Uranium induces oxidative stress in lung epithelial cells

Uranium compounds are widely used in the nuclear fuel cycle, antitank weapons, tank armor, and also as a pigment to color ceramics and glass. Effective management of waste uranium compounds is necessary to prevent exposure to avoid adverse health effects on the population. Health risks associated with uranium exposure includes kidney disease and respiratory disorders. In addition, several published results have shown uranium or depleted uranium causes DNA damage, mutagenicity, cancer and neurological defects. In the current study, uranium toxicity was evaluated in rat lung epithelial cells. The study shows uranium induces significant oxidative stress in rat lung epithelial cells followed by concomitant decrease in the antioxidant potential of the cells. Treatment with uranium to rat lung epithelial cells also decreased cell proliferation after 72 h in culture. The decrease in cell proliferation was attributed to loss of total glutathione and superoxide dismutase in the presence of uranium. Thus the results indicate the ineffectiveness of antioxidant system’s response to the oxidative stress induced by uranium in the cells.     

Cellular localization of uranium in the renal proximal tubules during acute renal uranium toxicity

Renal toxicity is a hallmark of uranium exposure, with uranium accumulating specifically in the S3 segment of the proximal tubules causing tubular damage. As the distribution, concentration and dynamics of accumulated uranium at the cellular level is not well understood, here, we report on high‐resolution quantitative in situ measurements by high‐energy synchrotron radiation X‐ray fluorescence analysis in renal sections from a rat model of uranium‐induced acute renal toxicity. One day after subcutaneous administration of uranium acetate to male Wistar rats at a dose of 0.5 mg uranium kg^–1 body weight, uranium concentration in the S3 segment of the proximal tubules was 64.9 ± 18.2 µg g^–1, sevenfold higher than the mean renal uranium concentration (9.7 ± 2.4 µg g^–1). Uranium distributed into the epithelium of the S3 segment of the proximal tubules and highly concentrated uranium (50‐fold above mean renal concentration) in micro‐regions was found near the nuclei. These uranium levels were maintained up to 8 days post‐administration, despite more rapid reductions in mean renal concentration. Two weeks after uranium administration, damaged areas were filled with regenerating tubules and morphological signs of tissue recovery, but areas of high uranium concentration (100‐fold above mean renal concentration) were still found in the epithelium of regenerating tubules. These data indicate that site‐specific accumulation of uranium in micro‐regions of the S3 segment of the proximal tubules and retention of uranium in concentrated areas during recovery are characteristics of uranium behavior in the kidney. Copyright © 2015 John Wiley & Sons, Ltd.     

Uranium dynamics and developmental sensitivity in rat kidney

Renal toxicity is the principal health concern after uranium exposure. Children are particularly vulnerable to uranium exposure; with contact with depleted uranium in war zones or groundwater contamination the most likely exposure scenarios. To investigate renal sensitivity to uranium exposure during development, we examined uranium distribution and uranium‐induced apoptosis in the kidneys of neonate (7‐day‐old), prepubertal (25‐day‐old) and adult (70‐day‐old) male Wistar rats. Mean renal uranium concentrations increased with both age‐at‐exposure and exposure level after subcutaneous administration of uranium acetate (UA) (0.1–2 mg kg^–1 body weight). Although less of the injected uranium was deposited in the kidneys of the two younger rat groups, the proportion of the peak uranium content remaining in the kidneys after 2 weeks declined with age‐at‐exposure, suggesting reduced clearance in younger animals. In situ high‐energy synchrotron radiation X‐ray fluorescence analysis revealed site‐specific accumulation of uranium in the S3 segment of the proximal tubules, distributed in the inner cortex and outer stripe of the outer medulla. Apoptosis and cell loss in the proximal tubules increased with age‐at‐exposure to 0.5 mg kg^–1 UA. Surprisingly, prepubertal rats were uniquely sensitive to uranium‐induced lethality from the higher exposure levels. Observations of increased apoptosis in generating/re‐generating tubules particularly in prepubertal rats could help to explain their high mortality rate. Together, our findings suggest that age‐at‐exposure and exposure level are important parameters for uranium toxicity; uranium tends to persist in developing kidneys after low‐level exposures, although renal toxicity is more pronounced in adults. Copyright © 2013 John Wiley & Sons, Ltd.     

