The Conflict between Regulatory Agencies over the 20,000-Fold Lowering of the Tolerable Daily Intake (TDI) for Bisphenol A (BPA) by the European Food Safety Authority (EFSA).

BACKGROUND: The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to 0.2 ng/kg body weight (BW)/day. BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA. OBJECTIVES: We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government-academic program model. DISCUSSION: We strongly endorse EFSA's revised TDI for BPA and support the European Commission's (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. https://doi.org/10.1289/EHP13812.

Pressures of the urban environment on the endocrine system: Adverse effects and adaptation.

With an increasing collective awareness of the rapid environmental changes, questions and theories regarding the adaptability of organisms are emerging. Global warming as well as chemical and non-chemical pollution have been identified as triggers of these adaptative changes, but can we link different kinds of stressors to certain phenotypic traits? The physiological adaptation, and particularly endocrine system adaptation, of living beings to urban environments is a fascinating way of studying urban endocrinology, which has emerged as a research field in 2007. In this paper, we stress how endocrine disruption in humans and environment can be studied in the urban environment by measuring the levels of pollution, endocrine activities or adversity. We broaden the focus to include not only exposure to the chemicals that have invaded our private spheres and their effects on wild and domestic species but also non-chemical effectors such as light, noise and climate change. We argue that taking into account the various urban stress factors and their effects on the endocrine system would enable the adoption of new approaches to protect living organisms.

Association of endocrine disrupting chemicals exposure with human chorionic gonadotropin concentrations in pregnancy.

BACKGROUND: Human chorionic gonadotropin (hCG) is produced by the placenta and plays an essential role in the maintenance of pregnancy. Endocrine disrupting chemicals (EDCs) have the potential to interfere with functions related to the production and secretion of hCG; however associations between exposure to EDCs and hCG concentrations in humans remain to be elucidated. OBJECTIVES: To investigate the association of urinary, serum and plasma concentrations of EDCs during pregnancy with serum hCG concentrations. METHODS: We utilized data form the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. We investigated the association of 26 EDCs measured in early pregnancy urine or blood with serum hCG concentrations using multi-variable adjusted linear regression models per EDC and Weighted Quantile Sum (WQS) regression with repeated holdout validation for the EDCs mixture. RESULTS: In 2,039 included women, higher exposure to bisphenol A was associated with lower hCG (beta [95% CI]: -0.06 [-0.11 to -0.002]) while higher triclosan exposure was associated with a higher hCG (0.02 [0.003 to 0.04]). Higher exposure to several phthalates, including mono-ethyl and mono-butyl phthalates (MEP and MBP) as well as metabolites of di-2-ethylhexyl phthalate (DEHP) was associated with a lower hCG (beta [95% CI] for sum of DEHP metabolites: -0.13 [-0.19 to -0.07]). Likewise, higher exposure to several polychlorinated biphenyls (PCBs) was associated with a lower hCG. In the WQS regression, each quartile increase in the EDCs mixture was associated with -0.27 lower hCG (95% CI: -0.34 to -0.19). DISCUSSION: Higher exposure to several EDCs during pregnancy was associated with a lower hCG; and despite the small effect sizes, still indicating that the exposure may negatively affect production or secretion of hCG by the placenta. Our results provide the impetus for future experimental studies to investigate the placenta as a target organ for adverse effects of EDCs.

From Cohort to Cohort: A Similar Mixture Approach (SMACH) to Evaluate Exposures to a Mixture Leading to Thyroid-Mediated Neurodevelopmental Effects Using NHANES Data.

Prenatal exposure to a mixture (MIX N) of eight endocrine-disrupting chemicals has been associated with language delay in children in a Swedish pregnancy cohort. A novel approach was proposed linking this epidemiological association with experimental evidence, where the effect of MIX N on thyroid hormone signaling was assessed using the Xenopus eleuthero-embryonic thyroid assay (XETA OECD TG248). From this experimental data, a point of departure (PoD) was derived based on OECD guidance. Our aim in the current study was to use updated toxicokinetic models to compare exposures of women of reproductive age in the US population to MIX N using a Similar Mixture Approach (SMACH). Based on our findings, 66% of women of reproductive age in the US (roughly 38 million women) had exposures sufficiently similar to MIX N. For this subset, a Similar Mixture Risk Index (SMRIHI) was calculated comparing their exposures to the PoD. Women with SMRIHI > 1 represent 1.1 million women of reproductive age. Older women, Mexican American and other/multi race women were less likely to have high SMRIHI values compared to Non-Hispanic White women. These findings indicate that a reference mixture of chemicals identified in a Swedish cohort-and tested in an experimental model for establishment of (PoDs)-is also of health relevance in a US population.

