Protective Effects and Mechanisms of Huangqi Decoction Against Radiation-Induced Bystander Effects / Efectos Protectores y Mecanismos de la Decocción de Huangqi Contra los Efectos Secundarios Inducidos por la Radiación

SUMMARY: The 12C6+ heavy ion beam irradiation can cause bystander effects. The inflammatory cytokines, endocrine hormones and apoptotic proteins may be involved in 12C6+ irradiation-induced bystander effects. This study characterized the protective effects and mechanisms of Huangqi decoction (HQD) against 12C6+ radiation induced bystander effects. Wistar rats were randomly divided into control, 12C6+ heavy ion irradiation model, and high-dose/medium-dose/low-dose HQD groups. HE staining assessed the pathological changes of brain and kidney. Peripheral blood chemical indicators as well as inflammatory factors and endocrine hormones were detected. Apoptosis was measured with TUNEL. Proliferating cell nuclear antigen (PCNA) expression was determined with real-time PCR and Western blot.Irradiation induced pathological damage to the brain and kidney tissues. After irradiation, the numbers of white blood cells (WBC) and monocyte, and the expression of interleukin (IL)-2, corticotropin-releasing hormone (CRH) and PCNA decreased. The damage was accompanied by increased expression of IL-1β, IL-6, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) as well as increased neuronal apoptosis. These effects were indicative of radiation-induced bystander effects. Administration of HQD attenuated the pathological damage to brain and kidney tissues, and increased the numbers of WBC, neutrophils, lymphocyte and monocytes, as well as the expression of IL-2, CRH and PCNA. It also decreased the expression of IL-1β, IL-6, CORT and ACTH as well as neuronal apoptosis. HQD exhibits protective effects against 12C6+ radiation-induced bystander effects. The underlying mechanism may involve the promotion of the production of peripheral blood cells, inhibition of inflammatory factors and apoptosis, and regulation of endocrine hormones.

La irradiación con haz de iones pesados 12C6+ puede provocar efectos secundarios. Las citoquinas inflamatorias, las hormonas endocrinas y las proteínas apoptóticas pueden estar involucradas en los efectos secundarios inducidos por la irradiación 12C6+. Este estudio caracterizó los efectos y mecanismos protectores de la decocción de Huangqi (HQD) contra los efectos externos inducidos por la radiación 12C6+. Las ratas Wistar se dividieron aleatoriamente en grupos control, modelo de irradiación de iones pesados 12C6+ y grupos de dosis alta/media/baja de HQD. La tinción con HE evaluó los cambios patológicos del cerebro y el riñón. Se detectaron indicadores químicos de sangre periférica, así como factores inflamatorios y hormonas endocrinas. La apoptosis se midió con TUNEL. La expresión del antígeno nuclear de células en proliferación (PCNA) se determinó mediante PCR en tiempo real y transferencia Western blot. La irradiación indujo daños patológicos en los tejidos cerebrales y renales. Después de la irradiación, disminuyó el número de glóbulos blancos (WBC) y monocitos, y la expresión de interleucina (IL)-2, hormona liberadora de corticotropina (CRH) y PCNA. El daño estuvo acompañado por una mayor expresión de IL-1β, IL-6, corticosterona (CORT) y hormona adrenocorticotrópica (ACTH), así como un aumento de la apoptosis neuronal. Estas alteraciones fueron indicativas de efectos inducidos por la radiación. La administración de HQD atenuó el daño patológico a los tejidos cerebrales y renales, y aumentó el número de leucocitos y monocitos, así como la expresión de IL-2, CRH y PCNA. También disminuyó la expresión de IL-1β, IL-6, CORT y ACTH, así como la apoptosis neuronal. HQD exhibe mecanismos protectores contra los efectos externos inducidos por la radiación 12C6+. El mecanismo subyacente puede implicar la promoción de la producción de células sanguíneas periféricas, la inhibición de factores inflamatorios y la apoptosis y la regulación de hormonas endocrinas.

