Increase In Relative Liver Weight Research Articles

Mode of action analysis for fluxapyroxad-induced rat liver tumour formation: evidence for activation of the constitutive androstane receptor and assessment of human relevance

The fungicide fluxapyroxad (BAS 700 F) has been shown to significantly increase the incidence of liver tumours in male Wistar rats at dietary levels of 1500 and 3000 ppm and in female rats at a dietary level of 3000 ppm via a non-genotoxic mechanism. In order to elucidate the mode of action (MOA) for fluxapyroxad-induced rat liver tumour formation a series of in vivo and in vitro investigative studies were undertaken. The treatment of male and female Wistar rats with diets containing 0 (control), 50, 250, 1500 and 3000 ppm fluxapyroxad for 1, 3, 7 and 14 days resulted in a dose-dependent increases in relative weight at 1500 and 3000 ppm from day 3 onwards in both sexes, with an increase in relative liver weight being also observed in male rats given 250 ppm fluxapyroxad for 14 days. Examination of liver sections revealed a centrilobular hepatocyte hypertrophy in some fluxapyroxad treated male and female rats. Hepatocyte replicative DNA synthesis (RDS) was significantly increased in male rats given 1500 and 3000 ppm fluxapyroxad for 3 and 7 days and in female rats given 50–3000 ppm fluxapyroxad for 7 days and 250–3000 ppm fluxapyroxad for 3 and 14 days; the maximal increases in RDS in both sexes being observed after 7 days treatment. The treatment of male and female Wistar rats with 250–3000 ppm fluxapyroxad for 14 days resulted in significant increases in hepatic microsomal total cytochrome P450 (CYP) content and CYP2B subfamily-dependent enzyme activities. Male Wistar rat hepatocytes were treated with control medium and medium containing 1–100 μM fluxapyroxad or 500 μM sodium phenobarbital (NaPB) for 4 days. Treatment with fluxapyroxad and NaPB increased CYP2B and CYP3A enzyme activities and mRNA levels but had little effect on markers of CYP1A and CYP4A subfamily enzymes and of the peroxisomal fatty acid β-oxidation cycle. Hepatocyte RDS was significantly increased by treatment with fluxapyroxad, NaPB and 25 ng/ml epidermal growth factor (EGF). The treatment of hepatocytes from two male human donors with 1–100 μM fluxapyroxad or 500 μM NaPB for 4 days resulted in some increases in CYP2B and CYP3A enzyme activities and CYP mRNA levels but had no effect on hepatocyte RDS, whereas treatment with EGF resulted in significant increase in RDS in both human hepatocyte preparations. Hepatocytes from male Sprague-Dawley wild type (WT) and constitutive androstane receptor (CAR) knockout (CAR KO) rats were treated with control medium and medium containing 1–16 μM fluxapyroxad or 500 μM NaPB for 4 days. While both fluxapyroxad and NaPB increased CYP2B enzyme activities and mRNA levels in WT hepatocytes, only minor effects were observed in CAR KO rat hepatocytes. Treatment with both fluxapyroxad and NaPB only increased RDS in WT and not in CAR KO rat hepatocytes, whereas treatment with EGF increased RDS in both WT and CAR KO rat hepatocytes. In conclusion, a series of in vivo and in vitro investigative studies have demonstrated that fluxapyroxad is a CAR activator in rat liver, with similar properties to the prototypical CAR activator phenobarbital. A robust MOA for fluxapyroxad-induced rat liver tumour formation has been established. Based on the lack of effect of fluxapyroxad on RDS in human hepatocytes, it is considered that the MOA for fluxapyroxad-induced liver tumour formation is qualitatively not plausible for humans.

Evaluation of Hepatic Detoxification Effects of Enteromorpha prolifera Polysaccharides against Aflatoxin B1 in Broiler Chickens.