A Mixture of Chemicals Found in Human Amniotic Fluid Disrupts Brain Gene Expression and Behavior in Xenopus laevis.

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, T4 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, T4 and the mixture have different gene signatures. Immunohistochemistry showed increased proliferation in the brains of T4-treated animals, whereas no difference was observed for the amniotic mixture. Further, we demonstrated diminished tadpoles' motility in response to T4 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.

Transient developmental exposure to low doses of bisphenol F negatively affects neurogliogenesis and olfactory behaviour in adult mice.

Neural stem cells in the murine subventricular zone (SVZ) reactivate during postnatal development to generate neurons and glia throughout adulthood. We previously demonstrated that a postnatal thyroid hormone (TH) peak orchestrates this remodelling, rendering this process vulnerable to endocrine disruption. We exposed mice to 2 or 200 µg/kg bw/day of the bisphenol A-replacement and suspected TH-disruptor bisphenol F (BPF) in the drinking water, from embryonic day 15 to postnatal day 21 (P21). In parallel, one group was exposed to the TH-synthesis blocker propylthiouracil (0.15 % PTU). In contrast to PTU, BPF exposure did not affect serum TH levels at P15, P21 or P60. RNA-seq on dissected SVZs at P15 revealed dysregulated neurodevelopmental genes in all treatments, although few overlapped amongst the conditions. We then investigated the phenotype at P60 to analyse long-term consequences of transient developmental exposure. As opposed to hypothyroid conditions, and despite dysregulated oligodendrogenesis-promoting genes in the P15 SVZ exposed to the highest dose of BPF, immunostainings for myelin and OLIG2/CC1 showed no impact on global myelin content nor oligodendrocyte maturation in the P60 corpus callosum, apart from a reduced thickness. The highest dose did reduce numbers of newly generated SVZ-neuroblasts with 22 %. Related to this were behavioural alterations. P60 mice previously exposed to the highest BPF dose memorized an odour less well than control animals did, although they performed better than PTU-exposed animals. All mice could discriminate new odours, but all exposed groups showed less interest in social odours. Our data indicate that perinatal exposure to low doses of BPF disrupts postnatal murine SVZ remodelling, and lowers the adult neuron/oligodendroglia output, even after exposure had been absent for 40 days. These anomalies warrant further investigation on the potential harm of alternative bisphenol compounds for human foetal brain development.

Increased oligodendrogenesis and myelination in the subventricular zone of aged mice and gray mouse lemurs.

The adult rodent subventricular zone (SVZ) generates neural stem cells (NSCs) throughout life that migrate to the olfactory bulbs (OBs) and differentiate into olfactory interneurons. Few SVZ NSCs generate oligodendrocyte precursor cells (OPCs). We investigated how neurogliogenesis is regulated during aging in mice and in a non-human primate (NHP) model, the gray mouse lemur. In both species, neuronal commitment decreased with age, while OPC generation and myelin content unexpectedly increased. In the OBs, more tyrosine hydroxylase interneurons in old mice, but fewer in lemurs, marked a surprising interspecies difference that could relate to our observation of a continuous ventricle in lemurs. In the corpus callosum, aging promoted maturation of OPCs into mature oligodendrocytes in mice but blocked it in lemurs. The present study highlights similarities and dissimilarities between rodents and NHPs, revealing that NHPs are a more relevant model than mice to study the evolution of biomarkers of aging.

Short- and Long-Term Effects of Chlorpyrifos on Thyroid Hormone Axis and Brain Development in Xenopus laevis.

