Hypothalamic-pituitary-thyroid Research Articles

A prospective, observational clinical trial on the impact of COVID-19-related national lockdown on thyroid hormone in young males

Trying to manage the dramatic coronavirus disease 2019 (COVID-19) infection spread, many countries imposed national lockdown, radically changing the routinely life of humans worldwide. We hypothesized that both the pandemic per se and the consequent socio-psychological sequelae could constitute stressors for Italian population, potentially affecting the endocrine system. This study was designed to describe the effect of lockdown-related stress on the hypothalamic-pituitary-thyroid (HPT) axis in a cohort of young men. A prospective, observational clinical trial was carried out, including patients attending the male infertility outpatient clinic before and after the national lockdown for COVID-19 pandemic. The study provided a baseline visit performed before and a follow-up visit after the lockdown in 2020. During the follow-up visit, hormonal measurements, lifestyle habits and work management were recorded. Thirty-one male subjects were enrolled (mean age: 31.6 ± 6.0 years). TSH significantly decreased after lockdown (p = 0.015), whereas no significant changes were observed in the testosterone, luteinising hormone, follicle-stimulating hormone, estradiol and prolactin serum levels. No patient showed TSH serum levels above or below reference ranges, neither before nor after lockdown. Interestingly, TSH variation after lockdown was dependent on the working habit change during lockdown (p = 0.042). We described for the first time a TSH reduction after a stressful event in a prospective way, evaluating the HPT axis in the same population, before and after the national lockdown. This result reinforces the possible interconnection between psychological consequences of a stressful event and the endocrine regulation.

Dynamic Interactions Between the Immune System and the Neuroendocrine System in Health and Disease.

The immune system and the neuroendocrine system share many common features. Both consist of diverse components consisting of receptors and networks that are widely distributed throughout the body, and both sense and react to external stimuli which, on the one hand control mechanisms of immunity, and on the other hand control and regulate growth, development, and metabolism. It is thus not surprising, therefore, that the immune system and the neuroendocrine system communicate extensively. This article will focus on bi-directional immune-endocrine interactions with particular emphasis on the hormones of the hypothalamus-pituitary-thyroid (HPT) axis. New findings will be discussed demonstrating the direct process through which the immune system-derived thyroid stimulating hormone (TSH) controls thyroid hormone synthesis and bone metamorphosis, particularly in the context of a novel splice variant of TSHβ made by peripheral blood leukocytes (PBL). Also presented are the ways whereby the TSHβ splice variant may be a contributing factor in the development and/or perpetuation of autoimmune thyroid disease (AIT), and how systemic infection may elicit immune-endocrine responses. The relationship between non-HPT hormones, in particular adipose hormones, and immunity is discussed.

Could Glyphosate and Glyphosate-Based Herbicides Be Associated With Increased Thyroid Diseases Worldwide?

The increased incidence of thyroid diseases raises a series of questions about what the main predisposing factors are nowadays. If dietary restriction of iodine was once a major global health concern, today, the processes of industrialization of food and high exposure to a wide variety of environmental chemicals may be affecting, directly or indirectly, thyroid function. The homeostasis of hypothalamus–pituitary–thyroid (HPT) axis is finely regulated through the negative feedback mechanism exerted by thyroid hormones. Allostatic mechanisms are triggered to adjust the physiology of HPT axis in chronic conditions. Glyphosate and glyphosate-based herbicides are pesticides with controversial endocrine disrupting activities and only few studies have approached their effects on HPT axis and thyroid function. However, glyphosate has an electrophilic and nucleophilic zwitterion chemical structure that may affect the mechanisms involved in iodide oxidation and organification, as well as the oxidative phosphorylation in the ATP synthesis. Thus, in this review, we aimed to: (1) discuss the critical points in the regulation of HPT axis and thyroid hormones levels balance, which may be susceptible to the toxic action of glyphosate and glyphosate-based herbicides, correlating the molecular mechanisms involved in glyphosate toxicity described in the literature that may, directly or indirectly, be associated to the higher incidence of thyroid diseases; and (2) present the literature regarding glyphosate toxicity in HPT axis.