Effect of Nutritional Supplementation on Oxidative Stress and Hormonal and Lipid Profiles in PCOS-Affected Females.

Polycystic ovary syndrome (PCOS) affects several reproductive and endocrine features in females and has a poorly understood etiology. Treatment strategies for PCOS are limited and are based primarily on diet and nutrient supplementation. Recent studies have recommended some nutrients such as vitamins, minerals and vitamin-like nutrients for the therapy for PCOS. Therefore, it is claimed that the cause of PCOS could be vitamin or mineral deficiency. This review provides a narrative on the effect of nutritional supplementation on oxidative stress induced in PCOS. Oxidative stress plays a formative role in PCOS pathophysiology. This article reviews oxidative stress, its markers, nutritional supplementation and clinical studies. We also aim to show the effect of nutritional supplementation on genes affecting hormonal and glucose-mediated pathways.

Differentiation of Human-Induced Pluripotent Stem Cell-Derived Endocrine Progenitors to Islet-like Cells Using a Dialysis Suspension Culture System.

The production of functional islet-like cells from human-induced pluripotent stem cells (hiPSCs) is a promising strategy for the therapeutic use and disease modeling for type 1 diabetes. However, the production cost of islet-like cells is extremely high due to the use of expensive growth factors for differentiation. In a conventional culture method, growth factors and beneficial autocrine factors remaining in the culture medium are removed along with toxic metabolites during the medium change, and it limits the efficient utilization of those factors. In this study, we demonstrated that the dialysis suspension culture system is possible to reduce the usage of growth factors to one-third in the differentiation of hiPSC-derived endocrine progenitor cells to islet-like cells by reducing the medium change frequency with the refinement of the culture medium. Furthermore, the expression levels of hormone-secretion-related genes and the efficiency of differentiation were improved with the dialysis suspension culture system, possibly due to the retaining of autocrine factors. In addition, we confirmed several improvements required for the further study of the dialysis culture system. These findings showed the promising possibility of the dialysis suspension culture system for the low-cost production of islet-like cells.

Is the commonly used UV filter benzophenone-3 a risk factor for the nervous system?

Benzophenone-3 (2-hydroxy-4-methoxybenzophenone, oxybenzone, or BP-3) is one of the most frequently used UV radiation absorbents, which are commonly referred to as sunscreen filters. Its widespread use in industrial applications provides protection against the photodegradation of a wide range of products but at the same time creates the risk of human exposure to benzophenone-3 unbeknownst to the individuals exposed. Topically applied benzophenone-3 penetrates individual skin layers, enters the bloodstream, and is excreted in the urine. In addition, benzophenone-3 easily crosses the placental barrier, which creates the risk of exposure to this substance in the prenatal period. Despite the widespread use and occurrence of benzophenone-3 in the human environment, little knowledge of the mechanisms underlying the effect of benzophenone-3 on the nervous system was available until recently. Only the most recent research, including studies by our group, has enabled the identification of new molecular mechanisms through which benzophenone-3 affects embryonic neuronal cells and the developing mammalian brain. Benzophenone-3 has been shown to induce neurotoxicity and apoptotic processes and inhibit autophagy in embryonic neuronal cells. Benzophenone-3 also alters expression and impairs function of receptors necessary for the proper development and function of the nervous system. The most worrying finding seems to be that benzophenone-3 contributes to an increased risk of developmental abnormalities and/or epigenetically based degeneration of neuronal cells by changing the epigenetic status of neuronal cells.

Endocrine adverse effects of immune checkpoint inhibitors.

Immune checkpoint inhibitors are increasingly being utilised as an effective therapy for a variety of cancers. However, they have the potential to cause serious autoimmune toxicities in multiple organ systems termed 'immunotherapy-related adverse events'. Endocrine toxicities are common, can occur well after commencement of therapy and can result in significant morbidity and mortality if not recognised. This makes it important for all physicians, in addition to endocrinologists and oncologists, to understand the nature of these reactions and the general approach to their diagnosis and management. This review aims to provide an overview of the epidemiology, pathophysiology, clinical presentation and management of the endocrine adverse events.