INTRODUCTION: The extensive use of the insecticide chlorpyrifos (CPF) throughout the world has brought increased scrutiny on its environmental and health impact. CPF is a cholinergic neurotoxicant; however, exposure to low noncholinergic doses is associated with numerous neurodevelopmental effects in animal models. In this study, we aimed to assess CPF for its potential to disrupt thyroid hormone signalling and investigate the short- and long-term effects on neurodevelopment by using Xenopus laevis. METHODS: The thyroid hormone (TH) disrupting potential of CPF was assessed using TH-sensitive transgenic Tg(thibz:eGFP) tadpoles. The consequences of early embryonic exposure were examined by exposing fertilized eggs for 72 h to environmentally relevant CPF concentrations (10-10 M and 10-8 M). Three endpoints were evaluated: (1) gene expression in whole embryonic brains immediately after exposure, (2) mobility and brain morphology 1 week after exposure, and (3) brain morphology and axon diameters at the end of metamorphosis (2 months after the exposure). RESULTS: CPF disrupted TH signalling in Tg(thibz:eGFP) tadpoles. The expression of genes klf9, cntn4, oatp1c1, and tubb2b was downregulated in response to CPF. Tadpoles exposed to CPF exhibited increased mobility and altered brain morphology compared to control tadpoles. Early embryonic exposure of CPF affected myelinated axon diameter, with exposed animals exhibiting shifted frequency distributions of myelinated axons diameters towards smaller diameters in the hindbrain of froglets. DISCUSSION/CONCLUSION: This study provides more evidence of the endocrine and neurodevelopment disrupting activity of CPF. Further experimental and epidemiological studies are warranted to determine the long-term consequences of early CPF exposure on brain development.

Association of per- and polyfluoroalkyl substances with thyroid homeostasis during pregnancy in the SELMA study.

OBJECTIVES: To investigate the association of exposure to per- and polyfluoroalkyl substances (PFAS) during early pregnancy with markers of the maternal thyroid system. METHODS: Serum concentrations of seven PFAS as well as thyroid stimulating hormone (TSH), free and total thyroxine (FT4 and TT4), free and total triiodothyronine (FT3 and TT3) were measured in pregnant women in early pregnancy in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. Outcomes were concentrations of TSH and thyroid hormones, FT4/FT3 or TT4/TT3 ratios, TSH/FT4 ratio as a marker of the negative feedback loop, TT4/FT4 or TT3/FT3 ratios as markers of the binding of thyroid hormones to binding proteins. RESULTS: The study population comprised 2,008 women with median (95% range) gestational age of 10 (6-14) weeks. There was no association between PFAS and TSH. Higher PFNA, PFDA, PFHpA and PFOA levels were associated with a higher FT4 (largest effect estimate for PFDA: ß [95% CI]: 0.27 [0.10 to 0.45], P = 0.002). Higher PFUnDA levels, but no other PFAS, were associated with a lower FT3 (ß [95% CI]: -0.05 [-0.09 to -0.01], P = 0.005). Higher PFUnDA levels were associated with lower TT4 (ß [95% CI]: -1.58 [-3.07 to -0.09]) and there was an inverted U-shaped association of PFOS with TT4 (P = 0.03). Higher PFDA, PFUnDA, PFHpA levels were associated with a lower TT3. Overall, higher PFAS concentrations were associated with a higher FT4/FT3 ratio and a higher TT4/TT3 ratio. There was no association of PFAS with the TSH/FT4 ratio. Higher concentrations of several PFAS were associated with lower TT4/FT4 and TT3/FT3 ratios. CONCLUSIONS: These findings translate results from experimental studies suggesting that exposure to PFAS may interfere with the thyroid system during pregnancy. Further experimental studies should take into account human evidence to better understand the potential underlying mechanisms of thyroid disruption by PFAS exposure.

Pollutants: a candidate as a new risk factor for osteoarthritis-results from a systematic literature review.