Cushing's Syndrome Effects on the Thyroid.

The most known effects of endogenous Cushing’s syndrome are the phenotypic changes and metabolic consequences. However, hypercortisolism can exert important effects on other endocrine axes. The hypothalamus–pituitary–thyroid axis activity can be impaired by the inappropriate cortisol secretion, which determinates the clinical and biochemical features of the “central hypothyroidism”. These findings have been confirmed by several clinical studies, which also showed that the cure of hypercortisolism can determine the recovery of normal hypothalamus–pituitary–thyroid axis activity. During active Cushing’s syndrome, the “immunological tolerance” guaranteed by the hypercortisolism can mask, in predisposed patients, the development of autoimmune thyroid diseases, which increases in prevalence after the resolution of hypercortisolism. However, the immunological mechanism is not the only factor that contributes to this phenomenon, which probably includes also deiodinase-impaired activity. Cushing’s syndrome can also have an indirect impact on thyroid function, considering that some drugs used for the medical control of hypercortisolism are associated with alterations in the thyroid function test. These considerations suggest the utility to check the thyroid function in Cushing’s syndrome patients, both during the active disease and after its remission.

Fasting reduces the number of TRH immunoreactive neurons in the hypothalamic paraventricular nucleus of male rats, but not in mice

During fasting or weight loss, the fall in leptin levels leads to suppression of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus of the hypothalamus (PVH) and, consequently, inhibition of the hypothalamic-pituitary-thyroid (HPT) axis. However, differently than rats, just few PVHTRH neurons express the leptin receptor in mice. In the present study, male adult rats and mice were submitted to 48 -h fasting to evaluate the consequences on proTRH peptide expression at the PVH level. Additionally, the proTRH peptide expression was also assessed in the brains of leptin-deficient (Lepob/ob) mice. We observed that approximately 50 % of PVHTRH neurons of leptin-injected rats exhibited phosphorylation of the signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin receptor activation. In contrast, very few PVHTRH neurons of leptin-injected mice exhibited pSTAT3. Rats submitted to 48 -h fasting showed a significant reduction in the number of PVHTRH immunoreactive neurons, as compared to fed rats. On the other hand, no changes in the number of PVHTRH immunoreactive neurons were observed between fasted and fed mice. Next, the number of TRH immunoreactive cells was determined in the PVH, dorsomedial nucleus of the hypothalamus and nucleus raphe pallidus of Lepob/ob and wild-type mice and no significant differences were observed, despite reduced plasma T4 levels in Lepob/ob mice. Taken together, these findings provide additional evidence of the important species-specific differences in the mechanisms used by fasting and/or leptin to regulate the HPT axis.

Sub-chronic exposure to ammonia inhibits the growth of juvenile Wuchang bream (Megalobrama amblycephala) mainly by downregulation of growth hormone/insulin-like growth factor axis.

In this study, healthy Wuchang bream (Megalobrama amblycephala) juveniles were exposed to 0, 5, 10, 20 and 30 mg/L total ammonia nitrogen for 30 days to elucidate toxic effects and mechanisms of ammonia on growth performance involved with the regulation of growth hormone/insulin-like growth factor (GH/IGF) and hypothalamic-pituitary-thyroid (HPT) axes. Our results showed that the increasing total ammonia nitrogen concentrations caused dose-depend decreases in the weight gain and specific growth rate but increases in the food conversion ratio and mortality in juvenile bream, indicating growth inhibitory effects induced by ammonia. Concurrently, GH, IGF-1 at protein and mRNA levels were significantly decreased in ammonia exposure groups (p < .05), while serum thyroid stimulating hormone, free thyroxine, free triiodothyronine levels were significantly reduced only in fish exposed to higher concentrations of 20 and 30 mg/L ammonia (p < .05), suggesting that ammonia exposure could perturb both GH/IGF-axis and HPT-axis functions. Furthermore, transcriptional levels of extracellular regulated protein kinases 2 (erk2), phosphatidylinositol 3-kinase (pi3k), protein kinase B (akt), target of rapamycin (tom) and ribosomal protein S6 kinase-polypeptide 1(s6k1) in the dorsal muscle were significantly down-regulated in the fish exposed to ammonia (p < .05). This fact indicated that MAPK/ERK pathway and PI3K/AKT pathway should be responsible for the growth inhibition. Combining the results of spearman correlation coefficient, it should be noted that the GH/IGF axis played a more important role in regulating the growth than the HPT axis in Wuchang bream under persistent ammonia stress.