Aflatoxin B1 (AFB1) is a major risk factor in animal feed. Seaweed (Enteromorpha prolifera)-derived polysaccharides (SDP) are natural antioxidants with multiple biological functions, which may have an in vivo detoxification effect on AFB1. The current study aimed to evaluate whether SDP could mitigate AFB1-induced hepatotoxicity in broilers. A total of 216 chickens (male, 5 weeks old) were randomly allocated to three groups with differing feeding patterns, lasting 4 weeks: (1) control group (CON, fed a basal diet); (2) AFB1 group (fed a basal diet mixed with 0.1 mg/kg AFB1); and (3) AFB1 + SDP group (AFB1 group + 0.25% SDP). The results showed that dietary SDP improved the liver function-related biochemical indicators in serum, and reversed the increase in relative liver weight, hepatic apoptosis and histological damage of broilers exposed to AFB1. SDP treatment also reduced the activity and mRNA expression of phase I detoxification enzymes, while increasing the activity and mRNA expression of phase II detoxification enzymes in the livers of AFB1-exposed broilers, which was involved in the activation of p38 mitogen-activated protein kinase (p38MAPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. In conclusion, dietary SDP alleviated AFB1-induced liver injury of broilers through inhibiting phase I detoxification enzymes and upregulating p38MAPK/Nrf2-mediated phase II detoxification enzymes pathway.

Exposure to GenX and Its Novel Analogs Disrupts Hepatic Bile Acid Metabolism in Male Mice.

Due to its wide usage and recent detection in environmental matrices, hexafluoropropylene oxide dimer acid (HFPO-DA, commercial name GenX) has attracted considerable attention. Here, we explored and compared the toxicity of GenX and its novel analogs with that of perfluorooctanoic acid (PFOA) to provide guidance on the structural design and optimization of novel alternatives to poly- and perfluoroalkyl substances (PFASs). Adult male BALB/c mice were continuously exposed to PFOA, GenX, perfluoro-2-methyl-3,6-dioxo-heptanoic acid (PFMO2HpA), and perfluoro-2-methyl-3,6,8-trioxo-nonanoic acid (PFMO3NA; 0, 0.4, 2, or 10 mg/kg/d) via oral gavage for 28 days. The PFOA, GenX, and PFMO3NA treatment groups showed an increase in relative liver weight, and bile acid metabolism was the most significantly affected pathway in all treatment groups, as shown via weighted gene coexpression network analysis. The highest total bile acid levels were observed in the 2 and 10 mg/kg/d PFMO3NA groups. The ratios of primary bile acids to all bile acids increased in the high-dose groups, while the ratios of secondary bile acids showed a downward trend. Thus, bile acid metabolism disorder may be a prominent adverse effect induced by exposure to GenX, its analogs, and PFOA. Results also showed that the hepatotoxicity of PFMO2HpA was lower than that of GenX, whereas the hepatotoxicity of PFMO3NA was stronger, suggesting that PFMO2HpA may be a potential alternative to GenX.

Effects of Combined Ethanol Extract of Anthocleista Vogelii and Alstonia Boonei Stem Barks on Liver Function Indices in Benign Prostatic Hyperplasia Induced

Objective: This study evaluated the effects of combined ethanol extract of Anthocleista vogelii and Alstonia boonei (CEAA) stem barks on the liver function indices of benign prostatic hyperplasia (BPH)-induced rats.Materials and Methods: Thirty (30) male Wistar rats were randomly grouped into five groups (n = 6). BPH was induced subcutaneously with 5 mg/kg/day of testosterone propionate in olive oil. Groups 1-3 served as normal, BPH control (untreated) and standard drug control respectively, while Groups 4 and 5 were BPH-induced rats and treated with 200 and 400 mg/kg/day of the CEAA respectively after one hour of the BPH induction. After twenty-eight days of treatments, biochemical and histopathological analyses were conducted using standard analytical procedures.Results: The acute toxicity result of CEAA indicated no mortality or adverse reactions. Significant body weight change was only observed in the first week from the group-administered 200 mg/kg/day of CEAA. Liver damage was evident in the BPH control characterized by significant (P<0.05) increase in relative liver weight and liver enzymes’ (AST, ALT, ALP) activities but a reduction in total protein and globulin levels. Treatment with CEAA attenuated the liver damage by significantly (P<0.05) reducing the elevated relative liver weight and liver enzyme function activities and elevated total protein and globulin levels.Conclusion: The revealed that the combined ethanol extract of Anthocleista vogelii and Alstonia boonei (CEAA) stem barks possess hepatoprotective effects that could improve liver integrity and functions in BPH induced rats.
 Keywords: Benign prostatic hyperplasia, liver marker indices, Anthocleista vogelii, Alstonia boonei, liver histomorphology

