Biology subjects

Ueda, Y.

Publications and source records attributed to Ueda, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

In vivo brain temperature measurement using quantum dot imaging temperature sensors

Temperature regulation in the brain is essential for maintaining neuronal function and preventing thermally induced damage. Here, we report the development and in vivo application of quantum dots (QDs) to high-resolution thermometry in the mouse brain using two-photon excitation microscopy. These QDs, via the red-to-green photoluminescence (PL) intensity ratios, enabled stable temperature measurements in both normal and chronically hypo-perfused cerebral tissue. Our findings show that localized neuronal activity leads to transient heat generation, which is rapidly dissipated by cerebrovascular responses. In a chronic hypoperfusion model, impaired vascular function resulted in exaggerated and prolonged brain temperature elevations. This thermometry system provides unprecedented insight into the mechanisms of cerebral thermoregulation and highlights the importance of vascular cooling in protecting the brain from heat-induced stress, particularly in pathological conditions such as stroke.

bioengineering↗

bioRxiv2026

FGFR1-phosphate sensing and crystal-induced gasdermin D signaling in neutrophils drive vascular calcification in CKD

Chronic kidney disease (CKD) confers disproportionate cardiovascular risk. In non-dialysis CKD, calcification accumulates primarily within the intimal layer. Clinical studies indicate that intimal calcification correlates with hyperphosphatemia, yet the cellular and molecular pathways remain unclear. Given evidence that osteocytes sense phosphate via fibroblast growth factor receptor 1 (FGFR1), we hypothesized that FGFR1-expressing vascular immune cells, especially neutrophils, act as mediators linking high phosphate to plaque mineralization. In vitro, phosphate triggered FGFR1-dependent signaling in human and murine neutrophils, inducing neutrophil extracellular traps (NETs). Activated neutrophils promoted the depletion of Fetuin-A, a major inhibitor of calcium-phosphate complexation, creating a milieu permissive to mineral nucleation. Newly formed calcium-phosphate particles amplified NETs through gasdermin D (GSDMD), establishing a feed-forward loop that enhanced mineralization and endothelial injury in co-culture assays. Human arteriosclerotic plaques from CKD patients showed NETs markers co-localizing with calcified deposits. In vivo, pharmacological FGFR inhibition attenuated arterial intimal calcification and suppressed NET formation in CKD mice. These findings identify phosphate sensing via neutrophil FGFR1 and subsequent crystal-induced GSDMD signaling as drivers of intimal vascular calcification in CKD. Targeting phosphate-sensing pathways, NET formation, and neutrophil-driven mineralization may mitigate vascular calcification and reduce cardiovascular risk in CKD.

immunology↗

bioRxiv2026

ECHOS enables spatial epigenome profiling at subcellular resolution

Biological structures and the epigenome are intertwined. For example, complex tissues are often the combined products of various groups of spatially patterned cell types with distinct epigenetic states. Furthermore, chromatin at various subnuclear locations within a cell often differ in their epigenetic properties. Thus, a systematic understanding of the relationship between the epigenome and its spatial distribution across biological scales would inform tissue and cellular functions as well as gene regulatory mechanisms. Yet, spatially resolved epigenome profiling--particularly at subcellular resolution--remains technically challenging. Here, we present Epigenetic CUT&Tag via High-resolution Optical Selection (ECHOS), a platform that combines high-resolution imaging and high-throughput sequencing to enable precise, spatially targeted epigenetic profiling across biological scales. At the cellular scale, ECHOS generates high-quality DNA-binding protein and histone modification datasets that show strong concordances with datasets from ChIP-seq and CUT&Tag experiments. Further optimization of ECHOS (ECHOS+) enables the characterization of the histone modification landscape of chromatin at the sub-micron resolution. Using ECHOS+, we revealed distinct gene regulatory logics at different layers of human ectocervical epithelium. We also showed that micronuclei--small nucleus-like structures formed by mitotic errors--exhibited a different epigenetic state from the same chromosome regions on the intact nuclei. Finally, we found that human aging altered the epigenetic state of the inactive X chromosome located in a subcellular nuclear structure called the Barr body, which may contribute to genes escaping X chromosome inactivation during female aging. Together, ECHOS and ECHOS+ represent a scalable and generalizable framework for spatial epigenomic analyses, with broad potential applications in various domains of biology.

