CdCl2-treated Rats Research Articles

Tomato Extract Antagonizes Cadmium-Induced Hepatotoxicity and Nephrotoxicity in Mice and HepG2 Cells: Inhibition of Oxidative Damage and Apoptosis

Cadmium (Cd), a highly toxic heavy metal, accumulates in the liver and kidneys in the human body by several routes. Tomatoes and related processed food possess multiple physiological functions such as antioxidation, antiinflammation, and anticancer. Herein, to investigate whether tomato extract (TE) can protect against cadmium chloride (CdCl2)-induced oxidative damage in the liver and kidneys, the oxidative damage models were established in vitro and in vivo, and the control group and TE intervention groups were also set up. A significant elevation was observed in Cd concentration and the level of alanine transaminase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (CR), and uric acid (UA) in the serum of CdCl2-treated rats compared with the control group, by contrast, these values were reduced following TE intervention. Moreover, it was found that exposure to CdCl2 decreased the superoxide dismutase (SOD) activity, glutathione (GSH) level, and catalase (CAT) activity and raised the malondialdehyde (MDA) level in serum, liver tissues, kidney tissues, and HepG2 cells, which can be reversed by TE to mitigate the oxidative damage. In addition, TE exerted an inhibitory effect on cell apoptosis in both liver and kidneys brought on by CdCl2 intoxication, as manifested by the downregulation of Caspase-3 protein and the up-regulation of B-cell lymphoma gene 2 (Bcl-2) protein after TE treatment. Altogether, our study reinforces previous findings that CdCl2 exposure disrupted the redox homeostasis, leading to oxidative damage in both liver and kidneys. More importantly, our findings suggest that the hepatorenal protective effect of TE against CdCl2 toxicity is implicated in the inhibition of oxidative stress and apoptosis.

Quercetin improves the impairment in memory function and attenuates hippocampal damage in cadmium chloride-intoxicated male rats by suppressing acetylcholinesterase and concomitant activation of SIRT1 signaling

This study examined if quercetin (QUR) prevents cadmium chloride (CdCl2)-induced hippocampal neurotoxicity in male rats by activating sirtuin-1 (SIRT1). Rats were divided into control, control + QUR, CdCl2, CdCl2 + QUR, and CdCl2 + QUR + EX-527 (a SIRT1 inhibitor). QUR (25 mg/kg) and CdCl2 (0.5 mg/kg) were administered orally for 30 days. QUR improved the structure of the dental gyrus and the spatial and avoidance memories of CdCl2-treated rats. Besides, QUR inhibited oxidative stress, inflammation, and apoptosis, increased glutathione (GSH) and manganese superoxide dismutase (MnSOD), acetylcholine (Ach), and brain-derived neurotrophic factor (BDNF) levels but downregulated acetylcholine esterase (AchE) in the hippocampi of rats. These effects were associated with higher hippocampal expression and activities of SIRT1 and decreased acetylation of Nrf2, NF-κB p65, and p53. Except for Ach and AChE, all these effects were prevented by EX-527. In conclusion, QUR prevents CdCl2 hippocampal neurotoxicity by activating SIRT1 and inhibiting AchE.

Kaempferol prevents cadmium chloride-induced liver damage by upregulating Nrf2 and suppressing NF-κB and keap1.

This study evaluated the protective effect of kaempferol, a natural flavonoid, against cadmium chloride (CdCl2)-induced liver damage and examined the possible anti-inflammatory and antioxidant mechanisms of protection. Adult male rats were divided into 4 groups (each of 8 rats) as control, kaempferol (50 mg/kg/day orally), CdCl2 (15 ppm/day), and CdCl2 (15 ppm/day) + kaempferol (50 mg/kg/day). All treatments were given for 30 days. With no effect on attenuating the reduced food intake, kaempferol significantly increased body weight and lowered serum levels of liver injury markers including bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase 1 (γ-GTT1) in the CdCl2-treated rats. It also restored normal liver architectures, prevented hepatocyte, loss, and swelling and reduced inflammatory cell infiltration. These effects were associated with a reduction in mitochondrial permeability transition pore, as well as in the expression of cytochrome-c and cleaved caspase-3, markers of mitochondrial damage, and intrinsic cell death. In both the control positive and CdCl2-treated rats, kaempferol significantly lowered the hepatic levels of reactive oxygen species, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), Interleukine-6 (IL-6), and the nuclear activity and localization of NF-κB p65. Besides, kaempferol significantly increased the hepatic total and nuclear levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1, as well as levels of superoxide dismutase (SOD) and reduced glutathione (GSH) but reduced the cytoplasmic protein levels of keap1. In conclusion, the protective effect of kaempferol against CdCl2-induced hepatic damage is mediated by antioxidant and anti-inflammatory effects driven by upregulating Nrf2/HO-1 axis and suppressing the NF-κB p65 and keap1.