Novel insights into di‑(2‑ethylhexyl)phthalate activation: Implications for the hypothalamus‑pituitary‑thyroid axis.

Di (2-ethylhexyl) phthalate (DEHP), an environmental pollutant, is widely used as a plasticizer and causes serious pollution in the ecological environment. As previously reported, exposure to DEHP may cause thyroid dysfunction of the hypothalamic-pituitary-thyroid (HPT) axis. However, the underlying role of DEHP remains to be elucidated. The present study performed intragastrical administration of DEHP (150, 300 and 600 mg/kg) once a day for 90 consecutive days. DEHP-stimulated oxidative stress increased the thyroid follicular cavity diameter and caused thyrocyte oedema. Furthermore, DEHP exposure altered mRNA and protein levels. Thus, DEHP may perturb TH homeostasis by affecting biosynthesis, biotransformation, bio-transportation, receptor levels and metabolism through disruption of the HPT axis and activation of the thyroid-stimulating hormone (TSH)/TSH receptor signaling pathway. These results identified the formerly unappreciated endocrine-disrupting activities of phthalates and the molecular mechanisms of DEHP-induced thyrotoxicity.

The possible hormetic effects of fluorene-9-bisphenol on regulating hypothalamic-pituitary-thyroid axis in zebrafish.

Fluorene-9-bisphenol (BHPF) is a bisphenol A substitute, which has been introduced for the production of so-called 'bisphenol A (BPA)-free' plastics. However, it has been reported that BHPF can enter living organisms through using commercial plastic bottles and cause adverse effects. To date, the majority of the toxicologic study of BHPF focused on investigating its doses above the toxicological threshold. Here, we studied the effects of BHPF on development, locomotion, neuron differentiation of the central nervous system (CNS), and the expression of genes in the hypothalamic-pituitary-thyroid (HPT) axis in zebrafish exposed to different doses of BHPF ranging from 1/5 of LD1 to LD50 (300, 500, 750, 1500, 3000, and 4500nM). As a result, the possible hormetic effects of BHPF on regulating the HPT axis were revealed, in which low-dose BHPF positively affected the HPT axis while this regulation was inhibited as the dose increased. Underlying mechanism investigation suggested that BHPF disrupted myelination through affecting HPT axis including related genes expression and TH levels, thus causing neurotoxic characteristics. Collectively, this study provides the full understanding of the environmental impact of BHPF and its toxicity on living organisms, highlighting a substantial and generalized ongoing dose-response relationship with great implications for the usage and risk assessment of BHPF.

The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions

The hypothalamus-pituitary-thyroid axis is one of several hormone regulatory systems from the hypothalamus to the pituitary and ultimately to the peripheral target organs. The hypothalamus and the pituitary gland are in close anatomical proximity at the base of the brain and extended through the pituitary stalk to the sella turcica. The pituitary stalk allows passage of stimulatory and inhibitory hormones and other signal molecules. The target organs are placed in the periphery and function through stimulation/inhibition by the circulating pituitary hormones. The several hypothalamus-pituitary-target organ axis systems interact in very sophisticated and complicated ways and for many of them the interactive and integrated mechanisms are still not quite clear. The diagnosis of central hypothyroidism is complicated by itself but challenged further by concomitant affection of other hypothalamus-pituitary-hormone axes, the dysfunction of which influences the diagnosis of central hypothyroidism. Treatment of both the central hypothyroidism and the other hypothalamus-pituitary axes also influence the function of the others by complex mechanisms involving both central and peripheral mechanisms. Clinicians managing patients with neuroendocrine disorders should become aware of the strong integrative influence from each hypothalamus-pituitary-hormone axis on the physiology and pathophysiology of central hypothyroidism. As an aid in this direction the present review summarizes and highlights the importance of the hypothalamus-pituitary-thyroid axis, pitfalls in diagnosing central hypothyroidism, diagnosing/testing central hypothyroidism in relation to panhypopituitarism, pointing at interactions of the thyroid function with other pituitary hormones, as well as local hypothalamic neurotransmitters and gut-brain hormones. Furthermore, the treatment effect of each axis on the regulation of the others is described. Finally, these complicating aspects require stringent diagnostic testing, particularly in clinical settings with lower or at least altered à priori likelihood of hypopituitarism than in former obvious clinical patient presentations.