genetics↗

bioRxiv2026

Chromatin landscape and epigenetic heterogeneity of acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive hematologic cancer characterized by proliferation of immature myeloblasts. It shows profound molecular heterogeneity, which has been primarily studied through genetic abnormalities, providing the basis for disease classification, prognostication, and therapeutic choice. However, genetic factors alone may not fully explain AML pathogenesis and diversity, while leaving the role of abnormal epigenome, particularly chromatin state, largely unexplored in a large cohort of patients. Here we show that AML is classified into 16 subgroups with distinct chromatin accessibility profiles based on ATAC-seq in 1,563 AML cases, including novel AML subgroups not previously recognized in conventional genomic classifications. By integrating multi-omics analyses of genome, transcriptome, and major histone marks, we show that these epigenetic subgroups exhibit unique features in clinical presentation, gene mutations, differentiation states, gene expression, and super-enhancer profiles, which are validated across independent cohorts. Single-cell sequencing demonstrates the presence of subgroup-specific ATAC signatures that are shared by all leukemic cells, confirming the definitive role of the epigenome in the ATAC-based classification. Mechanistically, each subgroup is associated with a distinct gene regulatory network centered on key transcription factors, where subgroup-specific super-enhancers play a pivotal role. These ATAC subgroups also have prognostic significance independent of genomic classification, and help reveal unexpected drug sensitivities. In summary, ATAC-based chromatin profiling in this large sample set, combined with multi-omics data, provides new insights into AML pathogenesis beyond genomic profiling and also serves as an invaluable resource for AML research.

cancer biology↗

bioRxiv2025

New rice varieties with improved phosphorus-efficiency for low-input smallholder rice production in Africa

Smallholder farmers in Sub-Saharan Africa frequently produce rice in marginal environments where low soil fertility and other biotic and abiotic stresses limit productivity. Rice varieties developed by centralized breeding under favorable conditions on research stations have often not been adopted by farmers in such marginal environments. Our objective was to develop modern rice varieties adapted to such low-input conditions through combining pre-breeding research with subsequent selection and variety testing directly in the target environment: smallholder farmers fields in Madagascar with phosphorus (P) fixing soils. Two breeding populations were developed for this purpose, one based on marker-assisted introgression of the Pup1 locus into IR64, the second using a donor (DJ123) for internal P utilization efficiency and external P acquisition efficiency. Selection within these populations was conducted in fields managed according to local farmers practice without mineral fertilizer addition. Selected breeding lines underwent government-supervised variety release testing including farmer participatory evaluations in four Malagasy regions between 18-1350 masl altitude, and two lines were released as varieties FyVary32 and VyVary85. Both had between 0.47-0.8 t ha-1 higher grain yield than parent IR64 and local check X265. Yield advantages were stable across a range from 2.1-5.5 t ha-1 (national average: 2.8 t ha-1). Higher yields were accompanied by superior root development and P uptake and by more efficient internal P utilization in FyVary85. Results show that decentralized breeding in marginal environments can produce varieties not only superior in lowest-yielding environments but across a broader range, clearly surpassing national average yields.

plant biology↗

bioRxiv2025

Postoperative Automated Platelet Count and Its Predictive Factors in Dogs Undergoing Mitral Valve Repair