Role of the olfactory receptor neurons in the direct transport of inhaled uranium to the rat brain

Uranium presents numerous industrial and military uses and one of the most important risks of contamination is dust inhalation. In contrast to the other modes of contamination, the inhaled uranium has been proposed to enter the brain not only by the common route of all modes of exposure, the blood pathway, but also by a specific inhalation exposure route, the olfactory pathway. To test whether the inhaled uranium enter the brain directly from the nasal cavity, male Sprague–Dawley rats were exposed to both inhaled and intraperitoneally injected uranium using the ²³⁶U and ²³³U, respectively, as tracers. The results showed a specific frontal brain accumulation of the inhaled uranium which is not observed with the injected uranium. Furthermore, the inhaled uranium is higher than the injected uranium in the olfactory bulbs (OB) and tubercles, in the frontal cortex and in the hypothalamus. In contrast, the other cerebral areas (cortex, hippocampus, cerebellum and brain residue) did not show any preferential accumulation of inhaled or injected uranium. These results mean that inhaled uranium enters the brain via a direct transfer from the nasal turbinates to the OB in addition to the systemic pathway. The uranium transfer from the nasal turbinates to the OB is lower in animals showing a reduced level of olfactory receptor neurons (ORN) induced by an olfactory epithelium lesion prior to the uranium inhalation exposure. These results give prominence to a role of the ORN in the direct transfer of the uranium from the nasal cavity to the brain.     

The effect of stress on the temporal and regional distribution of uranium in rat brain after acute uranyl acetate exposure

Long-term exposure to depleted uranium (DU) has been shown to increase brain uranium and alter hippocampal function; however, little is known about the short-term kinetics of DU in the brain. To address this issue, temporal and regional distribution of brain uranium was investigated in male Sprague-Dawley rats treated with a single intraperitoneal injection of 1 mg uranium/kg as uranyl acetate. Due to the inherent stress of combat and the potential for stress to alter blood-brain barrier permeability, the impact of forced swim stress on brain uranium distribution was also examined in this model. Uranium in serum, hippocampus, striatum, cerebellum, and frontal cortex was quantified by inductively coupled plasma-mass spectrometry (ICP-MS) at 8 h, 24 h, 7 d, and 30 d after exposure. Uranium entered the brain rapidly and was initially concentrated in hippocampus and striatum. While multiple phases of uranium clearance were observed, overall clearance was relatively slow and the uranium content of hippocampus, cerebellum, and cortex remained elevated for more than 7 d after a single exposure. Prior exposure to stress significantly reduced hippocampal and cerebellar uranium 24 h post-exposure and tended to reduce uranium in all brain regions 7 d after exposure. The application of stress appeared to increase brain uranium clearance, as initial tissue levels were similar in stressed and unstressed rats.     

Role of the sodium-dependent phosphate co-transporters and of the phosphate complexes of uranyl in the cytotoxicity of uranium in LLC-PK1 cells

Although uranium is a well-characterized nephrotoxic agent, very little is known at the cellular and molecular level about the mechanisms underlying the uptake and toxicity of this element in proximal tubule cells. The aim of this study was thus to characterize the species of uranium that are responsible for its cytotoxicity and define the mechanism which is involved in the uptake of the cytotoxic fraction of uranium using two cell lines derived from kidney proximal (LLC-PK(1)) and distal (MDCK) tubule as in vitro models. Treatment of LLC-PK(1) cells with colchicine, cytochalasin D, concanavalin A and PMA increased the sodium-dependent phosphate co-transport and the cytotoxicity of uranium. On the contrary, replacement of the extra-cellular sodium with N-methyl-D-glucamine highly reduced the transport of phosphate and the cytotoxic effect of uranium. Uranium cytotoxicity was also dependent upon the extra-cellular concentration of phosphate and decreased in a concentration-dependent manner by 0.1-10 mM phosphonoformic acid, a competitive inhibitor of phosphate uptake. Consistent with these observations, over-expression of the rat proximal tubule sodium-dependent phosphate co-transporter NaPi-IIa in stably transfected MDCK cells significantly increased the cytotoxicity of uranium, and computer modeling of uranium speciation showed that uranium cytotoxicity was directly dependent on the presence of the phosphate complexes of uranyl UO(2)(PO(4))(-) and UO(2)(HPO(4))(aq). Taken together, these data suggest that the cytotoxic fraction of uranium is a phosphate complex of uranyl whose uptake is mediated by a sodium-dependent phosphate co-transporter system.     