EFFECT OF FLAXSEED EXTRACT ON THE LIVER HISTOLOGICAL STRUCTURE IN STREPTOZOTOCIN INDUCED DIABETIC RATS

Introduction: Diabetes mellitus has become a serious warning to mankind health all over the world. The management goal of diabetes is to keep blood glucose levels as close as possible to healthy individuals. Medications used to treat diabetes are usually associated with complications and may cause different side effects. Many traditional anti-diabetic plants have become popular in the management of diabetes mellitus. Flaxseed has been used as traditional medicine for centuries. Objective: This study aimed to evaluate the hepatoprotective effects of flaxseed extract in streptozotocin (STZ)-induced diabetic rats. Methods: Diabetes mellitus was induced in Sprague-Dawley rats using a single injection of streptozotocin (60 mg/kg i.p.). The rats were divided into five groups of 8 rats each. Group NC, normal control rats; Group NF, normal rats treated with flaxseed extract (400 mg/kg); Group DC, diabetic control rats; Group DG, diabetic rats treated with glibenclamide (0.6 mg/kg); Group DF, diabetic rats treated with flaxseed extract (400 mg/kg); for 4 weeks. Results: There were significant increase in relative liver weight, blood glucose levels in DC group comparing to NC group (p<0.05). The disturbance of these parameters was ameliorated in DF and DG groups. Histological observation revealed congestion of central veins, degeneration of hepatocytes, and reduced glycogen granules in DC group. These pathological changes were ameliorated in the flaxseed extract and glibenclamide treated rats. Conclusion: Flaxseed extract may represent a candidate alternative treatment to control diabetes mellitus and its related hepatopathy.

Protective Effect of Zizyphus lotus L. (Desf.) Fruit against CCl4-Induced Acute Liver Injury in Rat.

In Morocco, “Zizyphus lotus L.” is one of the most widely and traditionally used plant species to treat various diseases, including liver disorders. The present study was conducted to evaluate the aqueous extract of Zizyphus lotus L. fruit against carbon tetrachloride- (CCL4-) induced liver damage in Wistar rats. The animals were daily treated with the aqueous extract of Zizyphus lotus L. fruit using two doses separately 200 and 400 mg/kg body weight for 14 days. CCL4 was injected intraperitoneally (1 ml/kg body weight) at two times, 7th and 14th days. At the end of the treatment, rats were sacrificed, and the blood was collected for the assessment of biochemical parameters. Moreover, the body weight as well as liver weight was determined. The injection of CCl4 to the rats induced various alterations such as the increase of relative liver weight, serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, triglycerides, very low-density lipoproteins, total cholesterol (slight increase), creatinine, urea, uric acid, and malondialdehyde. On the contrary, the effects of CCL4 lead to the reduction in serum levels of high-density lipoprotein. However, the daily administration of the aqueous extract of Zizyphus lotus L. fruit to the injected rats with CCL4 restored this abnormal variation in these biochemical parameters to normal values. Based on the results obtained in this study, it seems that the aqueous extract of Zizyphus lotus L. fruit has an hepatoprotective effect against hepatic lesions induced by CCL4 in rats.

Risk Assessment of Coumarin Intake in the Norwegian Population

Risk Assessment of Coumarin Intake in the Norwegian Population

Metazachlor: Mode of action analysis for rat liver tumour formation and human relevance