Thyroid Hormones Interaction With Immune Response, Inflammation and Non-thyroidal Illness Syndrome.

The interdependence between thyroid hormones (THs), namely, thyroxine and triiodothyronine, and immune system is nowadays well-recognized, although not yet fully explored. Synthesis, conversion to a bioactive form, and release of THs in the circulation are events tightly supervised by the hypothalamic–pituitary–thyroid (HPT) axis. Newly synthesized THs induce leukocyte proliferation, migration, release of cytokines, and antibody production, triggering an immune response against either sterile or microbial insults. However, chronic patho-physiological alterations of the immune system, such as infection and inflammation, affect HPT axis and, as a direct consequence, THs mechanism of action. Herein, we revise the bidirectional crosstalk between THs and immune cells, required for the proper immune system feedback response among diverse circumstances. Available circulating THs do traffic in two distinct ways depending on the metabolic condition. Mechanistically, internalized THs form a stable complex with their specific receptors, which, upon direct or indirect binding to DNA, triggers a genomic response by activating transcriptional factors, such as those belonging to the Wnt/β-catenin pathway. Alternatively, THs engage integrin αvβ3 receptor on cell membrane and trigger a non-genomic response, which can also signal to the nucleus. In addition, we highlight THs-dependent inflammasome complex modulation and describe new crucial pathways involved in microRNA regulation by THs, in physiological and patho-physiological conditions, which modify the HPT axis and THs performances. Finally, we focus on the non-thyroidal illness syndrome in which the HPT axis is altered and, in turn, affects circulating levels of active THs as reported in viral infections, particularly in immunocompromised patients infected with human immunodeficiency virus.

Acute Changes in Thyroid Hormone Levels among Thai Pesticide Sprayers.

The objective of this study was to investigate the relationship of acute pesticide exposures and acute changes in thyroid hormones among Thai farmers. We recruited 78 farmers, who were scheduled to spray insecticides (chlorpyrifos and/or cypermethrin) or herbicides (paraquat and/or glyphosate). On the day before spraying, farmers collected their first morning void urine and went for blood collection. On the spray day, urine samples were collected at end of the spraying event and they were interviewed with questionnaires. The next morning, the first morning void urine and blood samples were collected. Blood samples were analyzed for thyroid hormones. Urine samples were analyzed for the metabolites of the pesticide sprayed. The results showed that the thyroid hormones, free triiodothyronine (FT3) and total triiodothyronine (T3) were significantly reduced as urinary chlorpyrifos metabolite increased the day after spraying. Total thyroxine (T4) significantly increased as cypermethrin metabolites increased the day after spraying. T4 significantly increased as urinary glyphosate levels increased; however, FT3 and T3 decreased significantly as urinary paraquat levels increased the day after spraying. These findings suggest that acute exposures to the pesticides chlorpyrifos, cypermethrin, paraquat and glyphosate can produce acute effects on the hypothalamic–pituitary–thyroid (HPT) axis, acutely altering thyroid hormone levels.

Aging and the hypothalamic-pituitary-thyroid axis.