BACKGROUND: Considering non-classical environmental risk factors for osteoarthritis (OA), a systematic literature review (SLR) was performed to summarise existing knowledge on associations between OA and pollutants. METHODS: PubMed was used to identify studies reporting data on OA and pollutants in humans (examples of MeSH terms: "Pesticides" or "Polychlorinated Biphenyls" or 'Lead'). Reports included epidemiological clinical studies, pollutant assessments in ex vivo OA joint, and in vitro effects of pollutants on chondrocytes. RESULTS: Among the 193 potentially relevant articles, 14 were selected and combined with 9 articles obtained by manual search. Among these 23 articles there were: (1) 11 epidemiological studies on the relationship between OA and pollutants exposure, (2) 8 on pollutant concentrations in ex vivo OA joint, (3) 4 on the in vitro effects of pollutants on human chondrocytes. Epidemiological studies investigating mainly chlorinated and fluorinated pollutants suggested a possible link with OA. In cross-sectional studies, radiographic knee OA prevalence increased with higher serum lead levels. There was also a relationship between serum lead levels and serum/urine joint biomarkers. A high concentration of heavy metals in the cartilage tidemark was found in ex vivo joints. In vitro, the viability of chondrocytes was reduced in presence of some pollutants. However, the level of knowledge currently remains low, justifying the need for new methodologically sound studies. CONCLUSIONS: This SLR supports the hypothesis of a possible involvement of pollutants in OA disease risk. Large-scale epidemiological and biological studies and ideally big-data analysis are needed to confirm that pollutants could be risk factors for OA.

Developmental thyroid disruption permanently affects the neuroglial output in the murine subventricular zone.

Neural stem cells (NSCs) in the adult brain are a source of neural cells for brain injury repair. We investigated whether their capacity to generate new neurons and glia is determined by thyroid hormone (TH) during development because serum levels peak during postnatal reorganization of the main NSC niche, the subventricular zone (SVZ). Re-analysis of mouse transcriptome data revealed increased expression of TH transporters and deiodinases in postnatal SVZ NSCs, promoting local TH action, concomitant with a burst in neurogenesis. Inducing developmental hypothyroidism reduced NSC proliferation, disrupted expression of genes implicated in NSC determination and TH signaling, and altered the neuron/glia output in newborns. Three-month-old adult mice recovering from developmental hypothyroidism had fewer olfactory interneurons and underperformed on short-memory odor tests, dependent on SVZ neurogenesis. Our data provide readouts permitting comparison with adverse long-term events following thyroid disruptor exposure and ideas regarding the etiology of prevalent neurodegenerative diseases in industrialized countries.

From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures.

Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.

Association of phthalate exposure with thyroid function during pregnancy.

BACKGROUND: The extent of thyroid disruptive effects of phthalates during pregnancy remains unclear. AIM: To investigate the association of maternal urinary phthalates with markers of the thyroid system during early pregnancy. METHODS: Urinary concentrations of phthalate metabolites and serum concentrations of thyroid stimulating hormone (TSH), free and total thyroxine (FT4 and TT4) and free and total triiodothyronine (FT3 and TT3) were measured in pregnant women in early pregnancy in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study (2007-ongoing), a population-based prospective cohort. RESULTS: In the 1,996 included women, higher di-ethyl-hexyl phthalate (DEHP) metabolites were associated with a lower FT4 (ß [SE] for the molar sum: -0.13 [0.06], P = 0.03) and a higher TSH/FT4 ratio (0.003 [0.001], P = 0.03). Higher concentrations of di-iso-nonyl phthalate (DINP) metabolites were associated with a lower TT4 (ß [SE] for the molar sum: 0.93 [0.44], P = 0.03) as well as with lower TT4/FT4 and TT4/TT3 ratios. Higher metabolites of both dibutyl and butyl-benzyl phthalate (DBP and BBzP) were associated with lower T4/T3 ratio (free and total) and higher FT4/TT4 and FT3/TT3 ratios. A higher diisononyl cyclohexane dicarboxylate (DINCH) metabolite concentration was associated with a higher TT3. CONCLUSIONS: These results translate results from experimental studies suggesting that exposure to phthalates may interfere with the thyroid system during pregnancy. This is also true for compounds that have been introduced to replace known disruptive phthalates. Further experimental studies should take into account the human evidence to better investigate the potential underlying mechanisms of thyroid disruption by phthalates.