In a 2-year study the herbicide metazachlor (BAS 479H) was shown to significantly increase the incidence of liver tumours in female Wistar rats at a dietary level of 8000 ppm. As metazachlor is not a genotoxic agent, a series of in vivo and in vitro investigative studies were undertaken to elucidate the mode of action (MOA) for metazachlor-induced female rat liver tumour formation. Male and female Wistar rats were given diets containing 0 (control), 200 and 8000 ppm metazachlor for 3, 7, 14 and 28 days. The treatment of male rats with 200 and 8000 ppm metazachlor and female rats with 8000 ppm metazachlor resulted in significant increases in relative liver weight, which was associated with a centrilobular hepatocyte hypertrophy. Hepatocyte replicative DNA synthesis (RDS) was significantly increased in male rats given 8000 ppm metazachlor for 3 and 7 days and in female rats given 200 ppm metazachlor for 7–28 days and 8000 ppm metazachlor for 3–28 days. Significant increases in relative liver weight, centrilobular hepatocyte hypertrophy and hepatocyte RDS were also observed in male and female Wistar rats given and 500 ppm sodium phenobarbital (NaPB) for 3–28 days. The treatment of female Wistar rats with either 8000 ppm metazachlor for 7 days or with 500 ppm NaPB for 3 and 7 days resulted in the nuclear translocation of the hepatic constitutive androstane receptor (CAR). Treatment of male and female Wistar rats with 8000 ppm metazachlor for 14 days resulted in significant increases in hepatic microsomal total cytochrome P450 (CYP) content, CYP2B subfamily-dependent enzyme activities and mRNA levels, together with some increases in CYP3A enzyme activity and mRNA levels. The treatment of male Wistar rat hepatocytes with metazachlor (concentration range 0.5–50 μM) and NaPB (500 μM) for 4 days resulted in increased CYP2B enzyme activities and mRNA levels; with metazachlor and NaPB also producing significant increases in hepatocyte RDS levels. Studies were also performed with hepatocytes from male Sprague-Dawley wild type (WT) rats and CAR knockout (CAR KO) rats. While both treatment with metazachlor and NaPB for 4 days increased CYP2B enzyme activities and mRNA levels in WT rat hepatocytes, only minor effects were observed in CAR KO rat hepatocytes. Treatment with both metazachlor and NaPB only increased RDS in WT but not in CAR KO rat hepatocytes. The treatment of hepatocytes from two male human donors with 0.5–25 μM metazachlor or 500 μM NaPB for 4 days resulted in increases in CYP2B6 and CYP3A4 mRNA levels but had no effect on hepatocyte RDS. EGF as concurrently used positive control demonstrated the expected RDS response in all rat and human hepatocyte cultures. In conclusion, a series of in vivo and in vitro investigative studies have demonstrated that metazachlor is a CAR activator in rat liver, with similar properties to the prototypical CAR activator phenobarbital. A robust MOA for metazachlor-induced female rat liver tumour formation has been established. Based on the lack of effect of metazachlor on RDS in human hepatocytes, it is considered that the MOA for metazachlor-induced rat liver tumour formation is qualitatively not plausible for humans.

A 13-week subchronic toxicity study of vanillin propylene glycol acetal in F344 rats

Vanillin propylene glycol acetal (VPGA) has been used as a flavoring agent. Here, we performed a 13-week subchronic toxicity study of VPGA in F344 rats with oral administration by gavage at doses of 0, 100, 300, and 1000 mg/kg body weight (BW)/day. In the 1000 mg/kg BW group, loss of vigorous activity and listlessness immediately after administration were observed for both sexes throughout the experimental period. Reduction of body weight gain was noted in both sexes at 1000 mg/kg BW. Serum biochemistry demonstrated significant increases in total protein, albumin, total cholesterol, calcium, inorganic phosphorus, and γ-glutamyl transpeptidase in both sexes at 1000 mg/kg BW and increases in the albumin/globulin ratio and urea nitrogen in the male 1000 mg/kg BW group. A significant increase in relative liver weight was detected in both sexes at 1000 mg/kg BW. Histopathologically, centrilobular hepatocellular hypertrophy in the liver was observed in both sexes at 1000 mg/kg BW. In addition, the incidence of fatty changes in hepatocytes in the male 1000 mg/kg BW group was decreased compared with that in the control. Based on these results, the no-observed-adverse-effect level for VPGA was evaluated to be 300 mg/kg BW/day for both sexes in the current study.

Comparative Hepatotoxicity of Novel PFOA Alternatives (Perfluoropolyether Carboxylic Acids) on Male Mice.

