Endocrine-disrupting chemicals (EDCs) substantially cost society as a result of increases in disease and disability but-unlike other toxicant classes such as carcinogens-have yet to be codified into ...regulations as a hazard category. This Series paper examines economic, regulatory, and policy approaches to limit human EDC exposures and describes potential improvements. In the EU, general principles for EDCs call for minimisation of human exposure, identification as substances of very high concern, and ban on use in pesticides. In the USA, screening and testing programmes are focused on oestrogenic EDCs exclusively, and regulation is strictly risk-based. Minimisation of human exposure is unlikely without a clear overarching definition for EDCs and relevant pre-marketing test requirements. We call for a multifaceted international programme (eg, modelled on the International Agency for Research in Cancer) to address the effects of EDCs on human health-an approach that would proactively identify hazards for subsequent regulation.
Thyroid hormone regulates vital processes in early brain development such as neuronal stem cell proliferation, migration, and myelination. The fetal thyroid is not fully functional until ...mid-pregnancy (18–20 weeks), so placental transfer of maternal thyroid hormones during early pregnancy is crucial, as is the maternal iodine status. The volume of chemical production has increased 300-fold since the 1970s. Thus, chemical exposure is ubiquitous; every child born today has dozens of man-made xenobiotic compounds in its blood. Increasing evidence from both epidemiological and animal or in vitro studies demonstrates that many of these chemicals have the potential to interfere with thyroid hormone availability and action at different physiological levels. These chemicals are found in numerous consumer products and include certain plastics, pesticides, perfluorinated compounds, and flame retardants. The last decades have seen exponential increases in neurodevelopmental disease including autism spectrum disorder and attention deficit/hyperactivity disorder. We hypothesize that prenatal exposure to mixtures of thyroid hormone-disrupting chemicals, with iodine deficiency potentially exacerbating the situation, has a strong probability of contributing to this increased incidence of neurodevelopmental disease, but could also entail a surreptitious, but socio-economically consequential, loss of IQ. Thyroid hormone receptor actions can modulate gene transcription, most often through epigenetic mechanisms. Thus, interference with epigenetic regulations is increasingly thought to link neurodevelopmental disease and IQ loss to thyroid hormone disruption.
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
and
. 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.
Monocarboxylate transporter 8 (MCT8) deficiency or the Allan-Herndon-Dudley Syndrome (AHDS) is an X-linked psychomotor disability syndrome with around 320 clinical cases described worldwide.
gene ...mutations, encoding the thyroid hormone (TH) transporter MCT8, result in intellectual disability due to impaired TH uptake in the developing brain. MCT8 deficiency is a multi-organ affecting disease with a predominant neuronal cell-based pathology, with the glial component inadequately investigated. However, deficiency in myelin, a key component of white matter (WM) enabling fast nerve conduction, is a TH-dependent hallmark of the disease. Nevertheless, analysis of the myelin status in AHDS patients has led to conflicting interpretations. The majority of individual case studies reported delayed myelination, that was restored later in life. In contrast,
studies and high-resolution MRIs detected WM (micro-) abnormalities throughout adolescence, suggesting permanent hypomyelination. Thus, interpretations vary depending on methodology to investigate WM microstructure. Further, it is unknown whether the mutation within the MCT8 is linked to the severity of the myelin deficiency. Consequently, terminology is inconsistent among reports, and AHDS is occasionally misdiagnosed as another WM disorder. The evolutionary conserved TH signaling pathway that promotes the generation of myelinating oligodendrocytes enabled deciphering how the lack of MCT8 might affect myelinogenesis. Linking patient findings on myelination to those obtained from models of MCT8 deficiency revealed underlying pathophysiological mechanisms, but knowledge gaps remain, notably how myelination progresses both spatially and temporally in MCT8 deficiency. This limits predicting how myelin integrity might benefit therapeutically, and when to initiate. A recurrent observation in clinical trials is the absence of neurological improvement. Testing MCT8-independent thyromimetics in models, and evaluating treatments used in other demyelinating diseases, despite different etiologies, is crucial to propose new therapeutic strategies combatting this devastating disease.
Despite therapeutic advances, heart failure is the major cause of morbidity and mortality worldwide, but why cardiac regenerative capacity is lost in adult humans remains an enigma. Cardiac ...regenerative capacity widely varies across vertebrates. Zebrafish and newt hearts regenerate throughout life. In mice, this ability is lost in the first postnatal week, a period physiologically similar to thyroid hormone (TH)-regulated metamorphosis in anuran amphibians. We thus assessed heart regeneration in Xenopus laevis before, during, and after TH-dependent metamorphosis. We found that tadpoles display efficient cardiac regeneration, but this capacity is abrogated during the metamorphic larval-to-adult switch. Therefore, we examined the consequence of TH excess and deprivation on the efficiently regenerating tadpole heart. We found that either acute TH treatment or blocking TH production before resection significantly but differentially altered gene expression and kinetics of extracellular matrix components deposition, and negatively impacted myocardial wall closure, both resulting in an impeded regenerative process. However, neither treatment significantly influenced DNA synthesis or mitosis in cardiac tissue after amputation. Overall, our data highlight an unexplored role of TH availability in modulating the cardiac regenerative outcome, and present X. laevis as an alternative model to decipher the developmental switches underlying stage-dependent constraint on cardiac regeneration.