Controversies on Endocrine and Reproductive Effects of Glyphosate and Glyphosate-Based Herbicides: A Mini-Review.

Glyphosate-based herbicides (GBHs) are among the most used pesticides worldwide, presenting high potential for human exposure. Recently, a debate was raised on glyphosate risks to human health due to conflicting views over its potential carcinogenic and endocrine disruptive properties. Results from regulatory guideline studies, reports from Regulatory Agencies, and some literature studies point to a lack of endocrine disrupting properties of the active ingredient glyphosate. On the other hand, many in vivo and in vitro studies, using different experimental model systems, have demonstrated that GBHs can disrupt certain hormonal signaling pathways with impacts on the hypothalamic-pituitary-gonadal axis and other organ systems. Importantly, several studies showed that technical-grade glyphosate is less toxic than formulated GBHs, indicating that the mixture of the active ingredient and formulants can have cumulative effects on endocrine and reproductive endpoints, which requires special attention from Regulatory Agencies. In this mini-review, we discuss the controversies related to endocrine-disrupting properties of technical-grade glyphosate and GBHs emphasizing the reproductive system and its implications for human health.

Characterization of Estrogenic Activity and Site-Specific Accumulation of Bisphenol-A in Epididymal Fat Pad: Interfering Effects on the Endocannabinoid System and Temporal Progression of Germ Cells.

The objective of this work has been to characterize the estrogenic activity of bisphenol-A (BPA) and the adverse effects on the endocannabinoid system (ECS) in modulating germ cell progression. Male offspring exposed to BPA during the foetal-perinatal period at doses below the no-observed-adverse-effect-level were used to investigate the exposure effects in adulthood. Results showed that BPA accumulates specifically in epididymal fat rather than in abdominal fat and targets testicular expression of 3ß-hydroxysteroid dehydrogenase and cytochrome P450 aromatase, thus promoting sustained increase of estrogens and a decrease of testosterone. The exposure to BPA affects the expression levels of some ECS components, namely type-1 (CB1) and type-2 cannabinoid (CB2) receptor and monoacylglycerol-lipase (MAGL). Furthermore, it affects the temporal progression of germ cells reported to be responsive to ECS and promotes epithelial germ cell exfoliation. In particular, it increases the germ cell content (i.e., spermatogonia while reducing spermatocytes and spermatids), accelerates progression of spermatocytes and spermatids, promotes epithelial detachment of round and condensed spermatids and interferes with expression of cell-cell junction genes (i.e., zonula occcludens protein-1, vimentin and ß-catenin). Altogether, our study provides evidence that early exposure to BPA produces in adulthood sustained and site-specific BPA accumulation in epididymal fat, becoming a risk factor for the reproductive endocrine pathways associated to ECS.

Endocrine Disruptor Impacts on Fish From Chile: The Influence of Wastewaters.

Industrial wastewaters and urban discharges contain complex mixtures of chemicals capable of impacting reproductive performance in freshwater fish, called endocrine-disrupting compounds (EDCs). In Chile, the issue was highlighted by our group beginning over 15 years ago, by analyzing the impacts of pulp and paper mill effluents (PPME) in the Biobio, Itata, and Cruces River basins. All of the rivers studied are important freshwater ecosystems located in the Mediterranean region of Central Chile, each with a unique fish biodiversity. Sequentially, we developed a strategy based on laboratory assays, semicontrolled-field experiments (e.g., caging) and wild fish population assessments to explore the issue of reproductive impacts on both introduced and native fish in Chile. The integration of watershed, field, and laboratory studies was effective at understanding the endocrine responses in Chilean freshwater systems. The studies demonstrated that regardless of the type of treatment, pulp mill effluents can contain compounds capable of impacting endocrine systems. Urban wastewater treatment plant effluents (WWTP) were also investigated using the same integrated strategy. Although not directly compared, PPME and WWTP effluent seem to cause similar estrogenic effects in fish after waterborne exposure, with differing intensities. This body of work underscores the urgent need for further studies on the basic biology of Chilean native fish species, and an improved understanding on reproductive development and variability across Chilean ecosystems. The lack of knowledge of the ontogeny of Chilean fish, especially maturation and sexual development, with an emphasis on associated habitats and landscapes, are impediment factors for their conservation and protection against the threat of EDCs. The assessment of effects on native species in the receiving environment is critical for supporting and designing protective regulations and remediation strategies, and for conserving the unique Chilean fish biodiversity.