As novel alternatives to perfluorooctanoic acid (PFOA), perfluoropolyether carboxylic acids (multiether PFECAs, CF3(OCF2) nCOO-, n = 2-4) have been detected in various environmental matrices; however, public information regarding their toxicities remains unavailable. To compare the hepatotoxicity of multiether PFECAs (e.g., PFO2HxA, PFO3OA, and PFO4DA) with PFOA, male mice were exposed to 0.4, 2, or 10 mg/kg/d of each chemical for 28 d, respectively. Results demonstrated that PFO2HxA and PFO3OA exposure did not induce marked increases in relative liver weight; whereas 2 and 10 mg/kg/d of PFO4DA significantly increased relative liver weight. Furthermore, PFO2HxA and PFO3OA demonstrated almost no accumulation in the liver or serum; whereas PFO4DA was accumulated but with weaker potential than PFOA. Exposure to 10 mg/kg/d of PFO4DA led to 198 differentially expressed liver genes (56 down-regulated, 142 up-regulated), with bioinformatics analysis highlighting the urea cycle disorder. Like PFOA, 10 mg/kg/d of PFO4DA decreased the urea cycle-related enzyme protein levels (e.g., carbamoyl phosphate synthetase 1) and serum ammonia content in a dose-dependent manner. Both PFOA and PFO4DA treatment (highest concentration) caused a decrease in glutamate content and increase in both glutamine synthetase activity and aquaporin protein levels in the brain. Thus, we concluded that PFO4DA caused hepatotoxicity, as indicated by hepatomegaly and karyolysis, though to a lesser degree than PFOA, and induced urea cycle disorder, which may contribute to the observed toxic effects.

Olive fruit (Olea europaea L.): Chemopreventive effect in the rat model of hepatocellular carcinoma

Primary liver cancer or hepatocellular carcinoma (HCC) is an aggressive tumor with poor prognosis. Olea europaea L. commonly called olive contains diverse phytochemical constituents that have preventive effects against different diseases. The purpose of this investigation was to study the chemopreventive effect of aqueous extract of Olea europaea L. (AOE) against diethylnitrosamine (DEN)-induced HCC in rats. Olive-treated rats were pretreated with AOE intragastrically at three different doses two weeks prior to DEN injection that continued until 8 weeks. At three different time points, blood samples were collected for biochemical analysis. In the present investigation, a significant decrease in serum biomarkers of liver damage and cancer, including alfa-fetoprotein (AFP), gamma glutamyl transpeptidase (GGT), alanine transaminase (ALT), and aspartate transaminase (AST) were observed in AOE supplemented animals when compared to DEN-treated rats. In addition, AOE counteracted DEN-induced hepatic oxidative stress in rats illustrated by the restoration of reduced glutathione (GSH) and the reduction of lipid peroxidation in HCC rats. Furthermore, AOE prevented increase of relative liver weight as a prognostic marker in HCC. Finally, histopathological investigation in the liver sections confirmed the preventive effect of AOE against DEN-induced HCC. To conclude, olive has a preventive effect against DEN-induced hepatocarcinogenesis in rats.

Subchronic toxicity evaluation of 5-hexenyl isothiocyanate, a nature identical flavoring substance from Wasabia japonica, in F344/DuCrj rats

5-Hexenyl isothiocyanate (5-HeITC) is a naturally derived flavoring substance from Wasabia japonica. To clarify the toxicological profile of 5-HeITC, we performed a subchronic toxicity study of 5-HeITC with intragastric administration at daily doses of 0, 3, 12, or 48 mg/kg body weight (BW) to 6-week-old male and female F344/DuCrj rats for 13 weeks. Body weight gain was decreased in the male 48 mg/kg BW group. Decreased triglycerides were observed in the male over 12 mg/kg BW and female 48 mg/kg BW groups. Decreased total cholesterol was observed in the male 48 mg/kg BW group. Increases in relative liver weights were observed in the male 48 mg/kg BW and female over 12 mg/kg BW groups. Increases in absolute and relative heart weights were observed in the female over 12 mg/kg BW groups. Simple hyperplasia in the urinary bladder was found in the male and female 12 mg/kg BW groups, and nodular hyperplasia was found in the female 48 mg/kg BW group. Based on these findings, the target organs of 5-HeITC were determined to be the urinary bladder, heart, and liver. The no-observed-adverse-effect level of 5-HeITC for both sexes was estimated to be 3 mg/kg BW.

