Cadmium (Cd) is a widespread environmental contaminant that impairs male reproductive function; however, the metabolic mechanisms underlying Cd-induced testicular toxicity remain incompletely understood. This study investigated whether serine supplementation could alleviate Cd-induced testicular injury and explored its association with phosphoglycerate mutase 1 (PGAM1)- and phosphoglycerate dehydrogenase (PHGDH)-related serine metabolism. Forty male C57BL/6 mice were randomly assigned to four groups and received ultrapure water, serine (50 g/L), Cd (50 mg/L), or Cd plus serine in drinking water for 18 weeks. Testicular morphology, hormone levels, ion homeostasis, oxidative stress, inflammation, glycolytic metabolism, fibrosis, apoptosis, and the expression of PGAM1/PHGDH-related proteins were evaluated. Cd exposure induced marked testicular injury, characterized by reduced testicular weight and index, disrupted reproductive hormone levels, histopathological damage, ion imbalance, oxidative stress, inflammatory responses, and decreased expression of blood-testis barrier-associated proteins. Cd also suppressed glycolysis and serine biosynthesis, as evidenced by reduced activities of glycolytic enzymes, decreased lactate and pyruvate production, lower serine levels, inhibited PHGDH, PSAT1, and PSPH expression, and altered PGAM1 expression. These changes were accompanied by increased fibrosis and germ cell apoptosis. Serine supplementation substantially ameliorated these abnormalities, restoring metabolic homeostasis, improving antioxidant capacity, reducing inflammation, and attenuating fibrosis and apoptosis. In conclusion, serine exerts a strong protective effect against Cd-induced male reproductive toxicity by counteracting metabolic dyshomeostasis, highlighting its potential therapeutic value as a beneficial additive against heavy metal-associated reproductive damage.

Cadmium (Cd), an environmental toxicant, is known to cause significant damage to reproductive systems in human and animals. However, the detrimental effects of maternal Cd exposure during gestation on male offspring and the underlying mechanisms remain unknown. In this study, pregnant mice were exposed to Cd (32 mg/l) in drinking water throughout gestation to investigate the mechanisms underlying testicular and sperm injury and repair in male offspring. Results showed that maternal Cd exposure caused growth inhibition in male offspring at birth, accompanied by testicular DNA damage and upregulation of Rad51, a key protein involved in homologous recombination repair. After delivery, when Cd was removed, the male offspring exhibited compensatory growth and development. At 7 weeks of age, despite abnormally enlarged seminiferous tubules, spermatogonial stem cell meiosis arrest, and reduced total sperm motility, DNA damage levels, DNA repair capacity, and the motility function of surviving sperm were all at normal levels. Compared with controls, the offspring at 7 weeks of age showed no alterations in global 5-methylcytosine (5-mC) of sperm, whereas DNA methylation of Line1 were decreased. Meanwhile, DNA methylation of imprinted genes H19 and Peg3, which regulate sperm quality and post-fertilization embryonic development, remained normal. Cd exposure during gestation led to transcriptomic abnormalities in the testes of newborn male offspring, but these abnormalities were gradually repaired during postnatal growth and development. These findings indicate that although gestational Cd exposure impairs reproductive function of male offspring, postnatal growth and development, coupled with DNA repair mechanisms, can partially restore their reproductive potential.