ObjectivesThis study aimed to describe early postoperative changes in automated platelet counts (PLT) after mitral valve repair (MVR) in dogs with myxomatous mitral valve disease (MMVD) and to identify factors associated with these changes. DesignSingle-center retrospective cohort study. AnimalsDogs with MMVD that underwent MVR from July 2022 to July 2023. After data extraction, the ten most common breeds were selected, and mixed breeds as well as breeds known for inherent platelet abnormalities (Cavalier King Charles Spaniels and Norfolk Terriers) were excluded. Measurements and Main ResultsA total of 313 dogs representing seven breeds met the inclusion criteria. PLT levels were assessed preoperatively (Day 0) and daily for 4 days postoperatively (Days 1-4). Mean (standard deviation) PLT values were 393{+/-}127 x103/{micro}L on Day 0, 159{+/-}72 on Day 1, 137{+/-}67 on Day 2, 157{+/-}87 on Day 3, and 187{+/-}104 on Day 4. Postoperative thrombocytopenia (<100 x103/{micro}L) occurred in 124 of 313 dogs during Days 1-4. In a multivariable mixed-effects model, PLT declined significantly after surgery (Day 0 to 1; {beta} = -207.17 [x103/{micro}L per day], P < 0.001) and showed a postoperative upward trend (Day 1 to 4; {beta} = 20.62 [x103/{micro}L per day], P = 0.079). Older age was associated with higher PLT; Toy Poodles and Yorkshire Terriers demonstrated lower PLT than Chihuahuas; dogs with ACVIM Stages C- D had higher PLT compared with Stage B2; lower body weight correlated with lower PLT; and intact dogs tended to have higher PLT than neutered dogs. ConclusionsPLT decreased sharply following MVR and demonstrated partial recovery within 5 days. Age, breed, clinical stage, body weight, and neuter status were associated with postoperative PLT patterns, indicating their importance for perioperative assessment and monitoring.

physiology↗

bioRxiv2025

The influence of captivity on cardiac structure and function across age, in rhesus macaques

BackgroundCaptive non-human primates are widely used as models of human aging, yet the conditions they live in differ markedly from their naturalistic environment. Differences between captive and free-ranging environments may impact how the cardiovascular system adapts with age, potentially confounding studies of natural aging. This study characterized age-related cardiac phenotypes in free-ranging rhesus macaques and compared these patterns with their captive-housed counterparts to assess the influence of living environment on cardiac health across the lifespan. MethodologyWe performed transthoracic echocardiography in a cross-sectional cohort of 133 free-ranging rhesus macaques (Macaca mulatta, aged 7 - 25 years, 41 % female) living on Cayo Santiago, Puerto Rico. First, we compared structural and functional cardiac parameters between young (7 - 12 years; n = 48, 60% female) and old (18-26 years, n = 33, 42% female) free-ranging macaques. We then performed an ANCOVA, with age as a covariate, to compare cardiac structural and functional parameters between free-ranging and captive-housed macaques (n = 347, aged 7 - 32 years, 71% female). ResultsIn our free-ranging cohort, older macaques had greater interventricular septal thickness and relative wall thickness (RWT) than young. Males exhibited larger left ventricular (LV) internal dimensions, wall thickness, LV mass, and LV volumes than females, but these differences were attenuated when indexed to body mass. Diastolic function was lower with advanced age in both sexes, reflected by a lower E/A ratio, reduced myocardial tissue velocities during early diastole (e') and greater myocardial tissue velocities during atrial contraction (a). Compared with captive macaques, free-ranging animals exhibited better diastolic function, including a significantly higher E/A ratio, greater e, and lower a. Captive macaques also had significantly greater relative wall thickness across age and between sexes. Conclusions and implicationsOur study provides the first comprehensive characterization of age-related cardiac differences in free-ranging rhesus macaques, which show structural and functional cardiac differences similar to those observed with human aging. Captive macaques exhibited a more pronounced age-related cardiac phenotype than their free-ranging counterparts, including thicker left ventricular walls and lower diastolic function for a given age. These findings highlight the importance of considering the ecological context when interpreting animal models of cardiovascular aging.

physiology↗

bioRxiv2025

Natural variation in IBF1 disrupts its interaction with CHS1 and affects metabolism of hulls in rice