The Effect of Hydrated Sodium Calcium Aluminosilicate on Fatty Liver and the Composition of the Intestinal Microbiota in Overfed Landes Geese

ABSTRACT Goose fatty liver is a delicious food product and the overfeeding will cause the abnormal physiology of the geese. The objective of this study was to investigate the effect of supplementation with hydrated sodium calcium aluminosilicate (HSCAS) on the fatty liver, ileal and cecal microbiota of Landes geese during overfeeding. Sixty 70-day-old Landes geese (body weight= 3.0 ± 0.05 kg) were randomly divided into three groups, two of which were overfed with whole corn supplemented with or without HSCAS for 20 days when the fatty liver reaches to the maximum size and the negative control group was ad libitum access to the corn basal diet. The intestinal contents of the ileum and cecum from three geese per group were used for high-throughput sequencing. As a result of this study, the HSCAS-treatment led to an increase in relative liver weight (p<0.05) of geese compared with the overfeeding control group. The richness and diversity of the bacterial communities decreased in the ileum and ceca after overfeeding. Overfeeding increased the relative abundance of Firmicutes, especially Lactobacillus, in ileal samples. HSCAS supplementation increased the relative abundance of Lactobacillus, and decreased the relative abundance of Actinobacillus in the ileum and the relative abundance of Erysipelotrichi, Bacteroides and Escherichia in the ceca. Bacterial richness indicators were also increased in samples from ileum and ceca after HSCAS supplementation. In conclusion, dietary HSCAS supplementation promoted liver performance in overfed Landes geese. HSCAS treatment had a beneficial effect on the intestinal microbiota composition in geese during the overfeeding.

Curcumin Attenuates Lipopolysaccharide-Induced Hepatic Lipid Metabolism Disorder by Modification of m6 A RNA Methylation in Piglets.

N6 -methyladenosine (m6 A) regulates gene expression and affects cellular metabolism. In this study, we checked whether the regulation of lipid metabolism by curcumin is associated with m6 A RNA methylation. We investigated the effects of dietary curcumin supplementation on lipopolysaccharide (LPS)-induced liver injury and lipid metabolism disorder, and on m6 A RNA methylation in weaned piglets. A total of 24 Duroc × Large White × Landrace piglets were randomly assigned to control, LPS, and CurL (LPS challenge and 200 mg/kg dietary curcumin) groups (n = 8/group). The results showed that curcumin reduced the increase in relative liver weight as well as the concentrations of aspartate aminotransferase and lactate dehydrogenase induced by LPS injection in the plasma and liver of weaning piglets (p < 0.05). The amounts of total cholesterol and triacylglycerols were decreased by curcumin compared to that by the LPS injection (p < 0.05). Additionally, curcumin reduced the expression of Bcl-2 and Bax mRNA, whereas it increased the p53 mRNA level in the liver (p < 0.05). Curcumin inhibited the enhancement of SREBP-1c and SCD-1 mRNA levels induced by LPS in the liver. Notably, dietary curcumin affected the expression of METTL3, METTL14, ALKBH5, FTO, and YTHDF2 mRNA, and increased the abundance of m6 A in the liver of piglets. In conclusion, the protective effect of curcumin in LPS-induced liver injury and hepatic lipid metabolism disruption might be due to the increase in m6 A RNA methylation. Our study provides mechanistic insights into the effect of curcumin in protecting against hepatic injury during inflammation and metabolic diseases.

Establishing maximum tolerated doses for a 2-year combined chronic/carcinogenicity rat study based on toxicokinetic and toxicity gender differences

For agrochemicals tested in a carcinogenicity rodent study, it is often not possible to use the same high dose to achieve maximum tolerated dose (MTDs) without overdosing or insufficiently challenging one gender if significant gender differences are known. Toxicokinetic (TK) data for pesticide FR from a 28-day rat study showed that males required a 3-fold higher external dose compared to females to produce similar internal exposure levels of the parent compound. In the 90-day study, 8%/17% (M/F) decrease in bodyweight gain (BWG) and 15%/15% (M/F) increase in relative liver weights were observed in the 6000 ppm males and 2000 ppm females, respectively. Based on the above TK and toxicity data, different high dose levels were selected for females (1600 ppm) and males (4800 ppm) for a 2-year combined chronic/carcinogenicity study in rats. In the 2-year study, 14%, 13%, 13% and 21% reduction in BWG of males and 10%, 12%, 19% and 20% reduction in BWG of females were observed at weeks 13, 26, 52 and 104, respectively in the highest dose tested. Similar reductions in bodyweight gain in males and females at the different high dose levels clearly demonstrated that appropriate MTDs were reached. Therefore, it is scientifically sound and practical to use TK and toxicity data to use different high dose levels to achieve MTDs for a pesticide with large gender differences.