Cadmium is a common heavy metal pollutant in the environment. Kidney is the main target organ of cadmium toxicity, which can cause acute kidney injury. Fatty acid oxidation is the main source of energy produced by proximal renal tubular epithelial cells, and FXR is a bile acid receptor involved in lipogenesis. However, the regulatory mechanisms by which FXR on FAO remain unclear. In this study, both in vivo (SD rats) and in vitro (rPT cells) cadmium poisoning models were established to determine whether fatty acid oxidation is involved in cadmium-induced acute kidney injury. The results of in vivo experiments indicated that administration of 2.5 mg/kg Cd in rats induced acute kidney injury, characterized by a significant elevation in TG content and KIM-1 protein expression, as well as a marked reduction in the expression levels of fatty acid oxidation-related proteins, including CPT1A, PPAR γ, ATGL, SDHB, and FXR. Activation of FXR through its specific agonist significantly attenuated cadmium-induced renal damage. The in vitro results further revealed the effect of FXR on the abnormal FAO and lipid accumulation induced by cadmium. After FXR activation, the morphological damage of cells was significantly improved, the number of lipid droplets was significantly decreased, the expression of fatty acid oxidation related proteins was significantly increased, and the expression of Plin2 and KIM-1 proteins was significantly decreased. Next, to further explore the role of FXR/PPAR γ signaling in cadmium-induced lipid accumulation and FAO damage, we found that inhibited PPAR γ can significantly relieve cadmium induced rPT cells damage and lipid accumulation. In conclusion, regulation of fatty acid oxidation by FXR/PPAR γ pathway can effectively protect rats against acute kidney injury induced by cadmium.

It has been reported that hyperlipidemia can induce meibomian gland dysfunction (MGD). Lycium barbarum polysaccharides (LBP) has been proven to improve abnormal blood lipids. However, it is still unclear whether LBP exerts a protective effect on MGD caused by hyperlipidemia. This study aims to explore the effect and specific mechanism by which LBP on MGD induced by a high-fat diet (HFD). In present study, we clarified that HFD induced lipid accumulation, inhibited autophagy, and promoted aging by suppressing the AMPK pathway in mice meibomian glands (MG). Not only that, similar results were also obtained in the oleic acid (OA) induced in vitro model (human meibomian gland epithelial cells (HMGECs)). Subsequently, we discovered that LBP administration ameliorated OA-induced autophagy and aging by modulating p-AMPK/AMPK ratio, while also mitigated the lipid deposition in HMGECs. Importantly, using the autophagy inhibitor chloroquine (CQ) largely diminished the protective effects of LBP on OA caused lipid deposition and weakened the autophagy phenomenon, delayed the occurrence of aging and activated the AMPK pathway, which suggested that LBP plays protective effect through enhancing autophagy flux. In summary, these findings demonstrated that LBP alleviated OA-caused lipid accumulation via triggering lipophagy via the AMPK pathway. LBP is expected to be further developed as a new type of functional food additive for treating diet-caused obesity.

Cadmium, a global environmental pollutant, can accumulate in the bone tissue, representing a major risk factor for osteoporosis. However, the specific mechanisms remain unclear. First, a 4 month cadmium exposure study via drinking water was used to investigate its bone toxicity effects. Cadmium exposure significantly reduced bone density. Subsequently, we established osteoblast model cadmium exposure concentration points. Cadmium exposure induced osteoblast pyroptosis from the perspectives of morphology and the molecular level. The underlying mechanisms involve a P2X7R-medicated pyroptosis pathway. Finally, a p2x7r-/- mouse fed cadmium-exposed water for 4 months and p2x7r-/-osteoblasts exposed to cadmium, were used to validate the effect of core target P2X7R. The results demonstrated that p2x7r gene deletion obviously reduced pyroptosis-like osteoblasts, and p2x7r knockout mice did not develop osteoporosis; the expression of pyroptosis proteins was not significantly increased. Our study provides new insights into the damage caused by environmental pollutants to the body.

Ketosis in dairy cows is linked to endometritis, but the molecular mechanisms are unclear. We investigated whether P2X7R is crucial in ketosis-induced endometritis. Ketotic cows had higher levels of NLRP3, caspase-1, GSDMD, GSDME, and P2X7R in the uterine tissue. β-Hydroxybutyric acid (BHBA) exposure in bovine endometrial epithelial cells induced pyroptosis, increased pyroptosis protein and gene expression, and raised pyroptosis rates. P2X7R levels rose with BHBA, and BHBA also increased the level of extracellular ATP. Inhibitors of NLRP3, caspase-1, caspase-3, and P2X7R reduced BHBA-induced pyroptosis. P2X7R inhibition suppressed NLRP3, caspase-1, and caspase-3 activation, preventing pyroptosis. In P2rx7-/- mice with a ketosis model, blood BHBA was lower, and uterine tissue showed less pyroptosis-related protein expression compared to ketotic mice. P2X7R appears to regulate BHBA-induced pyroptosis through NLRP3 and caspase-3 signaling, suggesting it is a potential therapeutic target.