Secondary metabolites in plants have various physiological functions, including antioxidant and antibacterial activities. Previous studies have suggested genes and associated molecular mechanisms involved in the production of diverse secondary metabolites. However, much less is known about the genetic bases underlying within-species diversity in metabolite accumulation patterns, particularly in less focused tissues such as rice hulls. In this study, we aimed to identify the causal variant that affects flavonoid accumulation in rice hulls. We identified an F-box containing protein IBF1 is causal for genotypic differences in hull color through positional cloning. The variety IR64, with straw-white hulls, harbors functional IBF1 proteins that interact with a chalcone synthase, CHS1. Conversely, frame-shift mutations of IBF1 in the variety DJ123, which has pigmented hull color, resulted in a lack of a Kelch domain essential for the IBF1-CHS1 interaction. As a result, the DJ123 variant of IBF1 (IBF1DJ123) no longer interacted with CHS1, which was further supported by deep learning-based protein structural modeling. Further metabolome and transcriptome analyses using IR64 and an IR64-based chromosomal segment substitution line (CSSL) carrying IBF1DJ123 revealed an increase in the content of multiple flavonoids (such as naringenin and luteolin), while suppressing the expression of CAD involved in lignin synthesis. Metabolites in the CSSL carrying IBF1DJ123 suppressed the growth and siderophore generation activity of Pantoea species, which can act as beneficial or pathogenic endophytes. This study highlights the impact of a single gene on diverse metabolite accumulation patterns and suggests that this change may provide defense against pathogens.

plant biology↗

bioRxiv2025

Biodistribution-Driven Discovery Identifies a Glycosidase-Cleavable Linker to Reprogram Radiotheranostics

While radiopharmaceutical therapy (RPT) has become part of the standard-of-care for patients with advanced prostate cancers and neuroendocrine tumors (NETs), cures are elusive and normal tissue toxicity remain a challenge. Chemical groups susceptible to cleavage by enzymes present in tumors, tumor microenvironment or in normal tissues, have the potential to improve the therapeutic index for RPT. Using DOTA-TATE as an example and drawing from strategies used to develop antibody-drug conjugates, we designed, and synthesized, a chemically diverse series of linkers between the chelator (DOTA) and the targeting vector (TATE). Of the 10 agents we tested, two with cleavable linker domains reduced kidney retention compared to DOTA-TATE: the previously reported DOTA-MVK({varepsilon})-TATE, and a novel agent bearing cleavable beta-galactose ({beta}-Gal) unit, DOTA-{beta}-Gal-TATE. In murine models of NETs, positron emission tomography (PET) was used to image yttrium-86 (86Y)-labeled variants and show that, while the 86Y-DOTA-MVK({varepsilon})-TATE exhibits similar tumor uptake to the parent non-cleavable 86Y-DOTA-TATE, 86Y-DOTA-{beta}-Gal-TATE shows enhanced tumor uptake, resulting in up to 10-fold improvement in the tumor-to-kidney ratios compared to 86Y-DOTA-TATE. In vitro and in vivo studies confirm high efficiency, enzyme-specific cleavage of 86Y-DOTA-MVK({varepsilon})-TATE and 86Y-DOTA-{beta}-Gal-TATE, supporting a key role for cleavable linker chemistry in the observed outcomes. RPT studies using actinium-225 (225Ac)-labeled variants confirm that all agents are therapeutically effective and well tolerated. While both cleavable variants exhibit superior local control, overall survival, and more favorable toxicity profile when compared with 225Ac-DOTA-TATE, 225Ac-DOTA-{beta}-Gal-TATE demonstrated lower nephrotoxicity. Our findings suggest a potentially generalizable strategy for improving the pharmacokinetics of radiopharmaceutical therapy agents. One Sentence SummaryA {beta}-galactose-cleavable linker reduces kidney toxicity, enhances tumor targeting and therapeutic efficacy in radiopharmaceutical therapy.

cancer biology↗

bioRxiv2025

Weak and tunable adhesion-clutch drives rapid cell migration and glioblastoma motility

To move forward, migrating cells must exert backward forces against the extracellular environment. Recent studies have highlighted the importance of integrin-independent forces for cell migration; but the molecular machinery that exerts forces remains unclear. Here, we show that the clutch-linker molecule shootin1 and the cell adhesion molecule L1 transmit the backward force of treadmilling actin filaments to the adhesive environment for rapid dendritic cell migration. Notably, shootin1 and L1 transmit weak traction forces, [~]100 times weaker than integrin-based forces, by constituting an integrin-independent slippery adhesion-clutch. This adhesion-clutch system is tunable in response to the chemoattractant CCL19 and the adhesive ligand laminin and mediates chemotaxis through its polarized activation within cells. Furthermore, its aberrant activity enhances glioblastoma cell motility. Our results show that the weak adhesion-clutch is well-suited for rapid cell migration, without forming strong adhesions that impede cell motility, and provides a potential target for inhibiting abnormal cell motility.