A sensitive method for the determination of uranium in biological samples utilizing kinetic phosphorescence analysis (KPA)

Kinetic phosphorescence analysis is a technique that provides rapid, precise and accurate determination of uranium concentration in aqueous solutions. This technique utilizes a laser source to excite an aqueous solution of uranium, and measures the emission luminescence intensity over time to determine the luminescence decay profile. The lifetime of the luminescence decay profile and the linearity of the log luminescence intensity versus time profile are indications of the specificity of the technique for uranium determination. The luminescence intensity at the onset of decay (the initial luminescence intensity), which is the luminescence intensity at time zero after termination of the laser pulse used for excitation, is proportional to the uranium concentration in the sample. Calibration standards of known uranium concentrations are used to construct the calibration curve between the initial luminescence intensity and uranium concentration. This calibration curve is used to determine the uranium concentration of unknown samples from their initial luminescence intensity. We developed the sample preparation method that allows the determination of uranium concentrations in urine, plasma, kidney, liver, bone spleen and soft tissue samples. Tissue samples are subjected to dry-ashing in a muffle furnace at 600°C and wet-ashing with concentrated nitric acid and hydrogen peroxide twice to destroy the organic component in the sample that may interfere with uranium determination by KPA. Samples are then solubilized in 0.82 M nitric acid prior to analysis by KPA. The assay calibration curves are linear and cover the range of uranium concentrations between 0.05 μg 1⁻¹ and 1000 μg 1⁻¹ (0.05–1000 ppb). The developed sample preparation procedures coupled with the KPA technique provide a specific, sensitive, precise and accurate method for the determination of uranium concentration in tissue samples. This method was used to quantify uranium in different tissue samples obtained over a period of 90 days following a single intraperitoneal uranium dose of 0.1 mg kg⁻¹ in rats.     

Role of the sodium-dependent phosphate cotransporters and absorptive endocytosis in the uptake of low concentrations of uranium and its toxicity at higher concentrations in LLC-PK1 cells.

It has been suggested that uranium uptake and toxicity could be mediated by endocytosis and/or the type IIa sodium-dependent phosphate cotransporter (NaPi-IIa). The aim of this study was therefore to characterize in vitro the role of these two cellular mechanisms in the uptake and toxicity of low (200-3200 nM) and high (0.5 and 0.8 mM) concentrations of uranium, respectively. At low concentrations, uranium uptake in LLC-PK(1) cells was saturable (V(max) = 3.09 +/- 0.22 ng/mg protein) and characterized by a K(0.5) of 1022 +/- 63 nM and a Hill coefficient of 3.0 +/- 0.4. The potential involvement of endocytosis and NaPi-IIa in the uptake of uranium was assessed by the use of various drugs and culture conditions known to alter their relative activity, and (233)uranium uptake was monitored. Interestingly, the inhibitory effect of colchicine, cytochalasin D, phorbol 12-myristate 13-acetate, and chlorpromazine on endocytosis was highly correlated with their effect on uranium uptake, a relationship that was not true when the NaPi-IIa transport system was studied. Whereas the competitive inhibition of the NaPi-IIa by phosphonoformic acid (PFA) significantly decreased uranium uptake, this effect was not reproduced when NaPi-IIa inhibition was mediated by the replacement of extracellular Na(+) with N-methyl-D-glucamine. Uranium uptake was also not significantly altered when NaPi-IIa expression was stimulated in MDCK cells. More surprisingly, we observed by transmission electron microscopy that uranium cytotoxicity was dependent upon the extent of its intracellular precipitation, but not on its intracellular content, and was suppressed by PFA. In conclusion, our results suggest that low-dose uranium uptake is mainly mediated by absorptive endocytosis, and we propose PFA as a potential uranium chelator.     

Distribution of uranium in rats implanted with depleted uranium pellets.

During the Persian Gulf War, soldiers were injured with depleted uranium (DU) fragments. To assess the potential health risks associated with chronic exposure to DU, Sprague Dawley rats were surgically implanted with DU pellets at 3 dose levels (low, medium and high). Biologically inert tantalum (Ta) pellets were used as controls. At 1 day and 6, 12, and 18 months after implantation, the rats were euthanized and tissue samples collected. Using kinetic phosphorimetry, uranium levels were measured. As early as 1 day after pellet implantation and at all subsequent sample times, the greatest concentrations of uranium were in the kidney and tibia. At all time points, uranium concentrations in kidney and bone (tibia and skull) were significantly greater in the high-dose rats than in the Ta-control group. By 18 months post-implantation, the uranium concentration in kidney and bone of low-dose animals was significantly different from that in the Ta controls. Significant concentrations of uranium were excreted in the urine throughout the 18 months of the study (224 +/- 32 ng U/ml urine in low-dose rats and 1010 +/- 87 ng U/ml urine in high-dose rats at 12 months). Many other tissues (muscle, spleen, liver, heart, lung, brain, lymph nodes, and testicles) contained significant concentrations of uranium in the implanted animals. From these results, we conclude that kidney and bone are the primary reservoirs for uranium redistributed from intramuscularly embedded fragments. The accumulations in brain, lymph nodes, and testicles suggest the potential for unanticipated physiological consequences of exposure to uranium through this route.     