A Crab Is Not a Fish: Unique Aspects of the Crustacean Endocrine System and Considerations for Endocrine Toxicology.

Crustaceans-and arthropods in general-exhibit many unique aspects to their physiology. These include the requirement to moult (ecdysis) in order to grow and reproduce, the ability to change color, and multiple strategies for sexual differentiation. Accordingly, the endocrine regulation of these processes involves hormones, receptors, and enzymes that differ from those utilized by vertebrates and other non-arthropod invertebrates. As a result, environmental chemicals known to disrupt endocrine processes in vertebrates are often not endocrine disruptors in crustaceans; while, chemicals that disrupt endocrine processes in crustaceans are often not endocrine disruptors in vertebrates. In this review, we present an overview of the evolution of the endocrine system of crustaceans, highlight endocrine endpoints known to be a target of disruption by chemicals, and identify other components of endocrine signaling that may prove to be targets of disruption. This review highlights that crustaceans need to be evaluated for endocrine disruption with consideration of their unique endocrine system and not with consideration of the endocrine system of vertebrates.

New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation.

Hormones are potent endo-, para-, and autocrine endogenous regulators of the function of multiple organs, including the heart. Endocrine dysfunction promotes a number of cardiovascular diseases, including atrial fibrillation (AF). While the heart is a target for endocrine regulation, it is also an active endocrine organ itself, secreting a number of important bioactive hormones that convey significant endocrine effects, but also through para-/autocrine actions, actively participate in cardiac self-regulation. The hormones regulating heart-function work in concert to support myocardial performance. AF is a serious clinical problem associated with increased morbidity and mortality, mainly due to stroke and heart failure. Current therapies for AF remain inadequate. AF is characterized by altered atrial function and structure, including electrical and profibrotic remodelling in the atria and ventricles, which facilitates AF progression and hampers its treatment. Although features of this remodelling are well-established and its mechanisms are partly understood, important pathways pertinent to AF arrhythmogenesis are still unidentified. The discovery of these missing pathways has the potential to lead to therapeutic breakthroughs. Endocrine dysfunction is well-recognized to lead to AF. In this review, we discuss endocrine and cardiocrine signalling systems that directly, or as a consequence of an underlying cardiac pathology, contribute to AF pathogenesis. More specifically, we consider the roles of products from the hypothalamic-pituitary axis, the adrenal glands, adipose tissue, the renin-angiotensin system, atrial cardiomyocytes, and the thyroid gland in controlling atrial electrical and structural properties. The influence of endocrine/paracrine dysfunction on AF risk and mechanisms is evaluated and discussed. We focus on the most recent findings and reflect on the potential of translating them into clinical application.

Consumption of bitter apricot seeds affects lipid and endocrine profile in women.