Neurodegenerative diseases are characterized by chronic neuronal and/or glial cell loss, while traumatic injury is often accompanied by the acute loss of both. Multipotent neural stem cells (NSCs) in ...the adult mammalian brain spontaneously proliferate, forming neuronal and glial progenitors that migrate towards lesion sites upon injury. However, they fail to replace neurons and glial cells due to molecular inhibition and the lack of pro-regenerative cues. A major challenge in regenerative biology therefore is to unveil signaling pathways that could override molecular brakes and boost endogenous repair. In physiological conditions, thyroid hormone (TH) acts on NSC commitment in the subventricular zone, and the subgranular zone, the two largest NSC niches in mammals, including humans. Here, we discuss whether TH could have beneficial actions in various pathological contexts too, by evaluating recent data obtained in mammalian models of multiple sclerosis (MS; loss of oligodendroglial cells), Alzheimer’s disease (loss of neuronal cells), stroke and spinal cord injury (neuroglial cell loss). So far, TH has shown promising effects as a stimulator of remyelination in MS models, while its role in NSC-mediated repair in other diseases remains elusive. Disentangling the spatiotemporal aspects of the injury-driven repair response as well as the molecular and cellular mechanisms by which TH acts, could unveil new ways to further exploit its pro-regenerative potential, while TH (ant)agonists with cell type-specific action could provide safer and more target-directed approaches that translate easier to clinical settings.
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.
Choroid plexus epithelial cells produce and secrete transthyretin (TTR). TTR binds and distributes thyroid hormone (TH) to brain cells via the cerebrospinal fluid. The adult murine subventricular ...zone (SVZ) is in close proximity to the choroid plexus. In the SVZ, TH determines neural stem cell (NSC) fate towards a neuronal or a glial cell. We investigated whether the loss of TTR also disrupted NSC fate choice. Our results show a decreased neurogenic versus oligodendrogenic balance in the lateroventral SVZ of Ttr knockout mice. This balance was also decreased in the dorsal SVZ, but only in Ttr knockout male mice, concomitant with an increased oligodendrocyte precursor density in the corpus callosum. Quantitative RTqPCR analysis following FACS-dissected SVZs, or marked-coupled microbeads sorting of in vitro neurospheres, showed elevated Ttr mRNA levels in neuronal cells, as compared to uncommitted precursor and glial cells. However, TTR protein was undetectable in vivo using immunostaining, and this despite the presence of Ttr mRNA-expressing SVZ cells. Altogether, our data demonstrate that TTR is an important factor in SVZ neuro- and oligodendrogenesis. They also reveal important gender-specific differences and spatial heterogeneity, providing new avenues for stimulating endogenous repair in neurodegenerative diseases.
Food packaging is of high societal value because it conserves and protects food, makes food transportable and conveys information to consumers. It is also relevant for marketing, which is of economic ...significance. Other types of food contact articles, such as storage containers, processing equipment and filling lines, are also important for food production and food supply. Food contact articles are made up of one or multiple different food contact materials and consist of food contact chemicals. However, food contact chemicals transfer from all types of food contact materials and articles into food and, consequently, are taken up by humans. Here we highlight topics of concern based on scientific findings showing that food contact materials and articles are a relevant exposure pathway for known hazardous substances as well as for a plethora of toxicologically uncharacterized chemicals, both intentionally and non-intentionally added. We describe areas of certainty, like the fact that chemicals migrate from food contact articles into food, and uncertainty, for example unidentified chemicals migrating into food. Current safety assessment of food contact chemicals is ineffective at protecting human health. In addition, society is striving for waste reduction with a focus on food packaging. As a result, solutions are being developed toward reuse, recycling or alternative (non-plastic) materials. However, the critical aspect of chemical safety is often ignored. Developing solutions for improving the safety of food contact chemicals and for tackling the circular economy must include current scientific knowledge. This cannot be done in isolation but must include all relevant experts and stakeholders. Therefore, we provide an overview of areas of concern and related activities that will improve the safety of food contact articles and support a circular economy. Our aim is to initiate a broader discussion involving scientists with relevant expertise but not currently working on food contact materials, and decision makers and influencers addressing single-use food packaging due to environmental concerns. Ultimately, we aim to support science-based decision making in the interest of improving public health. Notably, reducing exposure to hazardous food contact chemicals contributes to the prevention of associated chronic diseases in the human population.
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