Quercetin alleviates cadmium chloride-induced renal damage in rats by suppressing endoplasmic reticulum stress through SIRT1-dependent deacetylation of Xbp-1s and eIF2α

Endoplasmic reticulum (ER) stress plays a key role in cadmium chloride (CdCl2)-induced nephrotoxicity. Sirtuin-1 (SIRT1) is a potent inhibitor of ER stress. In this study, we examined whether the protective effect of quercetin (QUR) against CdCl2-induced nephrotoxicity in rats involved modulation of SIRT1 and/or ER stress. Adult male rats were divided into five groups (n = 8, each) and treated for eight weeks as follows: control, control + QUR, CdCl2, CdCl2 + QUR, and CdCl2 + QUR + EX-527 (a SIRT1 inhibitor). Treatment of rats with QUR preserved the glomerulus and tubule structure, attenuated interstitial fibrosis, increased creatinine excretion, and reduced urinary levels of albumin, N-acetyl-β-D-glucosaminidase, and β2-microglobulin in CdCl2-treated rats. Concomitantly, QUR increased renal levels of Bcl-2, reduced mRNA levels of CHOP, and protein levels of Bax, caspase-3, and cleaved caspase-3, but failed to reduce the mRNA levels of GRP78, PERK, eIf2α, ATF-6, and xbp-1. QUR also reduced the renal levels of reactive oxygen species, tumour necrosis factor, and interleukin-6 and the nuclear activity of NF-κB in the control and CdCl2-treated rats but increased the nuclear activity of Nrf2 and levels of glutathione and manganese superoxide dismutase. Additionally, QUR increased the total levels and nuclear activity of SIRT1 and reduced the acetylation of eIf2α and xbp-1. The nephroprotective effects of QUR were abrogated by treatment with EX-527. Thus, QUR ameliorated CdCl2-induced nephrotoxicity through antioxidant and anti-inflammatory effects and suppressed ER stress mediated by the upregulation or activation of SIRT1-induced deacetylation of Nrf2, NF-κB p65, eIF2α, and xbp-1.

Kaempferol protects against cadmium chloride-induced hippocampal damage and memory deficits by activation of silent information regulator 1 and inhibition of poly (ADP-Ribose) polymerase-1

The neuroprotective effect of Kaempferol against cadmium chloride (CdCl2) -induced neurotoxicity is well reported. The silent information regulator 1 (SIRT1) and poly (ADP-Ribose) polymerase-1 (PARP1) are two related cellular molecules that can negatively affect the activity of each other to promote or inhibit cell survival, respectively. It is still largely unknown if the neurotoxicity of CdCl2 or the neuroprotection of Kaempferol are mediated by modulating SIRT1 and/or PAPR1 activities. In this study, we tested the hypothesis that CdCl2-induced memory deficit and hippocampal damage are associated with downregulation/inhibition of SIRT1 and activation of PAPR1, an effect that can be reversed by co-treatment with Kaempferol. Rats (n = 12/group) were divided into 4 groups as control, control + Kaempferol (50 mg//kg), CdCl2 (0.5 mg/kg), and CdCl2 + Kaempferol. All treatments were administered orally for 30 days daily. As compared to control rats, CdCl2 reduced rat's final body weights (21.8%) and their food intake (30%), induced oxidative stress and apoptosis in their hippocampi, and impaired their short and long-term recognition memory functions. Besides, the hippocampi of CdCl2-treated rats had higher levels of TNF-α (197%), and IL-6 (190%) with a concomitant increase in nuclear activity and levels of NF-κB p65 (721% & 554%). Besides, they showed reduced nuclear activity (53%) and levels (74%) of SIRT1, higher nuclear activity and levels of PARP1 (292% & 138%), increased nuclear levels of p53 (870%), and higher acetylated levels of NF-κB p65 (513%), p53 (644%), PARP1 (696%), and FOXO-2 (149%). All these events were significantly reversed in the CdCl2 + Kaempferol-treated rats. Of note, Kaempferol also increased levels of MnSOD (73.5%), and GSH (40%), protein levels of Bcl-2 (350%), and nuclear activity (67%) and levels (46%) of SIRT1 in the hippocampi of the control rats. In conclusion, Kaempferol ameliorates CdCl2-induced memory deficits and hippocampal oxidative stress, inflammation, and apoptosis by increasing SIRT1 activity and inhibiting PARP1 activity.

