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Thyroid hormones (TH) are essential for normal brain development, influencing neural cell differentiation, migration, and synaptogenesis. Multiple endocrine-disrupting chemicals (EDCs) are found in the environment, raising concern for their potential effects on TH signaling and the consequences on neurodevelopment and behavior. While most research on EDCs investigates the effects of individual chemicals, human health may be adversely affected by a mixture of chemicals. The potential consequences of EDC exposure on human health are far-reaching and include problems with immune function, reproductive health, and neurological development. We hypothesized that embryonic exposure to a mixture of chemicals (containing phenols, phthalates, pesticides, heavy metals, and perfluorinated, polychlorinated, and polybrominated compounds) identified as commonly found in the human amniotic fluid could lead to altered brain development. We assessed its effect on TH signaling and neurodevelopment in an amphibian model ( Xenopus laevis ) highly sensitive to thyroid disruption. Fertilized eggs were exposed for eight days to either TH (thyroxine, T 4 10 nM) or the amniotic mixture (at the actual concentration) until reaching stage NF47, where we analyzed gene expression in the brains of exposed tadpoles using both RT-qPCR and RNA sequencing. The results indicate that whilst some overlap on TH-dependent genes exists, T 4 and the mixture have different gene signatures. Immunohistochemistry showed increased proliferation in the brains of T 4 -treated animals, whereas no difference was observed for the amniotic mixture. Further, we demonstrated diminished tadpoles' motility in response to T 4 and mixture exposure. As the individual chemicals composing the mixture are considered safe, these results highlight the importance of examining the effects of mixtures to improve risk assessment.

Thyroid hormones (THs) play critical roles in profound changes in many vertebrates, notably in mammalian neurodevelopment, although the precise molecular mechanisms of these fundamental biological processes are still being unravelled. Environmental and health concerns prompted the development of chemical safety testing and, in the context of endocrine disruption, identification of thyroid hormone axis disrupting chemicals (THADCs) remains particularly challenging. As various molecules are known to interfere with different levels of TH signalling, screening tests for THADCs may not rely solely on in vitro ligand/receptor binding to TH receptors. Therefore, alternatives to mammalian in vivo assays featuring TH-related endpoints that are more sensitive than circulatory THs and more rapid than thyroid histopathology are needed to fulfil the ambition of higher throughput screening of the myriad of environmental chemicals. After a detailed introduction of the context, we have listed current assays and parameters to assess thyroid disruption following a literature search of recent publications referring to non-mammalian models. Potential THADCs were mostly investigated in zebrafish and the frog Xenopus laevis, an amphibian model extensively used to study TH signalling., (Copyright © 2020. Published by Elsevier B.V.)

Plant Protection Products, more commonly referred to as pesticides and biocides, are used to control a wide range of yield-reducing pests including insects, fungi, nematodes, and weeds. Concern has been raised that some pesticides may act as endocrine disrupting chemicals (EDCs) with the potential to interfere with the hormone systems of non-target invertebrates and vertebrates, including humans. EDCs act at low doses and particularly vulnerable periods of exposure include pre- and perinatal development. Of critical concern is the number of pesticides with the potential to interfere with the developing nervous system and brain, notably with thyroid hormone signaling. Across vertebrates, thyroid hormone orchestrates metamorphosis, brain development, and metabolism. Pesticide action on thyroid homeostasis can involve interference with TH production and its control, displacement from distributor proteins and liver metabolism. Here we focused on thyroid endpoints for each of the different classes of pesticides reviewing epidemiological and experimental studies carried out both in in vivo and in vitro. We conclude first, that many pesticides were placed on the market with insufficient testing, other than acute or chronic toxicity, and second, that thyroid-specific endpoints for neurodevelopmental effects and mixture assessment are largely absent from regulatory directives. [ABSTRACT FROM AUTHOR]

• This review identified and prioritized existing effect biomarkers for bisphenols. • 119 epidemiologic studies were selected, analyzed, tabulated and discussed. • An inventory of molecular and biochemical effect biomarkers was created. • BDNF, kisspeptin and gene expression of nuclear receptors were prioritized. • Adverse outcome pathway (AOP) data was gathered to cover knowledge gaps. 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 brain-derived 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. [ABSTRACT FROM AUTHOR]