The pyriproxyfen metabolite, 4'-OH-PPF, disrupts thyroid hormone signaling in neural stem cells, modifying neurodevelopmental genes affected by ZIKA virus infection.

North-Eastern Brazil saw intensive application of the insecticide pyriproxyfen (PPF) during the microcephaly outbreak caused by the Zika virus (ZIKV). ZIKV requires the neural RNA-binding protein Musashi-1 to replicate. Thyroid hormone (TH) represses MSI1. PPF is a suspected TH disruptor. We hypothesized that co-exposure to the main metabolite of PPF, 4'-OH-PPF, could exacerbate ZIKV effects through increased MSI1 expression. Exposing an in vivo reporter model, Xenopus laevis, to 4'-OH-PPF decreased TH signaling and increased msi1 mRNA and protein, confirming TH-antagonistic properties. Next, we investigated the metabolite's effects on mouse subventricular zone-derived neural stem cells (NSCs). Exposure to 4'-OH-PPF dose-dependently reduced neuroprogenitor proliferation and dysregulated genes implicated in neurogliogenesis. The highest dose induced Msi1 mRNA and protein, increasing cell apoptosis and the ratio of neurons to glial cells. Given these effects of the metabolite alone, we considered if combined infection with ZIKV worsened neurogenic events. Only at the fourth and last day of incubation did co-exposure of 4'-OH-PPF and ZIKV decrease viral replication, but viral RNA copies stayed within the same order of magnitude. Intracellular RNA content of NSCs was decreased in the combined presence of 4'-OH-PPF and ZIKV, suggesting a synergistic block of transcriptional machinery. Seven out of 12 tested key genes in TH signaling and neuroglial commitment were dysregulated by co-exposure, of which four were unaltered when exposed to 4'-OH-PPF alone. We conclude that 4'-OH-PPF is an active TH-antagonist, altering NSC processes known to underlie correct cortical development. A combination of the TH-disrupting metabolite and ZIKV could aggravate the microcephaly phenotype.

Thyroid hormone regulation of adult neural stem cell fate: A comparative analysis between rodents and primates.

Thyroid hormone (TH) signaling, a highly conserved pathway across vertebrates, is crucial for brain development and function throughout life. In the adult mammalian brain, including that of humans, multipotent neural stem cells (NSCs) proliferate and generate neuronal and glial progenitors. The role of TH has been intensively investigated in the two main neurogenic niches of the adult mouse brain, the subventricular and the subgranular zone. A key finding is that T3, the biologically active form of THs, promotes NSC commitment toward a neuronal fate. In this review, we first discuss the roles of THs in the regulation of adult rodent neurogenesis, as well as how it relates to functional behavior, notably olfaction and cognition. Most research uncovering these roles of TH in adult neurogenesis was conducted in rodents, whose genetic background, brain structure and rate of neurogenesis are considerably different from that of humans. To bridge the phylogenetic gap, we also explore the similarities and divergences of TH-dependent adult neurogenesis in non-human primate models. Lastly, we examine how photoperiodic length changes TH homeostasis, and how that might affect adult neurogenesis in seasonal species to increase fitness. Several aspects by which TH acts on adult NSCs seem to be conserved among mammals, while we only start to uncover the molecular pathways, as well as how other in- and extrinsic factors are intertwined. A multispecies approach delivering more insights in the matter will pave the way for novel NSC-based therapies to combat neurological disorders.

Absence of Both Thyroid Hormone Transporters MCT8 and OATP1C1 Impairs Neural Stem Cell Fate in the Adult Mouse Subventricular Zone.

Adult neural stem cell (NSC) generation in vertebrate brains requires thyroid hormones (THs). How THs enter the NSC population is unknown, although TH availability determines proliferation and neuronal versus glial progenitor determination in murine subventricular zone (SVZ) NSCs. Mice display neurological signs of the severely disabling human disease, Allan-Herndon-Dudley syndrome, if they lack both MCT8 and OATP1C1 transporters, or MCT8 and deiodinase type 2. We analyzed the distribution of MCT8 and OATP1C1 in adult mouse SVZ. Both are strongly expressed in NSCs and at a lower level in neuronal cell precursors but not in oligodendrocyte progenitors. Next, we analyzed Mct8/Oatp1c1 double-knockout mice, where brain uptake of THs is strongly reduced. NSC proliferation and determination to neuronal fates were severely affected, but not SVZ-oligodendroglial progenitor generation. This work highlights how tight control of TH availability determines NSC function and glial-neuron cell-fate choice in adult brains.