Kaempferol Protects Against Cadmium Chloride-Induced Memory Loss and Hippocampal Apoptosis by Increased Intracellular Glutathione Stores and Activation of PTEN/AMPK Induced Inhibition of Akt/mTOR Signaling.

This study investigated the protective effect of Kaempferol against CdCl2-induced hippocampal damage and memory deficit in rats and investigated if such effects involve modulating the activity of AMPK/PTEN/Akt/mTOR axis. Adult male rats (n = 12/group) were divided into control or CdCl2-treated rats received the vehicle of Kaempferol for consecutive 6 weeks. Also, hippocampal cells were treated with CdCl2 in the presence or absence of Kaempferol for 24 h with or without 1 h pre-incubation with compound C, an AMPK inhibitor or with bpV a PTEN inhibitor. Kaempferol improved the behavioral of CdCl2-treated rats, preserved hippocampus structure and reduced hippocampal levels of ROS and protein levels of Bax and cleaved caspase-3. In both control and CdCl2-treated rats, Kaempferol significantly increased hippocampal levels of GSH levels and protein levels of Nfr2, Bcl2 and synaptic proteins (SNAP-25, PSD-25, and synapsin). Concomitantly, it increased the activity of PTEN and AMPK and subsequently, decreased the activity of Akt and mTOR. In cultured cells, individual pharmacological inhibition of PTEN by bpv or AMPK of compound C (CC) partially prevented the stimulatory effect of Kaempferol on Akt/mTOR and its inhibitory effect on cell death whereas a combination of both inhibitors completely prevented this. Also, inhibition of PTEN alone completely abolished the inhibitory effect of Kaempferol by synaptic proteins, whereas inhibition of AMPK completely abolished its stimulatory effect of Nfr2. In conclusion, Kaempferol protects against CdCl2-induced memory deficits and hippocampal apoptosis by its antioxidant potential and inhibition of Akt/mTOR axis and requires the activation of PTEN and AMPK.

Rutin hydrate inhibits apoptosis in the brains of cadmium chloride-treated rats via preserving the mitochondrial integrity and inhibiting endoplasmic reticulum stress