The world's population is increasingly aging, this noted particularly in the Western world where there are ever greater numbers of centenarians and those over 85 years. Given the immense importance of the thyroid gland for optimal health and the fact that morphological and functional changes in the hypothalamic-pituitary-thyroid (HPT) axis take place as a natural adaptation to the aging process, a clear distinction must be made in older individuals between these and the onset of disease. However, this is problematic since, frequently, subtle differences exist between them, making diagnosis a challenging task, especially as concerns subclinical disease. The newly emerging interdisciplinary field of geroscience offers the prospect of being used as a platform to investigate the effect of disrupted HPT function on functional capacity and cognitive ability among the aged, as well as the risk or onset of age-associated diseases, thus enhancing healthspan and lifespan. Because optimal functioning of the thyroid gland is a prerequisite for longevity as well as for mental and physical wellbeing, this review summarizes the recent scientific data regarding HPT and aging while discussing alternative and personalized treatment approaches to maintaining a healthy thyroid as a means to ensuring a long, active, and healthy life.

Outcome of critically ill patients with non-thyroidal illness

Background: During period of critical illness, there are diverse alterations in the hypothalamus-pituitarythyroid (HPT) axis. This diversity in critically ill patients and the etiological relationship between underlying disease and non-thyroidal illness (NTI) is poorly understood. The aims of this study were to examine the features of NTI and outcomes in critically ill patients admitted in Critical Care Medicine (CCM) Department, BIRDEM General Hospital.&#x0D; Methods: A total of 86 patients admitted to CCM department, BIRDEM General Hospital during the period of July to December 2015 , having nonthyroidal illness, detected by thyroid function tests during ICU stay were enrolled in this study. All patients discharged from hospital were followed up for a period of 6 months. Patients with known thyroid diseases or taking medications that affect thyroid function were excluded. Condition at hospital discharge and mortality in the ICU or later at home after discharge within next 6 months was assessed as outcomes.&#x0D; Results: Mean age of the study subjects was 63.87(±13.5)years and 45(52.3%)of the study subjects were female. Most of the study subjects had diabetes (84.88%) and hypertension (82.55%).Mean (±SD) of FT3 (pmol/l), FT4(pmol/l), TSH (uIU/ml) were 2.85(±1.35),12.74(±8.17) and 2.81(±8.57)respectively. Among the total study subjects 44.18% patients died in ICU and 2.32% patients after shifting to ward. Among the patients having pneumonia, Myocardial Infarction(MI) /Arrhythmia, Stroke, Sepsis and Gastrointestinal disease, 50.94% 51.02%, 56.0%,53.85%,37.50% died in hospital (ICU or after shifting toward).The 46 patients ,who were discharged from hospital were followed up for next 6 months.&#x0D; Conclusion: NTI is a transient adaptive response affecting individuals with acute and chronic illness and is more common among patients admitted in intensive care unit (ICU). The prognosis of patients having NTI depends on severity of thyroid dysfunction.&#x0D; Birdem Med J 2021; 11(1): 47-51

Effects of SiO2 nanoparticles on the uptake of tetrabromobisphenol A and its impact on the thyroid endocrine system in zebrafish larvae

The coexistence of nanoparticles and organic toxicants in the environment modifies pollutant bioavailability and toxicity. This study investigated the influence of silicon dioxide nanoparticles (n-SiO2) on the uptake of tetrabromobisphenol A (TBBPA) and its impact on the thyroid endocrine system in zebrafish larvae. Zebrafish (Danio rerio) embryos were exposed to TBBPA at different concentrations (50, 100, and 200 μg/L) alone or in combination with n-SiO2 (25 mg/L) until 120 h post-fertilization (hpf). Chemical measurements showed that both TBBPA and n-SiO2 were bioconcentrated in zebrafish larvae, and the uptake of TBBPA was enhanced by n-SiO2. Furthermore, zebrafish larvae exposed to 200 μg/L TBBPA alone exhibited significantly increased T4 contents and decreased T3 contents, whereas n-SiO2 treatment alone did not have a detectable effect. Furthermore, the thyroid hormone levels changed more upon treatment with 200 μg/L TBBPA combined with 25 mg/L n-SiO2 than upon TBBPA treatment alone. Alterations in gene transcription along the related hypothalamic-pituitary-thyroid (HPT) axis were observed, and expression of the binding and transport protein transthyretin (TTR) was significantly decreased for both TBBPA alone and co-exposure with n-SiO2. Thus, the current study demonstrates that n-SiO2, even at the nontoxic concentrations, increases thyroid hormone disruption in zebrafish larvae co-exposed to TBBPA by promoting its bioaccumulation and bioavailability.