Distribution of soluble uranium in the nuclear cell compartment at subtoxic concentrations

Uranium is naturally found in the environment, and its extensive use results in an increased risk of human exposure. Kidney cells have mainly been used as in vitro models to study effects of uranium exposure, and very little about the effects on other cell types is known. The aim of this study was to assess the impact of depleted uranium exposure at the cellular level in human kidney (HEK-293), liver (HepG2), and neuronal (IMR-32) cell lines. Cytotoxicity studies showed that these cell lines reacted in a roughly similar manner to depleted uranium exposure, responding at a cytotoxicity threshold of 300-500 μM. Uranium was localized in cells with secondary ion mass spectrometry technology. Results showed that uranium precipitates at subtoxic concentrations (>100 μM). With this approach, we were able for the first time to observe the soluble form of uranium in the cell at low concentrations (10-100 μM). Moreover, this technique allows us to localize it mainly in the nucleus. These innovative results raise the question of how uranium penetrates into cells and open new perspectives for studying the mechanisms of uranium chemical toxicity.     

茶多酚二甲亚砜合剂对铀矿尘人支气管细胞毒性的防护作用

目的探讨铀矿尘所致人支气管细胞BEAS-2B细胞DNA损伤以及茶多酚二甲亚砜合剂对细胞的防护作用。方法 BEAS-2B细胞中加入铀矿尘、铀矿尘+茶多酚、铀矿尘+二甲亚砜、铀矿尘+茶多酚二甲亚砜合剂染毒24 h后,通过检测微核和多核细胞观察染色体损伤,彗星实验及H2AX蛋白磷酸化检测DNA的损伤,多核细胞法检测细胞次黄嘌呤磷酸核糖转移酶(HPRT)突变。结果与正常对照组相比,BEAS-2B细胞经铀矿尘染毒后,细胞的微核率、多核率和拖尾率明显升高,H2AX蛋白磷酸化表达增高,HPRT突变率明显增高(P<0.05),铀矿尘+茶多酚、铀矿尘+二甲亚砜和铀矿尘+茶多酚二甲亚砜合剂保护能有效降低上述变化(P<0.05),其中茶多酚二甲亚砜合剂的保护效果最好。结论铀矿尘对BEAS-2B细胞DNA具有损伤作用,茶多酚二甲亚砜合剂有较强防护作用。     

Reduction of uranium transfer by local chelation in simulated wounds in rats

The aim of the paper is to develop a new approach to treat uranium-contaminated wounds. The efficacy of a local uranium chelator, carballylic amido bis phosphonic acid (CAPBP) was assessed using two different uranium compounds. Rats were contaminated by intramuscular injections of uranyl nitrate or an industrial U04 compound to simulate wound contamination. CAPBP was injected intramuscularly (i.m.) or intraperitoneally (i.p.) at a dosage of 30 micromol kg(-1). In one experiment, the local administration of CAPBP was combined with a systemic administration of ethane-1-hydroxy-1,1-biphosphonate (EHBP). The local CAPBP treatment resulted in increased retention of uranium at the wound site: about 30% for uranyl nitrate or U04 after the first day and about 15% of UO4 after the third day. Consequently, it reduced uranium translocation into the blood and deposition in the kidneys and bone. The combined treatment reduced the uranium deposits in the kidneys, bone and carcass to about one-half of those observed in controls 3 days after U04 contamination. The local CAPBP treatment increased the interval of time between contamination and uranium deposit in the target organs. Thus, it can increase the efficacy of nonspecific local treatments or specific systemic treatments. It could be given rapidly through spray or gel after an accident.     