ABSTRACTRecent evidence has suggested that cadmium (Cd) ions-induced neurotoxicity is associated with increased oxidative stress and mitochondrial-dependent and endoplasmic reticulum (ER) stress-induced apoptosis. This study aimed to investigate if rutin hydrate (RH), a well-reported neuroprotective and an antioxidant flavonoid, can ameliorate cadmium chloride (CdCl2)-induced neurotoxicity by inhibiting the resultant ER stress. Rats were divided into 4 groups (n = 16/group) of control, control + RH (100 mg/kg), CdCl2 (5 mg/kg), and CdCl2 + RH. All treatments were administered orally for 30 days, on daily basis. Brain homogenates from CdCl2-treated rats showed increased oxidative stress and induced activation of ER stress characterized by increasing mRNA and protein levels of GRP78, ATF-6, CHOP and Xbp-1 and protein levels of p-elF2α, p-JNK1/2 and cleaved caspase-12. Also, CdCl2 significantly reduced Bcl-2, enhanced Bax translocation to the mitochondrial membrane, increased cytoplasmic levels of cytochrome-C and caspase-3, and reduced mitochondrial membrane potential (Δψm) (increased Vmax and reduced time to Vmax). In contrast, RH significantly enhanced levels GSH and activities of SOD, GSH-Px, decreased levels of MDA and inhibited mitochondrial permeability transition pore (mtPTP) in the brains of both control and CdCl2-treated rats. Interestingly, in brain homogenates of CdCl2-treated rats only, RH reduced all markers of ER stress, increased Bcl-2, reduced mitochondrial Bax translocation and improved mitochondrial coupling. It also reduced cytosolic levels of cytochrome-C, cleaved caspase-3, and cleaved caspase-12. Overall, these findings support the efficiency of RH to inhibit ER stress in brains CdCl2-treated rats which is added to its existing mechanisms of neuroprotection.Abbreviations: ATF-6: activating transcription factor-6; Bax: Bcl-associated x; BBB: blood-brain barrier; Bcl-2: B-cell lymphoma 2; BiP: immunoglobulin heavy-chain-binding protein; [Ca2+]i: intracellular free Ca2+ concentration; Cd: cadmium; CdCl2: cadmium chloride; CHOP: CCAAT/enhancer-binding protein-homologous protein; CMC: carboxymethyl cellulose; Δψm: mitochondrial membrane potential; elF2α: phospho-eukaryotic translation initiation factor 2-alpha; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERK1/2: extracellular signal-regulated kinases 1 and 2; GADD 153: growth arrest and DNA damage-inducible protein 153; GRP78, 78 kDa glucose-regulated protein; GSH: reduced glutathione; GSH: reduced glutathione; GSH-Px: glutathione peroxidase; GSSG: glutathione disulfide (oxidized glutathione); IRE-1: inositol-requiring enzyme-1; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; mTOR: Akt/mammalian target of rapamycin; mtPTP: mitochondrial permeability transition pore; ONOO−: peroxynitrite; PCR: polymerase chain reaction; PERK: protein kinase RNA-like ER kinase; p-JNK: phospho-JNK; qPCR: quantitative PCR; RCR: respiratory control ratio; RH: rutin hydrate; RHoGDI: Rho-GDP-dissociation inhibitor; ROS: reactive oxygen species; SOD: superoxide dismutase; UPR: unfolded protein response; VDAC: voltage-dependent anion channel; Vmax: maximal rate of pore opening; Xbp-1: X-box binding protein 1.

Trans-resveratrol Inhibits Tau Phosphorylation in the Brains of Control and Cadmium Chloride-Treated Rats by Activating PP2A and PI3K/Akt Induced-Inhibition of GSK3β.

This study investigated if resveratrol (RES) can protect against cadmium chloride (CdCl2)-induced memory loss and Tau protein hyperphosphorylation in rats and explored its effect on AMPK/PI3K/Akt signaling pathway. Rats (n = 10/group) were divided into seven groups as: control; control + DMSO; control + LY294002, a selective PI3K inhibitor (0.25µg/100g, i.p); control + RES (300mg/kg, orally); CdCl2 (5mg/kg, orally); CdCl2 + RES and CdCl2 + RES + LY294002. All treatments were carried out for 30 consecutive days ona daily basis. RES improved both short and long-term memory as analyzed by novel object recognition task and significantly increased brain levels of glutathione in both control and CdCl2-treated rats. It also inhibited ROS levels of malondialdehyde in the brains of CdCl2-treated rats. In both groups, RES decreased the phosphorylation rate of Tau at Ser199 and Ser296. Concomitantly, it significantly increased protein levels of p-GSK3β (Ser9) and p-PP2A and decreased p-GSK3β (Tyr216). Also, RES activated PI3K/Akt signaling pathway in both control and CdCl2 treated rats by increasing levels of p-PI3K (Tyr607) and p-Akt (Ser473). This was concomitant with significant increase in the levels of AMPK and p-AMPK, known upstream regulators of PI3K/Akt signaling pathway. Interestingly, all the above listed beneficial effects of RES, except their effect on AMPK/p-AMPK, were completely abolished in CdCl2 + RES + LY294002-treated rats. In conclusion, in addition to its antioxidant potential, RES inhibits Tau phosphorylation in rat's brain by activating PP2A protein and AMPK/PI3K/Akt-induced inhibition of GSK3β.

Effect of Aqueous Extract of Glycyrrhiza glabra on the Biochemical Changes Induced by Cadmium Chloride in Rats.