PM2.5 disrupts thyroid hormone homeostasis through activation of the hypothalamic-pituitary-thyroid (HPT) axis and induction of hepatic transthyretin in female rats 2.5

Fine particulate matter (PM2.5), a ubiquitous environmental pollutant, has been indicated to affect thyroid hormone (TH) homeostasis in women, but the detailed mechanism behind this effect remains unclear. The objective of this study was to evaluate the roles of the hypothalamic-pituitary-thyroid (HPT) axis and hepatic transthyretin in the thyroid-disrupting effects of PM2.5. Sprague Dawley rats were treated with PM2.5 (0, 15 and 30 mg/kg) by passive pulmonary inhalation for 49 days; and recovery experimental group rats were dosed with PM2.5 (30 mg/kg) for 35 days, and no treatment was done during the subsequent 14 days. PM2.5 was handled twice a day by passive pulmonary inhalation throughout the study. After treatment, pathological changes were analyzed by performing haemotoxylin and eosin staining, measuring levels of THs and urine iodine (UI) in serum, plasma, and urine samples using enzyme-linked immunoabsorbent assay, and expression of proteins in the hypothalamus, pituitary, thyroid, and liver tissues of rats were analyzed by immunohistochemistry and Western blotting. The levels of oxidative stress factors, such as reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (Gpx), and nuclear factor-kappa B (NF-κB) in female rats’ plasma were also evaluated by ELISA. The results of these analyses revealed that PM2.5 treatment induced pathologic changes in rat thyroid and liver characterized by increased follicular cavity size and decreased amounts of follicular epithelial cells and fat vacuoles, respectively. Serum levels of triiodothyronine, thyroxine, and thyroid stimulating hormone were significantly decreased, plasma NF-κB level was increased and plasma redox state was unbalanced (enhanced ROS, MDA and Gpx levels; reduced SOD activities) in female rats treated with PM2.5 (P < 0.05). PM2.5 treatment suppressed the biosynthesis and biotransformation of THs by increasing sodium iodide symporter, thyroid transcription factor 1, thyroid transcription factor 2, and paired box 8 protein expression levels (P < 0.05). Additionally, thyroid stimulating hormone receptor and thyroid peroxidase levels were significantly decreased (P < 0.05). Both thyrotropin releasing hormone receptor and thyroid stimulating hormone beta levels were enhanced (P < 0.05). Moreover, transport of THs was inhibited due to reduced protein expression of hepatic transthyretin upon treatment with PM2.5. In summary, PM2.5 treatment could perturb TH homeostasis by affecting TH biosynthesis, biotransformation, and transport, affecting TH receptor levels, and inducing oxidative stress and inflammatory responses. Activation of the HPT axis and altered hepatic transthyretin levels therefore appear to play a crucial role in PM2.5-induced thyroid dysfunction.

Central hypothyroidism improves with age in very young children with Prader-Willi syndrome.

