Journal of Endocrinology最新文献

Over the years, environmental exposure to pesticides has significantly increased. Several new pesticides are being developed and approved for use, although their full impact on health and the environment remains unclear. Pesticides interfere with the endocrine system by acting on hormonal pathways, including hormone-receptor interactions and hormonal metabolism. Concomitant with the increasing use of endocrine-disrupting chemical molecules, reduced fertility and reproductive alterations in men and women have attracted increasing attention in recent years. Given the potential of pesticides to impact the reproductive system significantly, we conducted a narrative review of relevant animal studies, including those conducted on humans, and in vitro models exploring changes in the male and female reproductive systems associated with exposure to various pesticide classes, such as organochlorines, organophosphates, pyrethroids, carbamates, and neonicotinoids. Key dysfunctions reported primarily in different experimental models include alterations in the hypothalamic-pituitary-gonadal axis, morphological changes in the ovaries and testes, increased numbers of atretic follicles, and reduced sperm motility. Although research in this area has increased, important gaps remain, including inconsistencies in findings, lack of long-term human exposure studies, and limited understanding of the synergistic effects of pesticide formulations. It is crucial to emphasize the impact of pesticide exposure on fertility and encourage further research to elucidate the pathophysiological, morphological, and molecular mechanisms involved, as well as the effects of exposure to mixtures of these pesticides, mimicking the human exposome.

Endocrine disruptors (EDs) are exogenous substances that interfere with the endocrine system, leading to adverse health outcomes. These substances, prevalent in industrial pollutants, pesticides, plastics, and personal care products, significantly impact hormonal regulation and disrupt various physiological processes. This review explores the sources and health impacts of EDs, focusing on their interference with hormonal axes, fetal development, and adipose tissue function. It highlights underlying mechanisms such as epigenetic modifications and discusses strategies to reduce ED exposure. Recent research reveals that EDs affect estrogen, androgen, and thyroid hormone signaling, contributing to developmental, reproductive, and metabolic disorders. Their interference with hormonal regulation is linked to abnormalities during fetal development and obesity through altered adipogenesis-related gene expression. Mechanisms such as DNA methylation, hypoxia-inducible factor signaling, and histone modifications play pivotal roles in ED-induced disruptions. Addressing ED exposure requires a multifaceted approach, incorporating lifestyle changes and public health initiatives to mitigate risks. Continued research is essential to better understand their effects and develop effective strategies for reducing their impact.

Hyperglycemia is the predominant endocrine and metabolic disorder, resulting in infertility in males. Adropin, a hepatokine, is a well-known insulin sensitizer that regulates glucose and lipid homeostasis. Our recent reports demonstrated the vital role of adropin in the regulation of testicular activity, but its role in testicular function during pathological conditions such as hyperglycemia has not yet been studied. Therefore, this study aimed to explore the effect of adropin treatment on reproductive and metabolic dysfunctions in hyperglycemic mice. Hyperglycemia was induced by streptozotocin (55 mg/kg body weight; i.p.) treatment followed by treatment with either adropin (450 nmol/kg body weight; i.p.) or metformin (500 mg/kg body weight; orally) for a period of 15 days. Treatment of hyperglycemic mice enhanced insulin sensitivity by increasing insulin receptor expression in the testis and decreasing HOMA-IR and circulating glucose level. Adropin treatment of hyperglycemic mice increased the production of testicular testosterone by promoting the expression of steroidogenic proteins. Moreover, adropin treatment also enhanced the proliferation and survival of testicular germ cells by increasing PCNA expression and decreasing BAX/Bcl2 ratio and TUNEL-positive cells in the testis of hyperglycemic mice. Flow cytometric analysis revealed an increased number of advanced germ cells in adropin-treated hyperglycemic mice. Notably, adropin treatment was more effective than metformin in restoring reproductive functions in hyperglycemic mice, as evidenced by the reestablishment of the testicular histoarchitecture and increased synthesis of testosterone in the testes. These findings suggest that adropin may serve as a viable therapeutic alternative to mitigate hyperglycemia-associated testicular dysfunction.

Statins are the most commonly used cholesterol-lowering medications, with proven efficacy in reducing cardiovascular disease in humans; however, statins are associated with a higher risk of new-onset type 2 diabetes (T2D). Mechanisms contributing to statin-induced diabetes are not well understood and may include effects on body composition, tissue insulin sensitivity, and/or pancreatic β-cell function. Given the essential role of the β-cell in maintaining normoglycemia, this review focuses on how statins may lead to the demise of the β-cell. We revisit what is known about the impact of statins on inhibition of the mevalonate pathway, including blockade of the synthesis of cholesterol and non-cholesterol products. We discuss aberrant expression of key β-cell genes and proteins, as well as dysregulation of β-cell components that facilitate normal insulin secretion, e.g., mitochondria and calcium channels. Importantly, we highlight areas that are understudied, including how statins alter cholesterol transport and metabolism in the β-cell, and the role of sex/gender in statin-induced β-cell dysfunction. As the number of statin users increases, there is an urgent need to address these gaps in our knowledge in order to shed light on strategies that limit statin-induced T2D.