Microplastics (MPs) have emerged as hazardous substances, eliciting widespread concern regarding their potential toxicity. Although our previous research has indicated that polystyrene MPs (PS-MPs) might cause male reproductive toxicity in mammals, their precise effects on sperm motility parameters and acrosomal development remain uncertain. Herein, the effects on sperm motility of PS-MPs at varied particle sizes (0.5 mu m, 4 mu m and 10 mu m) and the underlying mechanisms were examined. The results revealed that PS-MPs caused a decrease in sperm motility, accompanied by abnormalities in the structure and function of the sperm acrosome. Meanwhile, PS-MPs triggered the elevation of intracellular reactive oxygen species levels and the abnormal expression of antioxidant enzymes (gamma H2AX, GPX4, Peroxiredoxin 5 and SDHB), indicating disruption of the sperm antioxidant system. Furthermore, we observed aberrant expression of key factors involved in mitochondrial fission/fusion (Drp1, Fis1, Mfn1, Mfn2) and biogenesis (Tfam, Nrf1, Pgc1 alpha), potentially resulting in disrupted mitochondrial dynamics and biogenesis in mice testis and Sertoli cells exposed to PS-MPs. Additionally, PS-MPs induced mitochondrial dysfunction by regulating the Sirt1-Pgc1 alpha signaling pathway. Our data provided novel insights into potential mechanisms underlying the spermatogenesis disorders triggered by PS-MPs.

Obesity, a globally prevalent chronic disease, disrupts systemic homeostasis and impairs female fertility, yet the mechanisms linking adipose dysfunction to ovarian reserve remain unclear. Using high-fat diet-induced obese C57BL/6 mouse models (HFD) and exercise-diet intervention models (SE group), we systematically evaluated obesity-associated reproductive deficits. Histomorphological analysis revealed that HFD mice exhibited ovarian atrophy, increased atretic follicles, and reduced primordial/antral follicle counts, which were partially restored by SE intervention. TEM demonstrated lipid droplet accumulation and mitochondrial heterogeneity in HFD ovaries, with residual vacuolization persisting despite SE-mediated improvement. Superovulation assays demonstrated reduced oocyte production in HFD mice, accompanied by impaired in vivo maturation and blastocyst formation. Immunofluorescence revealed abnormal spindle assembly and heterogeneous mitochondrial distribution in HFD oocytes, potentially associated with elevated ROS. Mechanistically, HFD downregulated folliculogenesis regulators (BMP-15, HIF-1α, PTEN/AKT/FoxO3) while upregulating metabolic stress markers (Chemerin, CMKLR1). Western blot confirmed reduced ovarian protein acetylation and BMP-15/HIF-1α expression in HFD mice, with partial recovery following exercise-diet intervention. These findings demonstrate obesity-induced dual impairments: mitochondrial-ROS dysfunction compromising oocyte competence and BMP-15/HIF-1α suppression disrupting follicular survival through PTEN-AKT-FoxO3 signaling. Although exercise-diet intervention improved metabolic parameters and oocyte quality, residual abnormalities highlighted irreversible impairments. Our study identifies obesity as a driver of ovarian aging and emphasizes the fertility-enhancing potential of combined exercise-diet intervention in obese female mice.

Cadmium (Cd) exposure is strongly linked to various diseases and dysregulation of autophagy is a pivotal mechanism in Cd toxicity. Targeted autophagy strategies are promising for the treatment of autophagy dysregulation-related diseases, including Cd poisoning. However, the current understanding of autophagy mechanisms remains limited, hindering the development of effective strategies. Herein, a novel autophagy pathway, transcellular autophagy. Cd triggers this process in hepatocytes, facilitating the transfer of autophagosomes from damaged to healthy cells for degradation. Mechanistically, reactive oxygen species accumulation is a key driver of transcellular autophagy activation, while the disruption of autophagy fusion mechanisms triggers its activation. Notably, Cd-induced transcellular autophagy relies on the tumor necrosis factor, alpha-induced protein 2 (TNFAIP2)-tunneling nanotube (TNT) system. Blocking this system prevents autophagosome transfer and exacerbates Cd-induced autophagosome overload and apoptosis. The findings offer a novel perspective on autophagy, and provide new insights for targeted autophagy strategies to treat Cd poisoning and autophagy dysregulation-related diseases.