Abnormalities in the hypothalamic-pituitary-thyroid (HPT) axis have been implicated in Prader-Willi syndrome (PWS); however, limited information is currently available on age-dependent alterations in the HPT axis. We herein investigated age-dependent differences in thyroid hormone levels in PWS children. Free T4 (FT4), free T3 (FT3) and thyroid-stimulating hormone (TSH) concentrations were retrospectively compared between genetically confirmed PWS children (N=43, median age: 11.2months) and controls (N=85, median age: 14.5months) matched for age, sex, body weight-SD score (SDS), height-SDS, body mass index-SDS and serum albumin level, a marker of the nutritional status. Subjects were subdivided into two groups based on their age: an infant group aged between 1 and 11months (PWS: N=22, controls: N=30) and a toddler group aged between 12 and 47months (PWS: N=21, controls: N=55). None of the subjects had ever been treated with growth hormone or levothyroxine. After adjustments for confounding variables, in the infant group, FT4 levels (pmol/L) were significantly lower in PWS (11.24 in PWS vs 14.32 in controls, P=.0002), whereas no significant differences were observed in FT3 or TSH levels. In the toddler group, no significant differences were noted in FT4 (12.23 in PWS vs 15.31 in controls, P=.10), FT3 or TSH levels. The FT3/FT4 ratio was significantly increased in PWS in both groups. FT4 levels were positively correlated with age in PWS. Infants with PWS had lower FT4 levels, but FT3 levels were normal, indicating that the levothyroxine replacement therapy may not need to be routinely performed.

The joint effect of parental exposure to microcystin-LR and polystyrene nanoplastics on the growth of zebrafish offspring

The coexistence of nanoplastics (NPs) and various pollutants in the environment has become a problem that cannot be ignored. In order to identify the microcystin-LR (MCLR) bioaccumulation and the potential impacts on the early growth of F1 zebrafish (Danio rerio) offspring in the presence of polystyrene nanoplastics (PSNPs), PSNPs and MCLR were used to expose adult zebrafish for 21days. The exposure groups divided into MCLR (0, 0.9, 4.5 and 22.5μgL−1) alone groups and PSNP (100μgL−1) and MCLR co-exposure groups. F1 embryos were collected and developed to 120 h post-fertilization (hpf) in clear water. Compared with the exposure to MCLR only, the combined exposure increased the parental transfer of MCLR to the offspring and subsequently exacerbated the growth inhibition of F1 larvae. Further research clarified that combined exposure of PSNPs and MCLR could reduce the levels of thyroxine (T4) and 3, 5, 3′-triiodothyronine (T3) by altering the expression of hypothalamus–pituitary–thyroid (HPT) axis-related genes, eventually leading to growth inhibition of F1 larvae. Our results also exhibited combined exposure of PSNPs and MCLR could change the transcription of key genes of the GH/IGF axis compared with MCLR single exposure, suggesting the GH/IGF axis was a potential target for the growth inhibition of F1 larvae in PSNPs and MCLR co-exposure groups. The present study highlights the potential risks of coexistence of MCLR and PSNPs on development of fish offspring, and the environmental risks to aquatic ecosystems.

Waterborne uranium causes toxic effect and thyroid disruption in zebrafish larvae

Uranium is a radioactive element that is widely present in aquatic environment. However, limited knowledge is available about the effect of uranium on thyroid system, which plays a key role in the development of animals. In this study, zebrafish embryos were exposed to different environmentally relevant concentrations of uranium (2, 20 and 100 μg/L) for 120 h. The bioaccumulation, developmental toxicities, changes of thyroid hormones (THs) and key genes related to the hypothalamic–pituitary–thyroid (HPT) axis in larvae were analyzed after exposure. Results showed that uranium could bioaccumulate in zebrafish larvae, with the bioconcentration factors ranging from 49.6 to 523. Consequently, significant developmental toxicities and changes in locomotor activities were observed with a concentration-dependent manner. The levels of triiodothyronine (T3) levels in larvae were substantially decreased, whereas those of thyroxine (T4) were increased in fish bodies. The levels of THs were regulated by the negative feedback loops through HPT axis related genes, most of which (NIS, Deio1, Deio2, TRα, TSHβ and UGT1ab) were significantly depressed after exposure to uranium. Our results suggest the potential toxicities and thyroid disruption of uranium on zebrafish, which would provide baseline data set for better understanding the impact of waterborne uranium on aquatic organisms and the associated mechanisms. This study also highlights the key role of thyroid disruption in the ecological risk assessment of uranium pollution.