Twenty four rats were divided into four groups (6 rats/group): 1-control group; 2-licorice (Glycyrrhiza glabra) extract: rats administered with an oral dose of licorice (3mg/ml/kg/day) using stomach tube for 4weeks; 3-cadmium chloride group: rats administered with an oral dose of CdCl2 (10mg/kg/day) using stomach tube for 4weeks; and 4-licorice extract + CdCl2 group: rats administered orally with both licorice (3mg/ml/kg/day) and CdCl2 (10mg/kg/day) using stomach tube for 4weeks. Administration of CdCl2 induced significant increase in thiobarbituric acid reactive substance (TBARS), paraoxonase-1 (proxon-1), caspase-3 (casp-3) activities, and significant decrease in superoxide dismutase (SOD), catalase (CAT) activities, and glutathione (GSH) content in hepatic tissue. Significant increase in TBARS and kidney injury molecule-1 (KIM-1) and significant decrease in SOD, CAT activities, and GSH content in renal tissue were recorded. Significant increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) activities, urea, creatinine, and significant decrease in butyryl choline esterase (BChE), total triiodothyronine (T3), and total thyroxin (T4) were recorded in serum. Histological investigation of renal cells showed vacuolations of endothelium lining glomerular tuffs and vacuolations of epithelium lining renal tubules. Investigation of ovarian tissue showed dilatation of interstitial blood vessels and congestion of multiple corpus luteum in CdCl2-treated rats. Significant improvements in the biochemical and histological changes were observed in CdCl2 + licorice extract group. It could be concluded that licorice extract alleviates the hazardous effects of cadmium chloride, which may be attributed to its antioxidant properties.

Mitigation of cadmium-induced lung injury by Nigella sativa oil.

Induction of oxidative stress and inflammation are considered the primary mechanism of cadmium (Cd) toxicity. Nigella sativa (NS) seeds and their oil (NSO) have been reported to possess antioxidant and anti-inflammatory potential. This study was conducted to assess the protective effect of NSO on Cd-induced lung damage in rat. Forty adult male Wistar rats were divided equally into 4 groups. Animals in groups I, II, and III received 1ml of isotonic saline intraperitoneally (IP), 2mg/kg of cadmium chloride (CdCl2) dissolved in isotonic saline IP, and 1ml/kg of NSO by gastric gavage, respectively. Group IV rats received NSO an hour prior to CdCl2 administration via the same routes and doses as previously described. All animals were treated for 28days. At the end of the study, animals were sacrificed; lungs were harvested for histopathological studies using light and electron microscopy. Saline-treated and NSO-treated rats showed normal lung parenchyma. However, CdCl2-treated rats showed massive degenerative changes in alveolar epithelial lining, disrupted interalveolar septa, and hemolytic debris in alveoli. Rats treated with both NSO and CdCl2 (group IV) showed amelioration of most Cd-induced lung damage with minimal histopathological changes in lung architecture. This study elucidates the protective effects of NSO on Cd-induced lung injury in rats and highlights the possibility of using NSO as a protective agent in individuals at high risk of Cd-induced lung toxicity.

Noninvasive Biomarker Candidates for Cadmium-Induced Nephrotoxicity by 2DE/MALDI-TOF-MS and SILAC/LC-MS Proteomic Analyses.

Cadmium (Cd(2+)) is a major environmental pollutant that induces cytotoxicity by heavy-metal accumulation. Prolonged Cd(2+) exposure leads to cell damage by oxidative stress mainly in the kidneys, a critical organ for detoxification. To identify reliable on invasive protein biomarkers for Cd(2+)-induced nephrotoxicity, we performed 2-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization time of flight mass spectra and stable isotope labeling by amino acids in cell culture/liquid chromatography-mass spectrometry analyses using conditioned media (CM) of HK-2 human kidney epithelial cells treated with CdCl2. Here, we identified heat shock cognate 71 kDa protein isoform1 (HSPA8) and α-enolase (ENO1) as potential biomarker candidates for the evaluation of Cd(2+)-induced nephrotoxicity. Treatment with CdCl2 increased the protein level of HSPA8 in CM and lysates of HK-2 cells. The mRNA level of HSPA8 was also increased by CdCl2 treatment, indicating transcriptional regulation. The level of ENO1 was increased in CM, but not in lysates of CdCl2-treated HK-2 cells. CdCl2 did not affect the mRNA level of ENO1. We provide evidence that the increases of HSPA8 and ENO1 in CM were due to Cd(2+)-induced cell death through oxidative stress. The increases of HSPA8 and ENO1 levels were also detected in CM of HK-2 cells treated with other nephrotoxic agents, such as HgCl2, NaAsO2, cisplatin, amphotericin B, and cyclosporine A. Urine and kidney tissues of CdCl2-treated rats showed increased levels of HSPA8. Taken together, this study identified HSPA8 and ENO1 as noninvasive biomarker candidates by 2 comparative proteomic analyses. These new biomarker candidates may have potential as alternatives to traditional biomarkers for the efficient and sensitive assessment of nephrotoxicity.

