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Ammonia (NH 3) is a hazardous substance to human and animal health. Selenium (Se) is an essential micronutrient with multiple health benefits. The present study aimed to verify whether and how Se supplementation has a protective role against NH 3 mediated-nephrotoxicity in pigs. A Se-NH 3 interaction model was established in pigs and the kidney samples were collected after a 30-day treatment period. The results showed that NH 3 exposure inhibited the PI3K/AKT/mTOR pathway and enhanced the secretion of inflammatory cytokines to induce autophagy and inflammation. Se can regulate the PI3K/AKT/mTOR pathway and attenuate the secretion of inflammatory cytokines altered by NH 3 to reduce autophagy and inflammation. In addition, Se co-treatment inhibited ROS production, elevated the activities of antioxidant systems, and increased the expression of 13 selenoproteins in pig kidneys caused by NH 3 exposure. These results implied that L -selenomethionine can moderate NH 3 -induced nephrotoxicity in pigs. Our study gives new ideas for the specific mechanism of NH 3 nephrotoxicity and provides a reference for comparative medicine and clinical medication. [Display omitted] • Excess NH 3 induced inflammatory damage in pig kidneys. • NH 3 led to autophagy through inhibition of PI3K/AKT/mTOR pathway. • 0.50 mg/kg of Se showed a nephroprotective effect against NH 3. • Selenoproteins contributed to the detoxification of NH 3 by Se. [ABSTRACT FROM AUTHOR]

Ammonia (NH 3) emission is a common threat to farm animals. Selenium (Se) is known for its antioxidant property and can resist several stressors affecting farm animals. The aims of this study were (Ⅰ) to determine how excess NH 3 exert nephrotoxic effects in pigs and (Ⅱ) to investigate whether selenomethionine has an alleviative effect on NH 3 toxicity. Two diets supplemented with different doses of Se (0.22 mg/kg or 0.50 mg/kg) and two concentrations of NH 3 (< 5 mg/m3 or 89.8 mg/m3) were used in a 2 × 2 factorial design trial for a period of 30 days. The results showed that NH 3 exposure caused apoptosis and increased the number of apoptotic cells in pig kidneys. Further, the activities of antioxidant enzymes were decreased, and the transcriptional and translational levels of endoplasmic reticulum stress-related genes, Bcl-2 and Caspase family members were increased under NH 3 exposure. In addition, Wnt/β-catenin signaling pathway was suppressed after NH 3 treatment. Dietary supplement with selenomethionine appears to offer protection against NH 3 -induced kidney injury in pigs and the pathologic changes above were alleviated. Our findings provide additional insight into the mechanism of NH 3 toxicity in pigs while elucidating the role of Se as a potential antidote against NH 3 poisoning. [Display omitted] • Excess NH 3 induced apoptosis in pig kidneys. • ER stress, Bcl-2 and Caspase family members participated in apoptosis. • Selenomethionine had an alleviative effect on NH 3 toxicity. • Antioxidant and Wnt/β-catenin pathway linked with detoxification effect of Se. [ABSTRACT FROM AUTHOR]

Ammonia (NH 3), an environmental pollutant, poses a serious threat to human and avian health. Although previous studies have showed that NH 3 caused kidney injury, the molecular mechanisms of nephrotoxicity induced by NH 3 remain unclear. To explore the mechanisms of NH 3 nephrotoxicity, a total of 36 broiler chicks at one day of age were exposed to NH 3. After 42 days of exposure, blood samples were collected to determine creatinine and uric acid; and kidney samples were weighted and then collected to detect ultrastructural changes, oxidative stress parameters, ATPases, necroptosis- and mitochondrial dynamics-related genes. The results showed that chickens exposed to NH 3 showed lower relative kidney weight and an increase concentration in serum creatinine and uric acid. NH 3 exposure caused nephrocyte necrosis and increased the expression of necroptosis-related genes (TNF-α, RIPK1, RIPK3, MLKL, and JNK). Besides, the activities of antioxidant systems (SOD, CAT, GSH-Px, and T-AOC) were reduced, whereas the concentrations of H 2 O 2 and MDA were elevated. Lower activities of ATPases were obtained in NH 3 treatment groups. Furthermore, the mitochondrial fission-related genes drp1 and mff were activated, and mitochondrial fusion-related genes opa1, mfn1 and mfn2 were suppressed after NH 3 exposure. Based on the above results, we conclude that NH 3 caused-oxidative stress and mitochondrial dysfunction mediated nephrocyte necroptosis in chickens. This study may provide new insight into NH 3 nephrotoxicity. Image 1 • Excess NH 3 results in tissue damage and necrosis in chicken kidneys. • NH 3 induces nephrocyte necroptosis through RIP1-RIP3-MLKL pathway. • Oxidative stress and mitochondrial dysfunction co-contribute to necroptosis. [ABSTRACT FROM AUTHOR]

Ammonia (NH 3) is considered as environmental pollutant and toxic agent for animals and humans including poultry. Previous reports demonstrated that NH 3 suppressed broilers immunity. However, the harmful effects of NH 3 on broilers bursa of fabricius (BF) is still unknown. Functionally, apoptosis is very important for many physiological processes including homeostasis of lymphocyte population. Therefore, the present study was aimed to investigate the underlying mechanisms of NH 3 toxicity in the broilers BF. Histological observation showed lymphocyte accumulation, cavities and increased interstitial cells in BF. Ultrastructural observation indicated mitochondrial vacuoles, deformation and disappearance of mitochondrial membranes. Oxidative stress markers (CAT, MDA, H 2 O 2 , GGT, GSH-Px and GSH) showed that NH 3 -induced oxidative stress in BF. Meanwhile, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay revealed increased apoptotic cells. In addition, the mRNA and protein expression of dynamin-related protein 1 (Drp1), mitochondrial fission factor (Mff), mitofusin 1 and 2 (Mfn1 and Mfn2), optic atrophy 1 (Opa1) indicated imbalance between mitochondrial inner and outer membrane and results in mitochondrial dysfunction in broilers BF. The mRNA and protein expression of apoptosis-related genes including Caspase-3, Caspase-9, Caspase-8, Cytochrome-C (Cyt-C), p53, B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax) were significantly altered in broilers BF. Conclusively, these results displayed that excessive NH 3 causes BF damage and mitochondrial dysfunction through oxidative stress and apoptosis in BF and could affect immune function of BF. These findings provide possible therapeutic targets to prevent NH 3 induced toxicity in the BF of broilers. • The effects of ammonia (NH 3)-induced toxicity in broilers BF were investigated. • NH 3 -induced abnormal morphological and ultrastructural changes in the BF of broilers. • NH 3 inhalation causes a significant increase in oxidative stress and induced apoptosis. • The study provide possible therapeutic targets to prevent NH 3 -induced immune toxicity. [ABSTRACT FROM AUTHOR]