Effect of Flaxseed Extract on the Liver Histological Structure in Streptozotocin Induced Diabetic Rats

Introduction: Diabetes mellitus has become a serious warning to mankind health all over the world. The management goal of diabetes is to keep blood glucose levels as close as possible to healthy individuals. Medications used to treat diabetes are usually associated with complications and may cause different side effects. Many traditional anti-diabetic plants have become popular in the management of diabetes mellitus. Flaxseed has been used as traditional medicine for centuries. Objective: This study aimed to evaluate the hepatoprotective effects of flaxseed extract in streptozotocin (STZ)-induced diabetic rats. Methods: Diabetes mellitus was induced in Sprague-Dawley rats using a single injection of streptozotocin (60 mg/kg i.p.). The rats were divided into five groups of 8 rats each. Group NC, normal control rats; Group NF, normal rats treated with flaxseed extract (400 mg/kg); Group DC, diabetic control rats; Group DG, diabetic rats treated with glibenclamide (0.6 mg/kg); Group DF, diabetic rats treated with flaxseed extract (400 mg/kg); for 4 weeks. Results: There were significant increase in relative liver weight, blood glucose levels in DC group comparing to NC group (p&lt;0.05). The disturbance of these parameters was ameliorated in DF and DG groups. Histological observation revealed congestion of central veins, degeneration of hepatocytes, and reduced glycogen granules in DC group. These pathological changes were ameliorated in the flaxseed extract and glibenclamide treated rats. Conclusion: Flaxseed extract may represent a candidate alternative treatment to control diabetes mellitus and its related hepatopathy.

CHEMO PREVENTIVE EFFECT OF PIPERINE IN N-NITROSODIETHYLAMINEINDUCED AND PHENOBARBITAL PROMOTED EXPERIMENTAL RAT HEPATOCELLULAR CARCINOMA

Every year, almost 5, 00,000 new patients are diagnosed with hepatocellular carcinoma (HCC), primary malignancy of the liver that is associated with poor prognosis. In recent years, development of efficient anti-cancer agents from natural sources has become a major focus of researchers. The present study was designed to investigate the preventive and therapeutic effects of piperine against DEN induced HCC in male wistar rats. Twenty four rats were divided into four groups (n=6). Group I serves as Control, Group II were induced with HCC by DEN (200mg/kg b.wt) followed by phenobarbital (0.05 % w/V), Group III received same as Group II and followed by piperine (50mg/kg b.wt) and Group IV received piperine alone at a dose of 50mg/kg b.wt, up to 16 successive weeks. Results indicated that there is significant increase in relative liver weight (P&lt;0.001) and liver marker enzymes (SGOT, SGPT, ACP, ALP, LDH, gGT, TBIL, Total protein, DNA at P&lt;0.001), tumor marker enzymes (AFP, CEA at P&lt;0.001). also, significant abnormalities were observed in membrane bound enzymes (Ca2+, Na+/K+, Mg2+ ATP age at P&lt;0.001) and electrolytes (Na+, K+ , Ca2+, Mg2+ at P&lt;0.001), whereas the above said alterations were significantly restored in piperine treated groups compared with DEN treated group. The histopathological changes of liver were compared with respective control groups. These findings suggest that piperine can be used as an adjunct to conventional chemo preventive agent, which may provide a novel therapeutic approach to serve as promising agent for treatment of hepatocellular carcinoma.

