Prenatal exposure to environmental endocrine disruptors can affect development and induce irreversible abnormalities in both humans and wildlife. The northern part of Kibale National Park, a ...mid-altitude rainforest in western Uganda, is largely surrounded by industrial tea plantations and wildlife using this area (Sebitoli) must cope with proximity to human populations and their activities. The chimpanzees and baboons in this area raid crops (primarily maize) in neighboring gardens. Sixteen young individuals of the 66 chimpanzees monitored (25%) exhibit abnormalities including reduced nostrils, cleft lip, limb deformities, reproductive problems and hypopigmentation. Each pathology could have a congenital component, potentially exacerbated by environmental factors. In addition, at least six of 35 photographed baboons from a Sebitoli troop (17%) have similar severe nasal deformities. Our inquiries in villages and tea factories near Sebitoli revealed use of eight pesticides (glyphosate, cypermethrin, profenofos, mancozeb, metalaxyl, dimethoate, chlorpyrifos and 2,4-D amine). Chemical analysis of samples collected from 2014 to 2016 showed that mean levels of pesticides in fresh maize stems and seeds, soils, and river sediments in the vicinity of the chimpanzee territory exceed recommended limits. Notably, excess levels were found for total DDT and its metabolite pp′-DDE and for chlorpyrifos in fresh maize seeds and in fish from Sebitoli. Imidacloprid was detected in coated maize seeds planted at the edge the forest and in fish samples from the Sebitoli area, while no pesticides were detected in fish from central park areas. Since some of these pesticides are thyroid hormone disruptors, we postulate that excessive pesticide use in the Sebitoli area may contribute to facial dysplasia in chimpanzees and baboons through this endocrine pathway. Chimpanzees are considered as endangered by IUCN and besides their intrinsic value and status as closely related to humans, they have major economic value in Uganda via ecotourism. Identifying and limiting potential threats to their survival such be a conservation priority.
•Agricultural land expansion towards parks exposes wildlife to environmental pollution.•We studied the human-wildlife interface in Kibale National Park, Uganda.•Methods used were environmental chemistry, ethnological enquiries, and primatology.•Numerous chimpanzees and baboons display similar facial deformities and are exposed to agricultural pollutants.•We propose that the high levels of EDC pollution represent an underestimated threat to endangered chimpanzees.
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Steroid hormones regulate many physiological processes in vertebrates, nematodes, and arthropods through binding to nuclear receptors (NR), a metazoan-specif ic family of ligand-activated ...transcription factors. The main steps controlling the diversification of this family are now well-understood. In contrast the origin and evolution of steroid ligands remain mysterious, although this is crucial for understanding the emergence of modern endocrine systems. Using a comparative genomic approach, we analyzed complete metazoan genomes to provide a comprehensive view of the evolution of major enzymatic players implicated in steroidogenesis at the whole metazoan scale. Our analysis reveals that steroidogenesis has been independently elaborated in the 3 main bilaterian lineages, and that steroidogenic cytochrome P450 enzymes descended from those that detoxify xenobiotics.
Energy imbalance due to excess of calories is considered to be a major player in the current worldwide obesity pandemic and could be accompanied by systemic and central inflammation and mitochondrial ...dysfunctions. This hypothesis was tested by comparing the wild-derived diet-induced obesity- (DIO-) resistant mouse strain WSB/EiJ to the obesity-prone C57BL/6J strain. We analysed circulating and hypothalamic markers of inflammatory status and hypothalamic mitochondrial activity in both strains exposed to high-fat diet (HFD). We further analysed the regulations of hypothalamic genes involved in inflammation and mitochondrial pathways by high throughput microfluidic qPCR on RNA extracted from laser micro-dissected arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei. HFD induced increased body weight gain, circulating levels of leptin, cholesterol, HDL and LDL in C57BL/6J whereas WSB/EiJ mice displayed a lower inflammatory status, both peripherally (lower levels of circulating cytokines) and centrally (less activated microglia in the hypothalamus) as well as more reactive mitochondria in the hypothalamus. The gene expression data analysis allowed identifying strain-specific hypothalamic metabolic pathways involved in the respective responses to HFD. Our results point to the involvement of hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO.
We recently used an endoscopy-based resection method to explore the consequences of cardiac injury in adult
, obtaining the result that the adult
heart is unable to regenerate. At 11 months ...post-amputation, cellular and biological marks of scarring persisted. We thus concluded that, contrary to urodeles and teleosts, adult anurans share a cardiac injury outcome similar to adult mammals. However, in their work published in this journal on the 13 December 2017, Liao et al. showed that the adult
heart is capable of efficient, almost scar free regeneration, a result at odds with our previous observation. These findings contrast with and challenge the outcome of adult heart repair following injury in
species. Here we discuss the question of the intrinsic cardiac regenerative properties of an adult heart in anuran amphibians.