cell biology↗

bioRxiv2024

A DJ123 allele at the heading date quantitative trait locus qHd7.1 promotes early heading without yield penalties under natural short-day and low fertility conditions in Madagascar

QTL analysis of heading date (Hd) was performed using a recombinant inbred line population derived from a cross between rice cultivars IR64 and DJ123. Phenotypic data was obtained from sites in Japan and Madagascar differing in photoperiod and soil fertility. The Japan site had long-days (LD) and high fertility, while the Madagascar site had short-days (SD) and low fertility conditions. Under LD in Japan, we discovered two Hd QTL on chromosome 7, qHd7.1 and qHd7.2, whereas only one of these (qHd7.1) was detected under SD conditions in Madagascar. RILs carrying DJ123 alleles at both QTLs headed 9.5 days earlier in Japan (LD) compared to IR64 alleles, whereas the effect of DJ123 alleles at qHd7.1 under SD conditions of Madagascar was 4 days and a combined effect of qHd7.1 and qHd7.2 did not exist. In Madagascar, early heading did not carry a yield penalty, whereas it caused reduced grain yield in Japan. These results suggest that RILs harboring the DJ123 allele of qHd7.1 have high yield potential and good adaptation to low fertility conditions in Madagascar and that this can be achieved in a shortened cultivation period, improving resilience to effects of climate change for African rice farmers.

plant biology↗

bioRxiv2024

Phosphodiesterase 3 inhibitors boost bone outgrowth

C-type natriuretic peptide (CNP) stimulates skeletal growth by acting on the growth plates of long bones, and a CNP variant is clinically used for achondroplasia treatment. We previously reported that CNP stimulates the autonomic Ca2+ influx mediated by TRPM7 channels in growth plate chondrocytes to facilitate extracellular matrix synthesis for bone growth. Here, we report that phosphodiesterase 3 (PDE3) inhibitors facilitate the Ca2+ influx and promote bone outgrowth. The representative PDE3 inhibitor cilostazol elevated cGMP levels and activated cell-surface K+ channels probably due to protein kinase G-mediated phosphorylation in growth-plate chondrocytes. The resulting hyperpolarization likely facilitated TRPM7-mediated Ca2+ influx by increasing the Ca2+-driving force. Moreover, cilostazol simulated the elongation of cultured bones and enlarged the body size of juvenile mice. Several PDE3 inhibitors have been used for clinical treatment of thrombosis, heart failure and asthma, while our observations suggest that the repositioning of PDE3 inhibitors would provide novel medications for syndromes involving short stature.

pharmacology and toxicology↗

bioRxiv2024

A hemoperfusion column selectively adsorbs LAP+ lymphocytes to improve anti-tumor immunity and survival of tumor-bearing rats

A decrease of immune suppressive cells in blood is thought to be one of the means to activate anti-tumor immunity that works as a treatment for cancers. We have developed an adsorbent that selectively adsorbs lymphocytes expressing latency-associated peptide (LAP), which include regulatory T cells (Tregs). The adsorbent, diethylenetriamine-conjugated polysulfone coated on polyethylene terephthalate fibers, was packed in a column for direct hemoperfusion (DHP). The therapeutic efficacy of DHP with the column was examined in rats carrying KDH-V liver cancer cells, in which LAP+ cells were increased in blood. After DHP, LAP+ T cells were decreased in peripheral blood, and a cytotoxic T-lymphocyte response against KDH-V cells was increased in tumor-bearing rats that had been immunized with X ray-irradiated KDH-V cells. Furthermore, the survival time of the rats was longer than that of rats without DHP. Thus, the removal of LAP+ T cells can potentially be applied to the treatment of cancer regardless of the origin since an increase in the number of LAP+ cells has been observed in the peripheral blood of various cancer patients.