Natural products have been attracting increasing attention in human diet, both due to the possible negative effects of synthetic food additives on human health and the increased consumer perception. Apricot seeds contain a wide variety of bioactive components and their consumption is associated with a reduced risk of chronic diseases. The objective of the present study was to evaluate the effect of consumption of bitter apricot seeds on blood lipid and endocrine profile in Slovak women (n = 18, 41.60 ± 11.28 years) of reproductive age. Volunteers consumed 60 mg.kg-1 of body weight of bitter apricot seeds divided into 8-12 doses daily for 42 days. During the experiment, three blood collections were carried out (at the beginning of the experiment - day 0, and after 21 and 42 days of consumption apricot seeds). Lipid profile was measured in terms of - total cholesterol (T-C, enzymatic photometric method), low-density cholesterol (LDL-C, calculated using the Friedewald equation), high-density cholesterol (HDL-C, direct clearance method), triglycerides (TG, enzymatic colorimetric method) whereas endocrine profile - follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), 17ß-estradiol (E2), testosterone, and androstenedione was assessed by ELISA. The blood levels of T-C, HDL-C and T-C did not change significantly (P > 0.05), however, the level of LDL-C decreased significantly (P < 0.05) after 42 days. On the other hand, there was a significant (P < 0.05) increase of T-C and TG after 21 days. The blood level of FSH, testosterone and androstenedione increased significantly (P < 0.05) although the levels of LH, PRL, P4 and E2 did not change (P > 0.05) after 42 days. The level of PRL and testosterone significantly (P < 0.05) increased and E2 significantly decreased after 21 days of apricot seeds consumption. The study suggests that daily consumption of apricot seeds may affect plasma lipid and endocrine profile in women of reproductive age.

Bisphenol A and Bisphenol S Induce Endocrine and Chromosomal Alterations in Brown Trout.

Bisphenol A is a widely used compound found in large amount of consumer products. As concerns have been raised about its toxicological and public health effect, the use of alternatives to bisphenol A are now increasing. Bisphenol S is one of the analogues being used as a replacement for bisphenol A despite the fact that little is known about the effects of bisphenol S on living organisms. In this study, we investigated the potential endocrine and genotoxic effects of bisphenol A and bisphenol S in juvenile brown trout (Salmo trutta). The fish were exposed to the compounds for either 2 weeks or 8 weeks via sustained-release cholesterol implants containing doses of 2 mg/kg fish or 20 mg/kg fish of the substances. The effects on the thyroid hormone levels and the estrogenic disrupting marker vitellogenin were evaluated, along with the genotoxic markers micronucleated cells and erythrocyte nuclear abnormalities. An increase in plasma vitellogenin was observed in fish exposed to the high dose of bisphenol A for 2 weeks. At this experimental time the level of the thyroid hormone triiodothyronine (T3) in plasma was elevated after bisphenol S exposure at the high concentration, and paralleled by an increase of micronucleated cells. Moreover, bisphenol A induced an increase of micronuclei frequency in fish erythrocytes after the exposure at the lowest dose tested. Taken together the results indicate that both bisphenol A and its alternative bisphenol S cause endocrine disrupting and genotoxic effects in brown trout, although suggesting two different mechanisms of damage underlying bisphenol A and bisphenol S activity.

Endocrine Disrupting Chemicals: Current Understanding, New Testing Strategies and Future Research Needs.

Endocrine disrupting chemicals (EDCs) are exogenous chemicals which can disrupt any action of the endocrine system, and are an important class of substances which play a role in the Developmental Origins of Health and Disease (DOHaD) [...].

From Wingspread to CLARITY: a personal trajectory.

In the three decades since endocrine disruption was conceptualized at the Wingspread Conference, we have witnessed the growth of this multidisciplinary field and the accumulation of evidence showing the deleterious health effects of endocrine-disrupting chemicals. It is only within the past decade that, albeit slowly, some changes regarding regulatory measures have taken place. In this Perspective, we address some historical points regarding the advent of the endocrine disruption field and the conceptual changes that endocrine disruption brought about. We also provide our personal recollection of the events triggered by our serendipitous discovery of oestrogenic activity in plastic, a founder event in the field of endocrine disruption. This recollection ends with the CLARITY study as an example of a discordance between 'science for its own sake' and 'regulatory science' and leads us to offer a perspective that could be summarized by the motto attributed to Ludwig Boltzmann: "Nothing is more practical than a good theory".