Dose-response analysis of epigenetic, metabolic, and apical endpoints after short-term exposure to experimental hepatotoxicants

Identification of sensitive and novel biomarkers or endpoints associated with toxicity and carcinogenesis is of a high priority. There is increasing interest in the incorporation of epigenetic and metabolic biomarkers to complement apical data; however, a number of questions, including the tissue specificity, dose-response patterns, early detection of those endpoints, and the added value need to be addressed. In this study, we investigated the dose-response relationship between apical, epigenetic, and metabolomics endpoints following short-term exposure to experimental hepatotoxicants, clofibrate (CF) and phenobarbital (PB). Male F344 rats were exposed to PB (0, 5, 25, and 100 mg/kg/day) or CF (0, 10, 50, and 250 mg/kg/day) for seven days. Exposure to PB or CF resulted in dose-dependent increases in relative liver weights, hepatocellular hypertrophy and proliferation, and increases in Cyp2b1 and Cyp4a1 transcripts. These changes were associated with altered histone modifications within the regulatory units of cytochrome genes, LINE-1 DNA hypomethylation, and altered microRNA profiles. Metabolomics data indicated alterations in the metabolism of bile acids. This study provides the first comprehensive analysis of the apical, epigenetic and metabolic alterations, and suggests that the latter two occur within or near the dose response curve of apical endpoint alterations following exposure to experimental hepatotoxicants.

Investigation of the mechanism of triclosan induced mouse liver tumors

Chronic dietary exposure to Triclosan (TCS) produced increased incidence of liver tumors in mice. The mechanism for liver tumor induction has been attributed to activation of either peroxisome proliferator activated receptor α (PPARα) or constitutive androstane receptor (CAR). To further define the mechanism of TCS induced liver tumors, male CD-1 and C57BL/6 mice were treated with TCS at 0, 10, 100 and 200 mg/kg diet/day for 14 or 28 days. In addition, a recovery group and positive control groups for CAR or PPARα activation with either phenobarbital or diethylhexyl-phthalate were included in the 14-day study. TCS induced a dose-dependent increase in relative liver weight and centrilobular hypertrophy in both strains of mice. Hepatocyte DNA synthesis (BrdU labeling) was also increased in a dose-related pattern. In comparison with previous studies, TCS induced a significant increase in CAR/PXR (Cyp2b10, Cyp3a11) and PPARα (Cyp4a10) responsive genes in both CD-1 and C57BL/6 mice. The corresponding enzyme activity for CAR (7-pentoxyresorufin-O-dealkylase) and PPARα (peroxisomal Acyl-CoA oxidase) were also significantly increased in a similar fashion. Oxidative stress related genes Gpx1 and Aox1 were increased in the C57BL/6 but not in CD-1 mice. The increases in gene expression and enzyme activities returned to control levels after 14-day recovery. The present results demonstrate that both CAR and PPARα activation are involved in the TCS induced mouse liver tumor.

Lactational exposure to abamectin induced mortality and adverse biochemical and histopathological effects in suckling pups.

Information about the adverse effects of lactation transfer of abamectin (ABA) is important for human health, especially in the third-world countries where breastfeeding is the only source of nutrition for infants. So, the present study was undertaken to evaluate the adverse effects of breastfeeding exposure to ABA on oxidative damage and liver and kidney dysfunction in suckling rats. Dams were orally administered ABA at a doses 22.10, 11.05, and 2.21mga.i./kgb.wt from postnatal day 1 (PND1) until day 20 (PND20). The signs of toxicity and high mortality were recorded in suckling male (67.5%) and female (55.0%) pups whose mother exposed to the ABA at dose 22.1mg a.i./kgb.wt. ABA induced significantly decrease in body weights of mothers and their male and female pups and significant increase in relative liver weights. It caused oxidative stress in the liver and kidney of mothers and their pups by increasing the level of malondialdehyde (MDA) and decreased activities of superoxide dismutase (SOD) and glutathione-transferase (GST). ABA altered the level of serum liver and kidney dysfunction biomarkers either in the mothers or their male and female pups in a dose-dependent manner. It caused histopathological alterations in the liver and kidney tissues. It can be decided that ABA was accumulated in mother's milk, transferred through breast feeding, and induced mortality in their suckling pups. It caused oxidative stress, lipid peroxidation, and biochemical and histopathological alterations in the liver and kidney of mothers and their suckling pups. The results in the present study add some information about the adverse effect of lactation transfer of ABA, which is important for human health in the third-world countries where breastfeeding may be the only source of nutrition for infants in the first and most critical weeks of life.