The glucocorticoid receptor (GR) mediates many activating and repressive effects of glucocorticoids in multiple contexts. Glucocorticoids can robustly induce the transcriptionally active protein Zinc finger and BTB domain containing 16 (ZBTB16). We evaluated how cortisol-induced ZBTB16, in turn, affects various GR-mediated actions in human cells and in zebrafish. We found that prevention of ZBTB16 induction led to potentiated GR-dependent effects on the human endothelial cell barrier and blood glucose levels in zebrafish larvae. In contrast, zbtb16 functional knockout abolished the GR-dependent effects on the inflammatory response in zebrafish larvae. At the mRNA level, zbtb16 knockdown potentiated transactivation and attenuated transrepression in a subset of GR target genes. Finally, ZBTB16 protein was strongly induced by dexamethasone in fibroblast-like synoviocytes derived from osteoarthritis patients. The data suggest that cortisol-induced ZBTB16 acts as an intracellular modulator of glucocorticoid action by limiting GR-mediated activating effects and enhancing repressive effects. This mechanism may facilitate a return to the initial cellular state after (proinflammatory) stimulation and enhance GR's anti-inflammatory effects. This mechanism is similar to that of 'dissociated' GR ligands and may guide drug development that aims to reduce side effects while retaining the clinical benefits of glucocorticoid treatment.

Bariatric surgery (BS) is the most effective long-term approach for weight loss and improvement of obesity-related comorbidities. Growth differentiation factor 15 (GDF15), a cytokine that enhances insulin sensitivity and reduces food intake, is a promising therapeutic target for obesity. This study assessed changes in circulating GDF15 levels in obesity and following BS, examining their associations with anthropometric, clinical, and biochemical parameters. Circulating GDF15 levels were measured in normal-weight individuals and patients with obesity before BS and at 3, 6 and 12 months post-surgery. Correlation analyses and linear mixed models were used to investigate variations in circulating GDF15 levels and to identify variables associated with GDF15 concentration. Circulating GDF15 levels were elevated in patients with obesity compared to normal-weight individuals and were higher in men than in women. In the combined cohort of obese and normal-weight individuals, circulating GDF15 levels positively correlated with weight, BMI, fat mass, glucose markers, C-reactive protein, transaminases, triglycerides, urea, creatinine and uric acid, and negatively correlated with apolipoprotein A and total, HDL and LDL cholesterol. In the obese cohort, however, circulating GDF15 levels showed a negative correlation with fat mass, while other associations persisted. After BS, circulating GDF15 levels significantly decreased, particularly in patients with hypertension or type 2 diabetes (T2D). One year post-surgery, ΔGDF15 was negatively associated with BMI and positively with excess weight loss and excess BMI loss. In conclusion, BS significantly reduces circulating GDF15 levels, particularly in patients with hypertension or T2D, indicating an association with clinical improvement after BS.

Androgen excess is thought to play a crucial role in the onset and progression of polycystic ovary syndrome (PCOS), although the underlying mechanism remains unclear. Using our mild dihydrotestosterone (DHT)-exposed rat model, which more closely reproduces human PCOS phenotypes than conventional models, we examined whether the presence of ovaries is essential in the pathophysiology of PCOS induced by androgen excess. At 26 days of age, female rats were divided into two primary groups: bilaterally ovariectomized (OVX) and sham-operated (intact). Each group was further divided into PCOS (implanted with a tube filled with diluted DHT) and control (implanted with an empty tube) groups. Body weight and food intake were measured weekly. At 58 and 59 days of age, locomotor activity and body temperature were measured. At 87 days of age, brain, blood, and fat tissues were collected and analyzed. Body weight, food intake, adipocyte size, weight of visceral and subcutaneous fat, and serum leptin levels were higher in the intact-PCOS group than the intact-control group, but there were no significant differences between the OVX-PCOS and OVX-control groups. In the intact-PCOS group, compared with the intact-control group, locomotor activity was significantly lower, particularly in the light phase, and body temperature was significantly higher in the darkness phase, whereas there were no significant differences between the OVX-PCOS and OVX-control groups. The effects of androgen might depend on the estrogen milieu, suggesting that the presence of ovaries is essential in the pathophysiologic development and progression of androgen-induced PCOS.