Optimal sample preparation conditions for the determination of uranium in biological samples by kinetic phosphorescence analysis (KPA)

Kinetic phosphorescence analysis (KPA) is a proven technique for rapid, precise, and accurate determination of uranium in aqueous solutions. Uranium analysis of biological samples require dry-ashing in a muffle furnace between 400 and 600 degrees C followed by wet-ashing with concentrated nitric acid and hydrogen peroxide to digest the organic component in the sample that interferes with uranium determination by KPA. The optimal dry-ashing temperature was determined to be 450 degrees C. At dry-ashing temperatures greater than 450 degrees C, uranium loss was attributed to vaporization. High temperatures also caused increased background values that were attributed to uranium leaching from the glass vials. Dry-ashing temperatures less than 450 degrees C result in the samples needing additional wet-ashing steps. The recovery of uranium in urine samples was 99.2+/-4.02% between spiked concentrations of 1.98-1980 ng (0.198-198 microg l(-1)) uranium, whereas the recovery in whole blood was 89.9+/-7.33% between the same spiked concentrations. The limit of quantification in which uranium in urine and blood could be accurately measured above the background was determined to be 0.05 and 0.6 microg l(-1), respectively.     

Absorption, accumulation and biological effects of depleted uranium in Peyer's patches of rats

The digestive tract is the entry route for radionuclides following the ingestion of contaminated food and/or water wells. It was recently characterized that the small intestine was the main area of uranium absorption throughout the gastrointestinal tract. This study was designed to determine the role played by the Peyer's patches in the intestinal absorption of uranium, as well as the possible accumulation of this radionuclide in lymphoid follicles and the toxicological or pathological consequences on the Peyer's patch function subsequent to the passage and/or accumulation of uranium. Results of experiments performed in Ussing chambers indicate that the apparent permeability to uranium in the intestine was higher (10-fold) in the mucosa than in Peyer's patches ((6.21+/-1.21 to 0.55+/-0.35)x10(-6)cm/s, respectively), demonstrating that the small intestinal epithelium was the preferential pathway for the transmucosal passage of uranium. A quantitative analysis of uranium by ICP-MS following chronic contamination with depleted uranium during 3 or 9 months showed a preferential accumulation of uranium in Peyer's patches (1355% and 1266%, respectively, at 3 and 9 months) as compared with epithelium (890% and 747%, respectively, at 3 and 9 months). Uranium was also detected in the mesenteric lymph nodes ( approximately 5-fold after contamination with DU). The biological effects of this accumulation of depleted uranium after chronic contamination were investigated in Peyer's patches. There was no induction of the apoptosis pathway after chronic DU contamination in Peyer's patches. The results indicate no change in the cytokine expression (Il-10, TGF-beta, IFN-gamma, TNF-alpha, MCP-1) in Peyer's patches and in mesenteric lymph nodes, and no modification in the uptake of yeast cells by Peyer's patches. In conclusion, this study shows that the Peyer's patches were a site of retention for uranium following the chronic ingestion of this radionuclide, without any biological consequences of such accumulation on Peyer's patch functions.     

Influence of uranium(VI) speciation for the evaluation of in vitro uranium cytotoxicity on LLC-PK1 cells

Very few data are available concerning the in vitro toxicity of uranium. In this work, we have determined the experimental chemical conditions permitting the observation of uranium(VI) cytotoxicity on LLC-PK1 cells. Uranium solutions made either by dissolving uranyl acetate or nitrate crystals, or by complexing uranium with bicarbonate, phosphate or citrate ligands, were prepared and tested. Experiments demonstrated that only uranium solutions containing citrate and bicarbonate ligands concentrations tenfold higher than the metal, were soluble in the cell culture medium. Cytotoxicity studies of all these uranium compounds were performed on LLC-PK1 cells and compared using LDH release, neutral red uptake and MTT assays. Dose dependent cytotoxicity curves were only obtained with uranium-bicarbonate medium. This study has revealed a toxicity of uranium-bicarbonate complexes for 24 h expositions and for concentrations ranging from 7 x 10(-4)-10(-3) M, under these conditions, the CI50 (cytotoxicity index) was evaluated between 8.5 and 9 x 10(-4) M. In contrast, we noticed a lack of cytotoxicity response for uranium(VI)-citrate complexes. Electron transmission microscopy studies revealed, when LLC-PK1 cells were exposed to the uranium-bicarbonate system, that uranium penetrated and precipitated within the cytoplasmic compartment. Morphological studies conducted with citrate complexes did not show any cellular intake of uranium.     