Increased Oxidative DNA Damage in Placenta Contributes to Cadmium-Induced Preeclamptic Conditions in Rat.

To explore the possible mechanisms of cadmium (Cd)-induced preeclamptic conditions in rats. In the present study, we introduced the in vivo model of preeclampsia by giving intraperitoneal injections of cadmium chloride (CdCl2) to pregnant rats from gestational day (GD) 4 to 19. Maternal body weights were recorded on GD 0, 14, and 20, while their systolic blood pressures (SBPs) monitored on GD 3, 11, and 18. On GD 20, rats were sacrificed and the specimens were collected. The morphological changes of placenta and kidney tissues of pregnant rats were examined by hematoxylin and eosin staining assay. Blood Cd level was detected by inductively coupled plasma mass spectrometry. Total antioxidant capacity (TAC) was evaluated using FRAP method and total nitrite (NOx) was detected with Griess reagent. Antioxidative factors and DNA damage/repair biomarkers were measured by real-time qPCR, western blot or immunohistochemistry study. The current results showed that CdCl2-treated pregnant rats developed preeclampsia (PE)-like manifestations, such as hypertension, albuminuria, with decreased TAC and increased blood Cd level, and pro-oxidative/antioxidative or DNA damage/repair biomarkers. Our study demonstrated that increased oxidative DNA damage in placenta could contribute to Cd-induced preeclamptic conditions in rat.

Protective Role of Nigella Sativa Oil on Spermatogenesis and Testicular Structure in Cadmium Intoxicated Rats

Cadmium (Cd) is a common environmental pollutant associated with many industrial processes. Considering the high sensitivity of the testicular tissue to Cd insult, prevention and/or therapeutic intervention is of major concern. Previous experimental evidences indicated the involvement of oxidative stress in Cd-mediated tissue damage. The present study investigated the protective role of Nigella Sativa Oil (NSO) against the toxic effect of cadmium chloride (CdCl2) on rat testes.Forty adult male albino rats weighing 240-280 g were assigned into four groups: Group I(Control rats), Group II (NSO-treated rats), Group III (CdCl2-treated rats) and Group IV(rats treated with CdCl2 and NSO). Cadmium chloride was injected in a dose of 2mg/kg bw dissolved in isotonic saline intraperitoneal, whileNSO was administered in a dose of 1 ml/kg bwby gastric gavage.The present study found that administration of CdCl2 induced marked structural derangement in the seminiferous tubules of the rats’ testes associated with significant drop of spermatogenesis score. Concomitant administration of NSO and CdCl2 was associated with markedreduction in the adverse structural changes seen in the testes of CdCl2-intoxicated ratsbesides preservation of spermatogenesis.

Gene expression profiling in rat kidney after intratracheal exposure to cadmium-doped nanoparticles