Previous research showed that a maternal high-fat (HF) diet during the perinatal period impairs skeletal muscle metabolism in offspring. Supplementing the HF diet with fish oil (FO), a source of n-3 polyunsaturated fatty acids, during gestation partially mitigates these adverse effects at weaning. This study investigated whether maternal HF diet, with or without FO supplementation during gestation, alters the expression of muscle-secreted molecules (myokines) in female and male offspring at weaning. Female Wistar rats were fed a control (9% lipids) or HF diet (29% lipids) for 8 weeks before mating and throughout gestation and lactation. A subset of HF-fed dams received a 3% FO-supplemented HF diet (HFFO) during gestation. In glycolytic extensor digitorum longus (EDL) muscle, FO tended to decrease Nmb (neuromedin B) mRNA in females and increased Erfe (myonectin) mRNA in males, compared to sex-matched HF groups. HFFO males also exhibited elevated expression of genes involved in fatty acid uptake and oxidation, suggesting enhanced lipid metabolism. However, FO did not reverse the HF-induced downregulation of Igf1r in EDL or Igf1 in the oxidative soleus muscle of male offspring, and muscle fiber size remained unchanged across groups. In the soleus muscle, FO increased Il6 mRNA in females, while in males, FO induced FNDC5 (the irisin precursor), accompanied by increased uncoupling protein-1 in subcutaneous white adipose tissue, suggesting increased thermogenic activity. Gestational FO supplementation induces sex- and muscle-specific alterations in myokine expression in weanling offspring exposed to a maternal HF diet, potentially shaping early muscle metabolism and contributing to sex-dependent metabolic programming.

Graves' disease (GD) is an important risk factor for secondary osteoporosis (OP). Thyrotropin-receptor stimulating antibody (TSAb) is a pathogenic antibody detected in patients with GD. However, few studies have examined the effects of TSAb on bone. Consequently, this study aimed to explore the effect of TSAb on osteoblast differentiation and its possible mechanisms. MC3T3-E1 cells were treated with different concentrations of TSAb. The relative survival rate of cells was assessed using the cell counting kit-8 (CCK-8) assay. Osteoblast differentiation markers were determined using western blotting and immunofluorescence assays. To further evaluate the roles of TSAb in osteogenesis in vivo, a GD-induced OP mouse model was generated by Ad-TSHR289 immunization followed by intragastric administration of methimazole (MMI). Femurs were collected for micro-CT scanning and histomorphometry analysis. The viability of MC3T3-E1 cells did not significantly change with increasing TSAb concentrations. The protein levels of osteoblast differentiation markers (OCN, Col1a1, Runx2, and OPN) in MC3T3-E1 cells treated with 1 and 10 ng/mL TSAb were significantly reduced. Furthermore, TSAb significantly promoted the AKT/mTOR pathway. Moreover, inhibition of this signaling pathway attenuated the phosphorylation of AKT and mTOR enhanced by TSAb and reversed osteoblast differentiation. GD mice treated with MMI exhibited reduced bone mass and degraded bone formation. TSAb exacerbates bone loss in GD mice. These findings demonstrated that TSAb inhibits osteoblast differentiation by activating the AKT/mTOR pathway. This study revealed a novel function of TSAb in regulating osteoblast activity.

Disturbances in calciotropic hormones: parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23)/Klotho, and mineral homeostasis are often seen in chronic kidney disease (CKD) and are key factors driving vascular calcification (VC). Importantly, the role of these hormones in VC is poorly understood. Therefore, we investigated how the dysregulation of calciotropic hormones and mineral metabolism determines the dynamics of the VC process in adenine-induced CKD in rats. Male rats were fed a diet containing 0.3% adenine for 4, 6, and 8 weeks to establish CKD. Classical markers of renal function, mineral homeostasis, and progression of VC were determined. In the earlier stages of CKD, in conditions of low 1,25-dihydroxyvitamin-D3 (1,25(OH)2D3) and Klotho deficiency, PTH exhibited an effective phosphaturic effect, and the PTH/FGF-23/Klotho axis seems to have a protective function against VC. In the later stage of the disease, the predominance of PTH led to the activation of 1,25(OH)2D3 synthesis, which resulted in the rebuilding of Klotho resources and allowed FGF-23 to take over a phosphaturic role. As a result, PTH/1,25(OH)2D3/Klotho signaling seems to exert a procalcifying effect. Moreover, VC was directly and inversely associated with the minerals excreted in the urine, and receiver operating characteristic analysis revealed a high diagnostic potential of calcium excretion in VC prediction. The present study shows that measuring serum panel of calciotropic hormones and urine tests assessing the excretion of minerals performed in a laboratory routine may be helpful tools for predicting VC progression at different CKD stages.