto general metabolism (thermogenesis, fat burning, etc.). As number ofcompounds produced by chemical industries increased by 300 fold since the70’s, and many reports in the scientific literature show that many of thesechemicals are potential Endocrine disruptors (EDCs) we questioned the thyroidhormone disrupting effect of common chemicals. We hypothesized that this axiscould be a key target for disruption and hence alter normal brain development. Totest this hypothesis, we used a thyroid disruptor screening assay, the XenopusEmbryonic Thyroid Assay (XETA), RT-qPCR on brain tissue, and behavioranalysis. We used to independent strategies with different mixtures from humandata. First we recreated m a mixture of 15 compounds commonly found in Humanbeings and tested them at the concentration meassured in amniotic fluid and studythe effects on thyroid hormone signaling and adverse effects on our tadpolemodel. Second, a novel approach, developed within the European project, EDCMixRisk, was to classify adverse mixtures of chemicals found in population basedon epidemiological studies and test their EDC potential with both in vivo andin vitro assays. Samples from about 2,000 pregnant women were examined andretrospective analysis on offspring identified a chemical mixture for whichembryonic exposure was associated with language delay, an indication forneurodevelopmental delay. Results on the two kind of mixtures show significantmodification of TH availability (XETA assay) at the actual mixture concentrationfound in fluids of pregnant women. Second, mRNA levels of key genes involvedthe TH-signaling pathway showed significant alteration of TH-dependent genes atthe accrual exposure level. Finally, mixtures were found to alter tadpoles’mobilitybehavior. Taken together, these results show advantages of using differentstrategies and necessity to take into consideration mixture in both experimentalstudies and risk assessment

Thyroid-disrupting chemicals and brain development: an update.

This review covers recent findings on the main categories of thyroid hormone-disrupting chemicals and their effects on brain development. We draw mostly on epidemiological and experimental data published in the last decade. For each chemical class considered, we deal with not only the thyroid hormone-disrupting effects but also briefly mention the main mechanisms by which the same chemicals could modify estrogen and/or androgen signalling, thereby exacerbating adverse effects on endocrine-dependent developmental programmes. Further, we emphasize recent data showing how maternal thyroid hormone signalling during early pregnancy affects not only offspring IQ, but also neurodevelopmental disease risk. These recent findings add to established knowledge on the crucial importance of iodine and thyroid hormone for optimal brain development. We propose that prenatal exposure to mixtures of thyroid hormone-disrupting chemicals provides a plausible biological mechanism contributing to current increases in the incidence of neurodevelopmental disease and IQ loss

Les perturbateurs thyroïdiens et leurs conséquences sur le développement cérébral

International audienc

Que sait-on de l’action des perturbateurs endocriniens sur le neurodéveloppement ?

International audienceDevelopment of the central nervous system (CNS) relies on many endogenous factors. Thyroid hormones and sex steroid hormones are among the most studied endocrine systems for their regulation of neural functions, since early embryonic stages of development. Environmental exposure to low doses of chemicals is largely documented. The hypothesis that exposure to some of these molecules with endocrine disrupting activity, likely interfering with the production of these hormones and/or their underlying neural mechanisms is therefore plausible and supported by numerous studies. After having recalled the formation of the hypothalamo-hypophyseal axes, and the importance of thyroid and sexual hormones in neurodevelopment, we will present two examples of substances (BPA, PCBs) and their effects on brain development.Le développement du système nerveux central (SNC) dépend de nombreux facteurs endogènes. Les hormones thyroïdiennes et les hormones stéroïdes sexuelles figurent parmi les systèmes endocriniens les plus étudiés pour leurs effets neuraux, et ce dès les stades embryonnaires de développement. L'exposition environnementale à de faibles doses de substances chimiques est largement documentée. L'hypothèse que certaines de ces substances, appelées perturbateurs endocriniens, puissent interférer avec la production de ces hormones et/ou de leurs mécanismes au niveau central est donc plausible et soutenue par une multitude de travaux. Après avoir rappelé la formation des axes hypothalamo-hypophysaires et l'importance des hormones thyroïdiennes et sexuelles dans le neurodéveloppement, nous présenterons deux exemples de substances (bisphénol A, polychlorobiphényles) et leurs effets sur le développement cérébral