Uranium(VI) solubility and speciation in simulated elemental human biological fluids

The complete understanding of the human body response to uranium contamination exposure is vital to the development of exposure analysis and subsequent treatments for overexposure. Thermodynamic modeling has traditionally been used to study environmental metal contaminant migration (especially uranium and other radionuclides), allowing examination of chemical processes difficult to study experimentally. However, such techniques are rarely used in the study of metal toxicology. Chemical thermodynamics has a unique and valuable role in developing models to explain metal metabolism and toxicology. Previous computational models of beryllium in simulated biological fluids have been shown to be useful in predicting metal behavior in the human body. However, previous studies utilizing chemical thermodynamics in understanding uranium chemistry in body fluids are limited. Here, a chemical thermodynamic speciation code has been used to model and understand the chemistry of uranium in simulated human biological fluids such as intracellular, interstitial, and plasma fluids, saliva, sweat, urine, bile, gastric juice, pancreatic fluid, and a number of airway surface fluids from patients with acute lung conditions. The results show predicted uranium solubility, and speciation varies markedly between each biological fluid due to differences in fluid composition, ionic strength, and pH. The formation of uranium hydroxide, phosphate (sodium/potassium autunite), and calcium uranate was observed in most of the fluids. The results of this work, supported by experimental validation, can aid in understanding the metabolism and toxic effects of uranium with potential applications to biological monitoring as well as chelation treatment of uranium body burden.     

Uranium induces genomic instability and slows cell cycle progression in human lymphocytes in acute toxicity study

In the situation of radiation triage, accidental exposure to uranium, or uranium contamination in food or water; haematopoietic decline or bone marrow sickness is observed in the aftermath followed by other systemic effects. Most studies done previously have been on cytogenetic analysis in blood lymphocytes of uranium miners wherein causal relationship was difficult to be established. This study provides new insights into the minimum risk level of uranium to human lymphocytes, DNA damage induced and alterations in the cell cycle progression through 96-h acute toxicity study. Cytotoxicity studies by MTT assay and flow cytometry showed that uranyl nitrate concentration of 1280 μM lead to 50% cell death, 640 μM caused 25% death, 250 μM caused 10% cell death and 5 μM was the NOAEL. Uranium caused DNA damages in a dose dependent manner as evident from comet and CBMN assays. A marked increase in G2/M phase cells was observed in the test culture groups. Halting of cell cycle at G2/M checkpoint also signified the extent of double strand breaks and genetic instability with increasing uranium dose in this study. Better cell cycle responses and lower genetic damage index observed in lower dosage of exposure, suggests adaptability and repair responses in human lymphocytes. Together these results advance our understanding of uranium effects on mammalian cells.     

Hydrogen sulfide alleviates uranium‐induced acute hepatotoxicity in rats: Role of antioxidant and antiapoptotic signaling

As an endogenous gaseous mediator, H₂S exerts antioxidative, antiapoptotic, and cytoprotective effects in livers. This study was designed to investigate the protective role of H₂S against uranium‐induced hepatotoxicity in adult SD male rats after in vivo effect of uranium on endogenous H₂S production was determined in livers. The levels of endogenous H₂S and H₂S‐producing enzymes (CBS and CSE) were measured in liver homogenates from uranium ‐intoxicated rats. In rats injected intraperitoneally (i.p.) with uranyl acetate or NaHS (an H₂S donor) alone or in combination, we examined biochemical parameters to assess liver function, revealed hepatic histopathological alteration, investigated oxidative stress markers, and explored apoptotic signaling in liver homogenates. The results suggest that uranium‐intoxication in rats decreased CBS and CSE protein expression, H₂S synthesis capacity, and endogenous H₂S generation. NaHS administration in uranium‐intoxicated rats produced amelioration in liver biochemical indices and histopathological effects, decreased MDA content, and increased GSH level and antioxidative enzymes activities like SOD, CAT, GPx, and GST. NaHS administration in uranium‐intoxicated rats attenuated uranium‐activated phosphorylation state of JNK. NaHS treatment in uranium‐intoxicated rats increased antiapoptotic Bcl‐2 but decreased pro‐apoptotic Bax, resulting in the rise of Bcl‐2/Bax ratio. NaHS treatment in uranium‐intoxicated rats reduced the apoptosis mediator caspase‐3 and cytochrome c release and elevated ATP contents. Taken together, these data implicate that H₂S can afford protection to rat livers against uranium‐induced adverse effects mediated by up‐regulation of antioxidant and antiapoptotic signaling. The anti‐apoptotic property of H₂S may be involved, at least in part, in inhibiting JNK signaling. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 581–593, 2017.