Melatonin alleviates the deterioration of oocytes and hormonal disorders from mice subjected to glyphosate

Glyphosate (Gly) is the herbicide widely used in agricultural fields and landscaping. Mammalian exposure to glyphosate could cause neurotoxicity, blood, liver, kidney, endocrine, reproductive, genetic and other toxic effects. Melatonin (MT) is a neuroendocrine hormone secreted mainly by the pineal gland. It is unknown whether MT can improve reproductive defects and hormonal disorders in mice exposed to Gly. In this study, mice were exposed to 250 and 500 mg/kg Gly by intragastric administered and 15 mg/kg MT was treated via intraperitoneal injection for 7 days. Our results shown that the weight gain of mice, the ovarian coefficient and the ATP content in the ovaries were decreased significantly. Gly-treated oocytes showed that the first polar body extrusion failed, the level of oxidative stress increased, and the mitochondrial membrane potential (MMP) decreased. Subsequently, our results showed that increased expression level of BAX protein, reduced expression of BCL-2 protein, ATG12 and LC3 protein expression increased in ovaries after Gly treatment. At the same time, Gly exposure led to abnormal expression of Hypothalamic-Pituitary-Thyroid (HPT) axis-related genes and disrupted hormone homeostasis. After the injection of 15 mg/kg MT, the oocytes showed decreased oxidative stress level, increased mitochondrial membrane potential, incremental ATP content in the ovaries and the hormone levels were approached to the control group. Thus, our results demonstrated that melatonin can improve oocyte quality and maintain hormone homeostasis in mice exposed to glyphosate.

Prevalence of Hypothyroidism in Patients With Erdheim-Chester Disease

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis affecting multiple organs and commonly caused by somatic pathogenic variants in BRAF V600E and mitogen-activated protein kinase genes. Clinical features of ECD result from histiocytic involvement of various tissues; while endocrine involvement in ECD occurs frequently, the prevalence of central or primary hypothyroidism has not been thoroughly investigated. To assess hypothalamus-pituitary-thyroid (HPT) dysfunction in patients with ECD. This cross-sectional study included 61 patients with ECD who were enrolled in a natural history study at a tertiary care center between January 2011 and December 2018. ECD was diagnosed on the basis of clinical, genetic, and histopathological features. Data were analyzed in March 2020. Diagnosis of ECD. Main outcome was the prevalence of thyroid dysfunction in adults with ECD compared with community estimates. Patients underwent baseline evaluation with a thyroid function test, including thyrotropin, free thyroxine (fT4), and total thyroxine (T4), and sellar imaging with magnetic resonance imaging or computed tomography scan. The association of HPT dysfunction was assessed for differences in age, sex, body mass index, BRAF V600E status, high sensitivity C-reactive protein level, sellar imaging, and pituitary hormonal dysfunction. A total of 61 patients with ECD (46 [75%] men; mean [SD] age, 54.3 [10.9] years) were evaluated. Seventeen patients (28%) had hypothyroidism requiring levothyroxine therapy. The prevalence of both central and primary hypothyroidism were higher than community estimates (central hypothyroidism: 9.8% vs 0.1%; odds ratio, 109.0; 95% CI, 37.4-260.6; P < .001; primary hypothyroidism: 18.0% vs 4.7%; OR, 4.4; 95% CI, 2.1-8.7; P < .001). Patients with hypothyroidism (both primary and central), compared with patients with euthyroidism, had higher body mass index (median [interquartile range] 31.4 [28.3-38.3] vs 26.7 [24.4-31.9]; P = .004) and a higher prevalence of panhypopituitarism (7 [47%] vs 3 [7%]; P < .001). Among patients with hypothyroidism, those with central hypothyroidism, compared with patients with primary hypothyroidism, had a lower mean (SD) body mass index (28.3 [2.6] vs 36.3 [5.9]; P = .007) and higher frequencies of abnormal sellar imaging (5 [83%] vs 3 [27%]; P = .050) and panhypopituitarism (5 [83%] vs 3 [27%]; P = .050). In this cohort study, a higher prevalence of central and primary hypothyroidism was identified in patients with ECD compared with the community. There should be a low threshold for testing for hypothyroidism in patients with ECD, and treatment should follow standard guidelines.