The Role of the Unfolded Protein Response on Renal Lipogenesis in C57BL/6 Mice.

Renal injury observed in several pathologies has been associated with lipid accumulation in the kidney. While it has been suggested that the accumulation of renal lipids depends on free fatty acids released from adipose tissue, it is not known whether in situ renal lipogenesis due to endoplasmic reticulum (ER) stress contributes to kidney injury. The aim of the present study was to elucidate the role of pharmacological ER stress in renal structure and function and its effect on renal lipid metabolism of C57BL/6 mice. ER stress increased serum creatinine and induced kidney structural abnormalities. Tunicamycin-administered mice developed hyperinsulinemia, augmented lipolysis and increased circulating leptin and adiponectin. Renal unfolded protein response (UPR) gene expression markers, the lipogenic transcription factor SREBP1 and the phosphorylation of eIF2α increased 8 h after tunicamycin administration. At 24 h, an increase in BiP protein content was accompanied by a reduction in p-eIF2α and increased SREBP-1 and FASn protein content, in addition to a significant increase in triglyceride content and a reduction in AMPK. Thus, ER stress induces in situ lipid synthesis, leading to renal lipid accumulation and functional alterations. Future pharmacological and/or dietary strategies must target renal ER stress to prevent kidney damage and the progression of metabolic diseases.

Potential role of significant GATA3 mutation in male breast cancer responding to endocrine therapy: A case report.

A 60-year-old Chinese male with a hard mass, pressure pain, and ulcerous skin under his left axilla was first diagnosed with apocrine carcinoma, most likely metastasis from breast cancer. PET/CT scan detected multiple bone metastasis and enlarged lymph nodes at left axilla, mediastinal area 7, and left pulmonary hilus. Lumpectomy was performed to remove the mass followed by chemotherapy and radiotherapy against focal bone metastasis, left axillary lesion, and left subcutaneous chest wall. PET/CT examination showed progressive disease after the completion of the treatments. Two nontender hard nodules were noticed on the patient's left upper arm and multiple immobile nodules were palpated under his left axillary skin. Immunohistochemistry (HER2++, ER+, PR+, AR-) of the biopsy tissue combined with histopathology indicated invasive ductal carcinoma with neuroendocrine differentiation. Metastatic Luminal B subtype breast cancer was preferred. Anti-estrogen endocrine therapy was then performed and PET/CT scan showed partial remission after one month's fulvestrant administration. Two significant somatic mutations, AR R616H and GATA3 S408Afs*99, were detected in the biopsy tissue by next-generation sequencing. GATA3 is associated with estrogen receptor signaling and was identified as a driver gene of female breast cancer. However, the function of GATA3 in male breast cancer remains controversial. Report of this case hopefully will contribute to exploring the role of GATA3 mutation in molecular mechanisms and endocrine therapy of male breast cancer.

[Endocrine care of gender-incongruent persons]. / Prise en charge des personnes avec incongruence de genre : le point de vue de l'endocrinologue.

Health care of gender-incongruent persons deserves optimization. The new World Health Organization ICD-11, introduced this year, classifies gender-incongruence to « conditions related to sexual health ¼, and not anymore to « mental and behavioral disorders ¼. From an endocrine perspective, gender-affirming hormonal treatment induces physical changes consistent with gender identity, but good-quality, long follow-up studies concerning efficacy and safety are needed. Improvements in training of medical professionals as well as a specialized multidisciplinary approach are important measures to be taken.