immunology↗

bioRxiv2024

Comparative root transcriptome analysis suggests down-regulation of nitrogen assimilation in DJ123, a highly phosphorus-efficient rice genotype

Many cultivable lands across the globe are characteristically low for plant-available phosphorus (P). This necessitates application of P fertilisers, but this increases farming costs beyond the affordability of marginal farmers. Thus, developing cultivars with high P-use efficiency (PUE) is necessary in high-yielding modern rice varieties, which are typically inefficient in P usage. However, the molecular and physiological bases to increase PUE in crops remain elusive. Here, we studied root transcriptomes of two breeding parents contrasting in PUE via RNA-seq to elucidate key physiological and molecular mechanisms that underlies efficient use of P in rice. Examination of transcriptome data obtained from plants grown under P-sufficient and P-deficient hydroponic conditions in DJ123 (an upland rice genotype adapted to low P soils) and IR64 (a modern rice variety less efficient in P use) revealed that the genes encoding nitrogen assimilation-related enzymes such as glutamine synthetase [EC. 6.3.1.2], glutamate synthase [EC. 1.4.1.13], and asparagine synthetase [EC. 6.3.5.4] were down-regulated only in DJ123 roots while it was not significantly affected in IR64 under low P conditions. In addition, DJ123 roots had a lower total nitrogen (N) concentration than IR64 irrespective of P conditions. Taken together, we surmise that the low level of N concentration together with down-regulation of the N assimilation-related genes allow DJ123 to operate at a low level of N, thus leading to formation of root tissues with lower metabolic investment and a greater PUE.

plant biology↗

bioRxiv2024

High-throughput screening for Cushing's disease: therapeutic potential of thiostrepton via cell cycle regulation

Cushings disease is a life-threatening disorder caused by autonomous secretion of adrenocorticotropic hormone (ACTH) from pituitary neuroendocrine tumors (PitNETs). Few drugs are indicated for inoperative Cushings disease, in particular that due to aggressive PitNETs. To explore agents that regulate ACTH-secreting PitNETs, we conducted high-throughput screening (HTS) using AtT-20, a murine pituitary tumor cell line characterized by ACTH secretion. For the HTS, we constructed a live cell- based ACTH reporter assay for high-throughput evaluation of ACTH changes. This assay was based on HEK293T cells overexpressing components of the ACTH receptor and a fluorescent cAMP biosensor, with high-throughput acquisition of fluorescence images at the single-cell level. Of 2480 screened bioactive compounds, over 50% inhibition of ACTH secreted from AtT-20 cells was seen with 84 compounds at 10 M, and 20 compounds at 1 M. Among these hit compounds, we focused on thiostrepton (TS) and determined its antitumor effects in both in vitro and in vivo xenograft models of Cushings disease. Transcriptome and flow cytometry analyses revealed that TS administration induced AtT-20 cell cycle arrest at the G2/M phase, which was mediated by FOXM1-independent mechanisms including downregulation of cyclins. Simultaneous TS administration with a CDK 4/6 inhibitor that affected the cell cycle at the G0/1 phase showed cooperative antitumor effects. Thus, TS is a promising therapeutic agent for Cushings disease. Our list of hit compounds and new mechanistic insights into TS effects serve as a valuable foundation for future research.

cell biology↗

bioRxiv2023

Mutual interplay of actin meshwork and stress fibers in cellular adaptive response: Insights from percolation dynamics

Cells dynamically remodel their internal structures by modulating the arrangement of actin filaments (AFs). In this process, individual AFs exhibit stochastic behavior without knowing macroscopic higher-order structures they are meant to create or disintegrate. Cellular adaptation to environmental cues is accompanied with this type of self-assembly and disassembly, but the mechanism allowing for the stochastic process-driven remodeling of the cell structure remains incompletely understood. Here we employ percolation theory to explore how AFs interacting only with neighboring ones without recognizing the overall configuration can nonetheless construct stress fibers (SFs) at particular locations. To achieve this, we determine the binding and unbinding probabilities of AFs undergoing cellular tensional homeostasis, a fundamental property maintaining intracellular tension. We showed that the duration required for the assembly of SFs is shortened by the amount of preexisting actin meshwork, while the disassembly occurs independently of the presence of actin meshwork. This asymmetry between the assembly and disassembly, consistently observed in actual cells, is explained by considering the nature of intracellular tension transmission. Thus, our percolation analysis provides insights into the role of coexisting higher-order actin structures in their flexible responses during cellular adaptation.