Mechanistic insights into the synergistic activation of the RXR-PXR heterodimer by endocrine disruptor mixtures.

Humans are chronically exposed to mixtures of xenobiotics referred to as endocrine-disrupting chemicals (EDCs). A vast body of literature links exposure to these chemicals with increased incidences of reproductive, metabolic, or neurological disorders. Moreover, recent data demonstrate that, when used in combination, chemicals have outcomes that cannot be predicted from their individual behavior. In its heterodimeric form with the retinoid X receptor (RXR), the pregnane X receptor (PXR) plays an essential role in controlling the mammalian xenobiotic response and mediates both beneficial and detrimental effects. Our previous work shed light on a mechanism by which a binary mixture of xenobiotics activates PXR in a synergistic fashion. Structural analysis revealed that mutual stabilization of the compounds within the ligand-binding pocket of PXR accounts for the enhancement of their binding affinity. In order to identify and characterize additional active mixtures, we combined a set of cell-based, biophysical, structural, and in vivo approaches. Our study reveals features that confirm the binding promiscuity of this receptor and its ability to accommodate bipartite ligands. We reveal previously unidentified binding mechanisms involving dynamic structural transitions and covalent coupling and report four binary mixtures eliciting graded synergistic activities. Last, we demonstrate that the robust activity obtained with two synergizing PXR ligands can be enhanced further in the presence of RXR environmental ligands. Our study reveals insights as to how low-dose EDC mixtures may alter physiology through interaction with RXR-PXR and potentially several other nuclear receptor heterodimers.

Human Health and Ocean Pollution.