Off-season breeding is a method of encouraging animals through manual intervention to reproduce during the non-breeding season. The egg-laying period of the Zhedong white goose usually starts from September and ends in April of the following year. During the summer months from May to August, with long daylight hours and high temperatures, the white geese rest and do not lay eggs. This study explored the effects of off-season breeding on egg production performance, serum biochemical indicators, and hormone secretion in Zhedong white goose. The experiment was divided into normal breeding and off-seasonal breeding. The results suggested that the peak laying period lasted 3 months, and egg production was 15.62% higher than that in the control group in the off-season breeding group. The off-season breeding group had a 4.13% higher egg fertilization rate in November (laying period) than the control group, and the hatching rate of hatched eggs and fertilized eggs in the peak laying period was 2.77% and 2.3% higher, respectively, than the control group. The experimental group showed significantly higher serum P, ALB (albumin), TG (triglyceride), and TC (total cholesterol) levels; serum AST (glutamic oxalacetic transaminase) activity; and CREA (creatinine) and BUN (blood urea nitrogen) levels than the control group at different time points. The serum LH (luteinizing hormone), FSH (follicle-stimulating hormone), P4 (progesterone), and E2 (estradiol) levels were significantly higher in the off-season breeding group than in the control group. The serum T3 (triiodothyronine) and T4 (Tetraiodothyronine) levels were significantly higher in the off-season breeding group than in the control group at different points in the breeding cycle. The control group showed a significantly higher gene expression of GnRH (gonadotropin releasing hormone) in the hypothalamus; GnRH, FSH, and LH in the pituitary; and GnRH in the ovary and significantly lower gene expression of VIP (vasoactine intestinal peptide) and PRL (prolactin) in the pituitary than the off-season breeding group. Thus, the off-season breeding of Zhedong white geese may prolong the peak laying period and improve egg production performance, thus enhancing the economic benefits of goose breeding.

Intermittent fasting (IF) as a dietary intervention with potential health benefits has garnered significant attention in recent years. This study investigated the effects of varying fasting intensities on skeletal muscle growth using mouse models. Compared to the normal-diet (ND) control group, short-term fasting induced feeding amount-dependent alterations in skeletal muscle autophagy markers, characterized by elevated LC3B expression, reduced p62 levels, and decreased p-mTOR/mTOR ratio. Notably, short-term mild fasting (sMF) significantly upregulated myogenic (MYH, MyoD) and adipogenic (LPL, PPARγ) differentiation markers, whereas short-term severe fasting (sSF) suppressed myogenic markers without significantly affecting adipogenic factors. Pharmacological modulation using 3-methyladenine (3-MA) and rapamycin (RAPA) confirmed the critical role of autophagy in myogenic and adipogenic processes. Multi-cycle IF studies revealed that intermittent mild fasting (IMF) enhanced metabolic efficiency (evidenced by increased feed conversion ratio), elevated organ indices of gastrocnemius and quadriceps femoris muscles, and reduced groin fat. IMF also promoted intramuscular adipogenesis and myofiber remodeling. In contrast, intermittent severe fasting (ISF) impaired glucose tolerance, decreased triglyceride levels and aspartate aminotransferase (AST) activity, inhibited myofiber growth, and exhibited no significant effect on intramuscular adipogenesis. Our findings demonstrate that IMF enhances skeletal muscle mass and reduces visceral adiposity through mTOR-autophagy axis, providing an optimized fasting regimen for metabolic health and body composition regulation.