While nephrotoxicity of cadmium is well documented, very limited information exists on renal effects of exposure to cadmium-containing nanomaterials. In this work, “omics” methodologies have been used to assess the action of cadmium-containing silica nanoparticles (Cd-SiNPs) in the kidney of Sprague-Dawley rats exposed intratracheally. Groups of animals received a single dose of Cd-SiNPs (1 mg/rat), CdCl2 (400 μg/rat) or 0.1 ml saline (control). Renal gene expression was evaluated 7 and 30 days post exposure by DNA microarray technology using the Agilent Whole Rat Genome Microarray 4x44K. Gene modulating effects were observed in kidney at both time periods after treatment with Cd-SiNPs. The number of differentially expressed genes being 139 and 153 at the post exposure days 7 and 30, respectively. Renal gene expression changes were also observed in the kidney of CdCl2-treated rats with a total of 253 and 70 probes modulated at 7 and 30 days, respectively. Analysis of renal gene expression profiles at day 7 indicated in both Cd-SiNP and CdCl2 groups downregulation of several cluster genes linked to immune function, oxidative stress, and inflammation processes. Differing from day 7, the majority of cluster gene categories modified by nanoparticles in kidney 30 days after dosing were genes implicated in cell regulation and apoptosis. Modest renal gene expression changes were observed at day 30 in rats treated with CdCl2. These results indicate that kidney may be a susceptible target for subtle long-lasting molecular alterations produced by cadmium nanoparticles locally instilled in the lung.

IMPROVING THE CADMIUM-INDUCED CENTRIACINAR EMPHYSEMA MODEL IN RATS BY CONCOMITANT ANTI-OXIDANT TREATMENT

1. The aim of the present study was to perform an evolutionary analysis of the morphometrical, biochemical and functional parameters of centriacinar emphysema induced by cadmium chloride (CdCl2) in rats and to determine the effects of concomitant N-acetylcysteine (NAC) administration. 2. Male Wistar rats were instilled orotracheally with either CdCl2 (n = 24) or saline (n = 24). One group of rats, consisting of both CdCl2- and saline-treated rats, was fed a normal diet (n = 24), whereas the other group received NAC (n = 24). 3. Changes in inspiratory capacity (IC), lung compliance (CL), expiratory flow at 75% (F75), forced vital capacity (FVC) and hydroxyproline content were assessed 2, 8, 21 and 45 days after instillation. Polymorphonuclear cells were evaluated 2 and 8 days after instillation and the mean linear intercept (Lm) was determined at 21 and 45 days. 4. Over time, CdCl2 instillation causes several changes that are bound up with centriacinar emphysema. The concomitant administration of NAC to CdCl2-treated rats partially reversed Lm at 21 days compared with CdCl2 alone (115 +/- 2 vs 127 +/- 2, respectively; P < 0.05). However, 45 days after instillation, NAC improved lung function in CdCl2-treated rats compared with that in the saline-treated control group (IC 14.64 vs 15.25, respectively (P = 0.054); FVC 16.94 vs 16.28, respectively (P = 0.052), F75 31.41 vs 32.48, respectively (P = 0.062)). In addition, 45 days after instillation, NAC reduced lung collagen content in both the saline-treated control (100 vs 81% alone and in the presence of NAC, respectively) and CdCL2-treated groups (213 vs 161% alone and in the presence of NAC, respectively). In addition, although the results were not significant, NAC tended to reduce Lm and enhance CL in NAC + CdCl2-treated rats. 5. In conclusion, NAC partially improved emphysematous changes and reduced collagen deposition, which diminished the CdCl2-induced fibrotic component of centriacinar emphysema.

Protective Effect Of Melatonin, Methionine And Zink On Cadmium Nephrotoxicity: Histopathologically, Histochemically And AgNORs Quantitation

Cadmium (Cd) is a highly toxic heavy metal that is naturally present in the environment. Chronic exposure to Cd causes hepatotoxicity and nephrotoxicity. The present study aimed to study the protective effect of melatonin, methionine and zinc against histopathological, histochemical and proliferative effects of cadmium on the kidney of rats. A total of 80 female albino rats were included in this study and divided into 8 groups. They were injected intraperitonealy with cadmium chloride (CdCl2) (2 mg / kg b.w.), melatonin (10 mg / kg b.w.), methionine (42.8 mg / b.w.) or zinc (20 mg / kg b.w.) with or without CdCl2 daily for 10 days. Treatment with CdCl2 induced marked tubular cell degeneration with large areas of interstitial hemorrhage.There were marked destruction of the brush borders with decrease in glycogen and protein contents of the degenerated tubules. AgNORs count significantly increased. Injection of melatonin or methionine to CdCl2 treated rats resulted in improvement of Cd-induced histopathological and histochemical changes. AgNORs count significantly decreased. Zinc injection partially protected the kidney from Cd-induced effects. In conclusion, melatonin and methionine have a more protective effect than zink against Cd nephrotoxicity.