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.
Genome-wide functional analyses require high-resolution genome assembly and annotation. We applied ChIA-PET to analyze gene regulatory networks, including 3D chromosome interactions, underlying ...thyroid hormone (TH) signaling in the frog Xenopus tropicalis. As the available versions of Xenopus tropicalis assembly and annotation lacked the resolution required for ChIA-PET we improve the genome assembly version 4.1 and annotations using data derived from the paired end tag (PET) sequencing technologies and approaches (e.g., DNA-PET gPET, RNA-PET etc.). The large insert (~10 Kb, ~17 Kb) paired end DNA-PET with high throughput NGS sequencing not only significantly improved genome assembly quality, but also strongly reduced genome "fragmentation", reducing total scaffold numbers by ~60%. Next, RNA-PET technology, designed and developed for the detection of full-length transcripts and fusion mRNA in whole transcriptome studies (ENCODE consortia), was applied to capture the 5' and 3' ends of transcripts. These amendments in assembly and annotation were essential prerequisites for the ChIA-PET analysis of TH transcription regulation. Their application revealed complex regulatory configurations of target genes and the structures of the regulatory networks underlying physiological responses. Our work allowed us to improve the quality of Xenopus tropicalis genomic resources, reaching the standard required for ChIA-PET analysis of transcriptional networks. We consider that the workflow proposed offers useful conceptual and methodological guidance and can readily be applied to other non-conventional models that have low-resolution genome data.
Reference genes are essential for gene expression analysis when using real-time quantitative PCR (RT-qPCR). Xenopus laevis is a popular amphibian model for studying vertebrate embryogenesis and ...development. Further, X. laevis is ideal for studying thyroid signaling due to its thyroid dependent metamorphosis, a stage comparable to birth in humans. When using PCR based studies, a primary concern is the choice of reference genes. Commonly used references are eef1a1, odc1, rpl8, and actnB, although there is a lack of ad hoc reference genes for X. laevis. Here, we used previously published RNA-seq data on different X. laevis stages and identified the top 14 candidate genes with respect to their expression levels as a function of developmental stage and degree of variation. We further evaluated the stability of these and other candidate genes using RT-qPCR on various stages including the unfertilised eggs, whole embryos during early development and brains during late development. We used four different statistical software packages: deltaCT, geNorm, NormFinder and BestKeeper. We report optimized reference gene pair combinations for studying development (early whole embryos), brains at later stages (metamorphosis and adult), and thyroid signalling. These reference gene pairs are suitable for studying different aspects of X. laevis development and organogenesis.
The histone code, notably H3 methylation, contributes to the precise control of gene expression that underlies complex physiological T3 responses.
The diversity of thyroid hormone T3 effects in vivo ...makes their molecular analysis particularly challenging. Indeed, the current model of the action of T3 and its receptors on transcription does not reflect this diversity. Here, T3-dependent amphibian metamorphosis was exploited to investigate, in an in vivo developmental context, how T3 directly regulates gene expression. Two, direct positively regulated T3-response genes encoding transcription factors were analyzed: thyroid hormone receptor β (TRβ) and TH/bZIP. Reverse transcription-real-time quantitative PCR analysis on Xenopus tropicalis tadpole brain and tail fin showed differences in expression levels in premetamorphic tadpoles (lower for TH/bZIP than for TRβ) and differences in induction after T3 treatment (lower for TRβ than for TH/bZIP). To dissect the mechanisms underlying these differences, chromatin immunoprecipitation was used. T3 differentially induced RNA polymerase II and histone tail acetylation as a function of transcriptional level. Gene-specific patterns of TR binding were found on the different T3 -responsive elements (higher for TRβ than for TH/bZIP), correlated with gene-specific modifications of H3K4 methylation (higher for TRβ than for TH/bZIP). Moreover, tissue-specific modifications of H3K27 were found (lower in brain than in tail fin). This first in vivo analysis of the association of histone modifications and TR binding/gene activation during vertebrate development for any nuclear receptor indicate that chromatin context of thyroid-responsive elements loci controls the capacity to bind TR through variations in histone H3K4 methylation, and that the histone code, notably H3, contributes to the fine tuning of gene expression that underlies complex physiological T3 responses.
•Higher exposure to most PFAS was associated with a higher FT4.•There was no association of PFAS with TSH or TSH/FT4 ratio.•Higher PFAS exposure is possibly associated with reduced peripheral ...conversion of T4.•Higher PFAS exposure is likely to be associated with displacement of T4 and T3 from distributor proteins.
To investigate the association of exposure to per- and polyfluoroalkyl substances (PFAS) during early pregnancy with markers of the maternal thyroid system.
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.
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: β 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 (β 95% CI: −0.05 -0.09 to −0.01, P = 0.005). Higher PFUnDA levels were associated with lower TT4 (β 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.
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.
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.
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