Background: Pollution - unwanted waste released to air, water, and land by human activity - is the largest environmental cause of disease in the world today. It is responsible for an estimated nine million premature deaths per year, enormous economic losses, erosion of human capital, and degradation of ecosystems. Ocean pollution is an important, but insufficiently recognized and inadequately controlled component of global pollution. It poses serious threats to human health and well-being. The nature and magnitude of these impacts are only beginning to be understood. Goals: (1) Broadly examine the known and potential impacts of ocean pollution on human health. (2) Inform policy makers, government leaders, international organizations, civil society, and the global public of these threats. (3) Propose priorities for interventions to control and prevent pollution of the seas and safeguard human health. Methods: Topic-focused reviews that examine the effects of ocean pollution on human health, identify gaps in knowledge, project future trends, and offer evidence-based guidance for effective intervention. Environmental Findings: Pollution of the oceans is widespread, worsening, and in most countries poorly controlled. It is a complex mixture of toxic metals, plastics, manufactured chemicals, petroleum, urban and industrial wastes, pesticides, fertilizers, pharmaceutical chemicals, agricultural runoff, and sewage. More than 80% arises from land-based sources. It reaches the oceans through rivers, runoff, atmospheric deposition and direct discharges. It is often heaviest near the coasts and most highly concentrated along the coasts of low- and middle-income countries. Plastic is a rapidly increasing and highly visible component of ocean pollution, and an estimated 10 million metric tons of plastic waste enter the seas each year. Mercury is the metal pollutant of greatest concern in the oceans; it is released from two main sources - coal combustion and small-scale gold mining. Global spread of industrialized agriculture with increasing use of chemical fertilizer leads to extension of Harmful Algal Blooms (HABs) to previously unaffected regions. Chemical pollutants are ubiquitous and contaminate seas and marine organisms from the high Arctic to the abyssal depths. Ecosystem Findings: Ocean pollution has multiple negative impacts on marine ecosystems, and these impacts are exacerbated by global climate change. Petroleum-based pollutants reduce photosynthesis in marine microorganisms that generate oxygen. Increasing absorption of carbon dioxide into the seas causes ocean acidification, which destroys coral reefs, impairs shellfish development, dissolves calcium-containing microorganisms at the base of the marine food web, and increases the toxicity of some pollutants. Plastic pollution threatens marine mammals, fish, and seabirds and accumulates in large mid-ocean gyres. It breaks down into microplastic and nanoplastic particles containing multiple manufactured chemicals that can enter the tissues of marine organisms, including species consumed by humans. Industrial releases, runoff, and sewage increase frequency and severity of HABs, bacterial pollution, and anti-microbial resistance. Pollution and sea surface warming are triggering poleward migration of dangerous pathogens such as the Vibrio species. Industrial discharges, pharmaceutical wastes, pesticides, and sewage contribute to global declines in fish stocks. Human Health Findings: Methylmercury and PCBs are the ocean pollutants whose human health effects are best understood. Exposures of infants in utero to these pollutants through maternal consumption of contaminated seafood can damage developing brains, reduce IQ and increase children's risks for autism, ADHD and learning disorders. Adult exposures to methylmercury increase risks for cardiovascular disease and dementia. Manufactured chemicals - phthalates, bisphenol A, flame retardants, and perfluorinated chemicals, many of them released into the seas from plastic waste - can disrupt endocrine signaling, reduce male fertility, damage the nervous system, and increase risk of cancer. HABs produce potent toxins that accumulate in fish and shellfish. When ingested, these toxins can cause severe neurological impairment and rapid death. HAB toxins can also become airborne and cause respiratory disease. Pathogenic marine bacteria cause gastrointestinal diseases and deep wound infections. With climate change and increasing pollution, risk is high that Vibrio infections, including cholera, will increase in frequency and extend to new areas. All of the health impacts of ocean pollution fall disproportionately on vulnerable populations in the Global South - environmental injustice on a planetary scale. Conclusions: Ocean pollution is a global problem. It arises from multiple sources and crosses national boundaries. It is the consequence of reckless, shortsighted, and unsustainable exploitation of the earth's resources. It endangers marine ecosystems. It impedes the production of atmospheric oxygen. Its threats to human health are great and growing, but still incompletely understood. Its economic costs are only beginning to be counted.Ocean pollution can be prevented. Like all forms of pollution, ocean pollution can be controlled by deploying data-driven strategies based on law, policy, technology, and enforcement that target priority pollution sources. Many countries have used these tools to control air and water pollution and are now applying them to ocean pollution. Successes achieved to date demonstrate that broader control is feasible. Heavily polluted harbors have been cleaned, estuaries rejuvenated, and coral reefs restored.Prevention of ocean pollution creates many benefits. It boosts economies, increases tourism, helps restore fisheries, and improves human health and well-being. It advances the Sustainable Development Goals (SDG). These benefits will last for centuries. Recommendations: World leaders who recognize the gravity of ocean pollution, acknowledge its growing dangers, engage civil society and the global public, and take bold, evidence-based action to stop pollution at source will be critical to preventing ocean pollution and safeguarding human health.Prevention of pollution from land-based sources is key. Eliminating coal combustion and banning all uses of mercury will reduce mercury pollution. Bans on single-use plastic and better management of plastic waste reduce plastic pollution. Bans on persistent organic pollutants (POPs) have reduced pollution by PCBs and DDT. Control of industrial discharges, treatment of sewage, and reduced applications of fertilizers have mitigated coastal pollution and are reducing frequency of HABs. National, regional and international marine pollution control programs that are adequately funded and backed by strong enforcement have been shown to be effective. Robust monitoring is essential to track progress.Further interventions that hold great promise include wide-scale transition to renewable fuels; transition to a circular economy that creates little waste and focuses on equity rather than on endless growth; embracing the principles of green chemistry; and building scientific capacity in all countries.Designation of Marine Protected Areas (MPAs) will safeguard critical ecosystems, protect vulnerable fish stocks, and enhance human health and well-being. Creation of MPAs is an important manifestation of national and international commitment to protecting the health of the seas.

Thyroid Hormone and Neural Stem Cells: Repair Potential Following Brain and Spinal Cord Injury.

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 toward 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.