biophysics↗

bioRxiv2023

Transcriptomic Landscape of Hyperthyroidism in Mice Overexpressing Thyroid Stimulating Hormone

Hyperthyroidism is a condition with excessive thyroid hormone secretion. Activation of thyroid stimulating hormone receptor (TSHR) fundamentally leads to hyperthyroidism. The details of TSHR signaling remain to be elucidated. We conducted transcriptome analyses for hyperthyroid mice that we generated by overexpressing TSH. TSH overexpression via hydrodynamic gene delivery with pLIVE-TSHB and pLIVE-CGA vectors consistently caused hyperthyroidism and goiters for at least 4 weeks in C57BL/6J mice. RNA sequencing analysis of their thyroid glands revealed that thiamazole slightly changed the thyroid transcriptome, which reinforces a conventional theory that thiamazole decreases thyroid hormone secretion via inhibition of thyroid peroxidase activity. Meanwhile, TSH overexpression drastically changed the thyroid transcriptome. In particular, enrichment analyses identified the cell cycle, phosphatidylinositol-3 kinase/Akt pathway, and Ras-related protein 1 pathway as possibly associated with goiter development. Regarding the role of TSHR signaling in hyperthyroidism, it is noteworthy that Slc26a4 was exclusively upregulated among genes crucial to thyroid hormone secretion at both 1 and 4 weeks after hydrodynamic gene delivery. To verify the relationship between this upregulation and hyperthyroidism, we overexpressed TSH in Slc26a4 knockout mice. TSH overexpression caused hyperthyroidism in Slc26a4 knockout mice, equivalent to that in control mice. To summarize, we analyzed hyperthyroid mice generated by TSH overexpression. We did not observe significant changes in known genes and pathways involved in thyroid hormone secretion. Thus, our datasets might include candidate genes that have not yet been identified as regulators of thyroid function. Our transcriptome datasets regarding hyperthyroidism can contribute to future research on TSHR signaling.

physiology↗

bioRxiv2022

TRIAC disrupts cerebral thyroid hormone action via a negative feedback loop and heterogenous distribution among organs

3,3,5-triiodothyroacetic acid (TRIAC) is a metabolite of endogenous thyroid hormones (THs) that can bind to and activate TH receptors. As TRIAC was previously detected in sewage effluent, we aimed to investigate exogenous TRIACs potential for endocrine disruption. We administered either TRIAC or 3,3,5-triiodo-L-thyronine (LT3) to both euthyroid mice and 6-propyl-2-thiouracil-induced hypothyroid mice. In hypothyroid mice, TRIAC alleviated growth retardation, suppressed the hypothalamus-pituitary-thyroid (HPT) axis, and upregulated TH-responsive genes in the pituitary gland, liver, and heart. We observed that, unlike LT3, TRIAC does not upregulate the expression of TH-responsive genes in the cerebrum. Measurement of organ-specific TRIAC levels suggested that TRIAC was not efficiently trafficked into the cerebrum. Furthermore, by analyzing euthyroid mice, we found that cerebral TRIAC levels did not increase despite TRIAC administration at higher concentrations, whereas serum and cerebral TH levels were substantially decreased. Hence, TH-responsive genes in the cerebrum appear to be downregulated by TRIAC. In summary, TRIAC administration decreases circulating TH levels by suppressing the HPT axis, while the consequent attenuation of TH actions was compensated by TRIAC in peripheral tissues but not in the cerebrum due to the relative impermeability of the blood-brain barrier towards TRIAC. We verified that exogenous TRIAC disrupts TH actions in the cerebrum. This disruption is apparently due to the additive effects of circulating endogenous THs being depleted via a negative feedback loop involving the HPT axis and heterogenous distribution of TRIAC among different organs. Our findings indicate that environmental TRIAC poses a potential neurodevelopmental risk.

ecology↗