BACKGROUND:Mitochondrial dysfunction caused by metabolic stress is a key part of diabetic nephropathy. Dapagliflozin exerts significant hypoglycemic and nephroprotective effects; however, the precise mechanisms underlying its renoprotective actions remain to be fully elucidated. OBJECTIVE:This study aimed to elucidate the molecular mechanisms through which dapagliflozin mitigates diabetic nephropathy (DN), with particular emphasis on its regulatory role in the Sirt1-Pink1-Parkin axis and the restoration of mitochondrial homeostasis via mitophagy. METHODS:Rats were fed a high-fat/high-sugar diet and streptozotocin. They were then divided into groups of various treatments. In vitro, high glucose-induced NRK-52E cell injury was treated with dapagliflozin. Evaluations included renal histopathology, urinary biomarkers, apoptosis, reactive oxygen species, mitochondrial membrane potential, and Sirt1/Pink1/Parkin pathway activation. RESULTS:Dapagliflozin exerted significant protective effects against streptozotocin-induced diabetic nephropathy. Dapagliflozin treatment in vitro restored mitochondrial membrane potential and reduced ROS levels in high glucose-induced NRK-52E cells. High glucose exposure markedly upregulated the expression of mitochondria-associated apoptotic proteins in NRK-52E cells, which was reduced by dapagliflozin. This study revealed that Sirt1/Pink1/Parkin-mediated mitophagy was suppressed in DN and high glucose-induced NRK-52E cells but was activated following dapagliflozin treatment. CONCLUSION:Our findings demonstrate that dapagliflozin modulates Sirt1/Pink1/Parkin-mediated mitochondrial autophagy and effectively restores mitochondrial homeostasis in diabetic nephropathy. Modulating mitochondrial autophagy through this pathway may serve as a promising therapeutic strategy for diabetic nephropathy.

Cadmium, a pervasive environmental pollutant, exerts detrimental effects on various tissues and cells, particularly targeting the reproductive system, thereby posing significant risks to both animal food safety and human health. Despite its widespread impact, research on substances capable of mitigating cadmium-induced reproductive toxicity remains scarce, especially concerning female reproductive health. Metformin, a widely used oral antihyperglycemic drug, has demonstrated a range of beneficial effects, including anti-aging and antioxidant properties. This study aims to investigate the potential and underlying mechanisms of metformin in alleviating cadmium-induced reproductive toxicity in females. Over a period of 35 consecutive days, mice were exposed to cadmium-contaminated water (32 mg/l) and orally administered 10 mg metformin dissolved in 0.2 ml normal saline. Our findings reveal that metformin effectively mitigates cadmium-induced disruptions in the estrous cycle, follicular development, and oocyte meiotic maturation. Specifically, metformin enhances ATP production in oocytes by boosting mitochondrial mass and biosynthesis, thereby counteracting cadmium-induced oxidative stress and spindle morphology defects during meiosis. Additionally, metformin restores the DNA repair capacity of oocytes, alleviating cadmium-induced DNA damage. This restorative effect is partially mediated by metformin's ability to improve key epigenetic modifications, such as histone acetylation, histone methylation, and DNA methylation in oocytes. These results underscore metformin's potential as a protective or therapeutic agent against cadmium reproductive toxicity, primarily by maintaining cellular homeostasis to bolster oocyte resilience against cadmium toxicity and preserving normal epigenetic modifications to ensure oocyte quality.

Ketotic cows exhibit a heightened secondary endometritis risk through an unknown mechanism. We investigated the role of Nrf2 in ketosis-induced endometritis. Uterine tissues from ketotic cows showed higher levels of caspase-1 and GSDMD but lower levels of Nrf2 and LC3. β-Hydroxybutyrate (BHBA) treatment induced pyroptosis in bovine endometrial epithelial cells (BEECs), upregulated pyroptosis-related proteins, and increased the rate of pyroptosis. Nrf2 and its downstream oxidative stress proteins were decreased, and autophagic flux was blocked. NAC, Rapa, and Nrf2 activators alleviated BHBA-induced pyroptosis by promoting autophagic flux. In a mouse ketosis model, intervention with NAC significantly reduced blood levels of BHBA and pro-inflammatory cytokines, and the expression of pyroptosis-related proteins in uterine tissues was decreased compared with ketotic model mice. Overall, Nrf2 promoted BHBA-induced pyroptosis in BEECs by modulating autophagy mediated by oxidative stress, suggesting that it may serve as a potential therapeutic target.