Protective Effect Of Melatonin, Methionine And Zink On Cadmium Nephrotoxicity: Histopathologically, Histochemically And AgNORs Quantitation

Cadmium (Cd) is a highly toxic heavy metal that is naturally present in the environment. Chronic exposure to Cd causes hepatotoxicity and nephrotoxicity. The present study aimed to study the protective effect of melatonin, methionine and zinc against histopathological, histochemical and proliferative effects of cadmium on the kidney of rats. A total of 80 female albino rats were included in this study and divided into 8 groups. They were injected intraperitonealy with cadmium chloride (CdCl2) (2 mg / kg b.w.), melatonin (10 mg / kg b.w.), methionine (42.8 mg / b.w.) or zinc (20 mg / kg b.w.) with or without CdCl2 daily for 10 days. Treatment with CdCl2 induced marked tubular cell degeneration with large areas of interstitial hemorrhage.There were marked destruction of the brush borders with decrease in glycogen and protein contents of the degenerated tubules. AgNORs count significantly increased. Injection of melatonin or methionine to CdCl2 treated rats resulted in improvement of Cd-induced histopathological and histochemical changes. AgNORs count significantly decreased. Zinc injection partially protected the kidney from Cd-induced effects. In conclusion, melatonin and methionine have a more protective effect than zink against Cd nephrotoxicity.

Effect of pentoxifylline on CdCl2-induced nephrotoxicity in the rat.

We developed a rat model of cadmium (Cd)-induced nephrotoxicity and tried to prevent renal damage by treating the animals with pentoxifylline (PTX). Sprague-Dawley (SD) rats given CdCl2 3.0 mg/kg sc, daily for 2 wk showed evidences of renal proximal tubular damage, including significant increases in urine volume, urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), and fractional excretion of sodium (FENa), and a decrease in the percentage of tubular reabsorption of phosphate (%TRP). PTX significantly improved the urinary excretion of NAG and %TRP. Urine volume was increased threefold in the CdCl2-treated rats and fivefold in the Cd + PTX-treated rats, respectively, as compared with saline-treated control. Total protein, AAP, and creatinine clearance, showed no change after PTX administration. Concentration of Cd in the renal cortex was three times higher than that in the renal medulla, but there were no differences in concentration between the Cd-treated rats and the Cd + PTX-treated rats. Our animal model was useful in studying the renal tubular damage produced by cadmium. PTX appears useful for improving the nephrotoxicity of Cd.

Absence of in vivo lipid peroxidation in CdCl 2-treated rats as measured by exhaled pentane

We have used a new sensitive and non-invasive method, measuring exhaled pentane production, to evaluate in vivo lipid peroxidation (LP) in rats treated i.p. with CdCl 2. Pentane, a by-product of LP, was measured 2, 6, 12, 24, 72 h and 8, 15, 22 days after treatment. No increase in pentane production was detected at these time periods for cadmium (Cd) doses reported to increase malondialdehyde (MDA) in major organs such as liver and lungs. This suggests that Cd cannot induce LP in vivo, but a prooxidant state which fragilized the tissues. Cd could also cause changes either in the production or in the metabolism of LP by-products (e.g. pentane).

Relationship between testis injury and tocopherols in vivo in rat intoxicated by cadmium.

To examine the mechanism of the enhancement of tocopherol concentration in the testis of rats when the inflammation was induced by CdCl2 administration, we measured concentrations of tocopherol homologues in the serum, liver and testis of CdCl2-treated rats as a function of time. In the serum, α-and β-tocopherol concentrations increased significantly at 15 h after CdCl2 administration, and those levels in the testis increased significantly at 24 h or 48 h after the metal administration. No significant change of the concentrations of tocopherols in the liver was seen by CdCl2 administration. On the other hand, the incorporations of 3H-α-tocopherol into the testis and the epididymis, when injected into the rat treated with CdCl2, increased 6-and 8-fold as compared with those in control rats, respectively. These results indicate that α-tocopherol is actively incorporated into the inflammed testis via blood stream.