Les soins médicaux offerts aux personnes avec incongruence de genre méritent d'être optimisés. La nouvelle Classification internationale des maladies, 11e version, de l'OMS, présentée cette année, classe l'incongruence de genre parmi les « conditions liées à la santé sexuelle ¼, et non plus dans les « troubles mentaux et du comportement ¼. Sur le plan endocrinien, les traitements hormonaux d'affirmation de genre permettent d'induire des changements physiques correspondant à l'identité du genre, mais des études d'efficacité et sécurité de meilleure qualité et au long cours sont nécessaires. La prise en charge de cette population par une équipe spécialisée et multidisciplinaire et l'amélioration de la formation du corps médical sont des mesures indispensables pour le futur.

New understanding of novel brominated flame retardants (NBFRs): Neuro(endocrine) toxicity.

Traditional brominated flame retardants (BFRs) negatively affect the environment and human health, especially in the sensitive (developing) nervous system. Considering the physicochemical similarities between novel brominated flame retardants (NBFRs) and BFRs, more and more evidence reveals the neurotoxic effects of NBFRs. We reviewed the neuro(endocrine) toxic effects of NBFRs in vivo and in vitro and discussed their action mechanisms based on the available information. The neurotoxic potential of NBFRs has been demonstrated through direct neurotoxicity and disruption of the neuroendocrine system, with adverse effects on neurobehavioral and reproductive development. Mechanistic studies have shown that the impact of NBFRs is related to the complex interaction of neural and endocrine signals. From disrupting the gender differentiation of the brain, altering serum thyroid/sex hormone levels, gene/protein expression, and so on, to interfere with the feedback effect between different levels of the HPG/HPT axis. In this paper, the mechanism of neurotoxic effects of NBFRs is explored from a new perspective-neuro and endocrine interactions. Gaps in the toxicity data of NBFRs in the neuroendocrine system are supplemented and provide a broader dataset for a complete risk assessment.

Investigating the effect of nitrate on juvenile turbot (Scophthalmus maximus) growth performance, health status, and endocrine function in marine recirculation aquaculture systems.

Nitrate (NO3-), a potential toxic nitrogenous compound to aquatic animals, is distributed in aquatic ecosystems worldwide. The aim of this study was to investigate the effects of different NO3- levels on growth performance, health status, and endocrine function of juvenile turbot (Scophthalmus maximus) in recirculating aquaculture systems (RAS). Fish were exposed to 0 mg/L (control, CK), 50 mg/L (low nitrate, LN), 200 mg/L (medium nitrate, MN), and 400 mg/L (high nitrate, HN) NO3-N for 60 d in experimental RAS. Cumulative survival (CS) was significantly decreased with increasing NO3- levels in LN, MN, and HN. The lowest CS was 35% in the HN group. Growth parameters, including absolute growth rate, specific growth rate, and feed conversion rate, were significantly different in HN compared with that in the CK. Histological survey of gills and liver revealed dose-dependent histopathological damage induced by NO3- exposure and significant differences in glutamate pyruvate transaminase and glutamate oxalate transaminase in MN and HN compared with that in the CK. The hepatosomatic index in HN was significantly higher than that in the CK. Additionally, NO3- significantly increased bioaccumulation in plasma in LN, MN, and HN compared to that in the CK. Significant decreases in hemoglobin and increases in methemoglobin levels indicated reduced oxygen-carrying capacity in HN. Additionally, qRT-PCR and enzyme-linked immunosorbent assay (ELISA) were developed to investigate key biomarkers involved in the GH/IGF-1, HPT, and HPI axes. Compared with that in the CK, the abundance of GH, GHRb, and IGF-1 was significantly lower in HN, whereas GHRa did not differ between treatments. The plasma T3 level significantly decreased in LN, MN, and HN and T4 significantly decreased in HN. The CRH, ACTH, and plasma cortisol levels were significantly upregulated in HN compared with that in the CK. We conclude that elevated NO3- exposure leads to growth retardation, impaired health status, and endocrine disorders in turbot and the NO3- level for juvenile turbot culture should not exceed 50 mg/L NO3-N in RAS. Our findings indicate that endocrine dysfunction of the GH/IGF-1, HPT, and HPI axes might be responsible for growth inhibition induced by NO3- exposure.