Sry on the Y-chromosome upregulates Sox9, which in turn upregulates a set of genes such as Fgf9 to initiate testicular differentiation in the XY gonad. In the absence of Sry expression, genes such as Rspo1, Foxl2, and Runx1 support ovarian differentiation in the XX gonad. These two pathways antagonize each other to ensure the development of only one gonadal sex in normal development. In the B6.Y-TIR mouse, carrying the Y-TIR-chromosome on the B6 genetic background, Sry is expressed in a comparable manner with that in the B6.XY mouse, yet, only ovaries or ovotestes develop. We asked how testicular and ovarian differentiation pathways interact to determine the gonadal sex in the B6.Y-TIR mouse. Our results showed that (1) transcript levels of Sox9 were much lower than in B6.XY gonads while those of Rspo1 and Runx1 were as high as B6.XX gonads at 11.5 and 12.5 days postcoitum. (2) FOXL2-positive cells appeared in mosaic with SOX9-positive cells at 12.5 days postcoitum. (3) SOX9-positive cells formed testis cords in the central area while those disappeared to leave only FOXL2-positive cells in the poles or the entire area at 13.5 days postcoitum. (4) No difference was found at transcript levels of all genes between the left and right gonads up to 12.5 days postcoitum, although ovotestes developed much more frequently on the left than the right at 13.5 days postcoitum. These results suggest that inefficient Sox9 upregulation and the absence of Rspo1 repression prevent testicular differentiation in the B6.Y-TIR gonad.

Maternal cadmium exposure during pregnancy has been demonstrated to have detrimental effects on offspring development. However, the impact of maternal cadmium exposure on offspring oocytes remains largely unknown, and the underlying mechanisms are not fully understood. In this study, we found that maternal cadmium exposure during pregnancy resulted in selective alteration in epigenetic modifications of mouse oocytes in offspring, including a decrease in H3K4me2 and H4K12ac, as well as an increase in DNA methylation of H19. Although ROS levels and mitochondrial activity remain at normal levels, the DNA damage marker γH2AX was significantly increased and the DNA repair marker DNA-PKcs was remarkably decreased in offspring oocytes from maternal cadmium exposure. These alterations are responsible for the decrease in the quality of mouse oocytes in offspring induced by maternal cadmium exposure. As a result, the meiotic maturation of oocytes and subsequent early embryonic development are influenced by maternal cadmium exposure. RNA-seq results showed that maternal cadmium exposure elicits modifications in the expression of genes associated with metabolism, signal transduction, and endocrine regulation in offspring ovaries, which also contribute to the disorders of oocyte maturation and failures in early embryonic development. Our research provides direct evidence of transgenerational epigenetic inheritance of cadmium reproductive toxicity in mouse germ cells.

Cadmium (Cd), is a highly toxic environmental pollutant, which seriously threatens the health of poultry and humans. The occurrence of osteoporosis is the main manifestation of cadmium toxicity. Pyroptosis plays an important role in the development of osteoporosis. Melatonin has been shown to affect preserving bone health. However, the underlying mechanism has not been elucidated. In the present study, these functions of melatonin have been investigated in duck bone tissue and osteoblast during cadmium exposure. In vivo, the studies suggest that melatonin protects against cadmium-induced duck osteoporosis by improving the osteogenesis function, inhibiting bone resorption, and suppressing the occurrence of pyroptosis. In vitro, the findings demonstrated that melatonin alleviated the inhibition effect of cadmium on duck bone marrow-derived mesenchymal stem cells (BMSC) osteogenic differentiation, and suppressed the cadmium-induced osteoclast differentiation. In addition, we also found that melatonin prevents cytokines release of lactate dehydrogenase (LDH), interleukin-18 (IL-18), and interleukin-1β (IL-1β) by cadmium-induced, and reduces the expression of n-terminal Gasdermin D (N-GSDMD), alleviates the osteoblast death rate. In short, melatonin as a potential therapeutic agent has bright prospects in cadmium-induced bone toxicity.