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Archives of Toxicology (v.80, #4)
Subacute oral toxicity study of di(2-ethylhexyl)adipate based on the draft protocol for the “Enhanced OECD Test Guideline no. 407” by Katsumi Miyata; Keiji Shiraishi; Satsuki Houshuyama; Nobuya Imatanaka; Takaaki Umano; Yasushi Minobe; Kanji Yamasaki (pp. 181-186).
We performed a 28-day repeated-dose toxicity study of di(2-ethylhexyl)adipate (DEHA) based on the draft protocol of the “Enhanced OECD Test Guideline 407” to investigate whether it has endocrine-mediated properties according to this assay. DEHA was orally administered to SD rats at doses of 0, 40, 200 and 1,000 mg/kg/day for at least 28 days, and disturbance of the estrous cycle and increased ovarian follicle atresia were detected in the 1,000 mg/kg group.
Keywords: Di(2-ethylhexyl)adipate; Enhanced; TG 407; Rat; Endocrine effects
Subacute oral toxicity study of di(2-ethylhexyl)adipate based on the draft protocol for the “Enhanced OECD Test Guideline no. 407” by Katsumi Miyata; Keiji Shiraishi; Satsuki Houshuyama; Nobuya Imatanaka; Takaaki Umano; Yasushi Minobe; Kanji Yamasaki (pp. 181-186).
We performed a 28-day repeated-dose toxicity study of di(2-ethylhexyl)adipate (DEHA) based on the draft protocol of the “Enhanced OECD Test Guideline 407” to investigate whether it has endocrine-mediated properties according to this assay. DEHA was orally administered to SD rats at doses of 0, 40, 200 and 1,000 mg/kg/day for at least 28 days, and disturbance of the estrous cycle and increased ovarian follicle atresia were detected in the 1,000 mg/kg group.
Keywords: Di(2-ethylhexyl)adipate; Enhanced; TG 407; Rat; Endocrine effects
Short-term hepatic effects of depleted uranium on xenobiotic and bile acid metabolizing cytochrome P450 enzymes in the rat by Y. Guéguen; M. Souidi; C. Baudelin; N. Dudoignon; S. Grison; I. Dublineau; C. Marquette; P. Voisin; P. Gourmelon; J. Aigueperse (pp. 187-195).
The toxicity of uranium has been demonstrated in different organs, including the kidneys, skeleton, central nervous system, and liver. However, few works have investigated the biological effects of uranium contamination on important metabolic function in the liver. In vivo studies were conducted to evaluate its effects on cytochrome P450 (CYP) enzymes involved in the metabolism of cholesterol and xenobiotics in the rat liver. The effects of depleted uranium (DU) contamination on Sprague–Dawley were measured at 1 and 3 days after exposure. Biochemical indicators characterizing liver and kidney functions were measured in the plasma. The DU affected bile acid CYP activity: 7α-hydroxycholesterol plasma level decreased by 52% at day 3 whereas microsomal CYP7A1 activity in the liver did not change significantly and mitochondrial CYP27A1 activity quintupled at day 1. Gene expression of the nuclear receptors related to lipid metabolism (FXR and LXR) also changed, while PPARα mRNA levels did not. The increased mRNA levels of the xenobiotic-metabolizing CYP3A enzyme at day 3 may be caused by feedback up-regulation due to the decreased CYP3A activity at day 1. CAR mRNA levels, which tripled on day 1, may be involved in this up-regulation, while mRNA levels of PXR did not change. These results indicate that high levels of depleted uranium, acting through modulation of the CYP enzymes and some of their nuclear receptors, affect the hepatic metabolism of bile acids and xenobiotics.
Keywords: Depleted uranium; Cytochromes P450; Bile acids; Xenobiotics; Liver
Short-term hepatic effects of depleted uranium on xenobiotic and bile acid metabolizing cytochrome P450 enzymes in the rat by Y. Guéguen; M. Souidi; C. Baudelin; N. Dudoignon; S. Grison; I. Dublineau; C. Marquette; P. Voisin; P. Gourmelon; J. Aigueperse (pp. 187-195).
The toxicity of uranium has been demonstrated in different organs, including the kidneys, skeleton, central nervous system, and liver. However, few works have investigated the biological effects of uranium contamination on important metabolic function in the liver. In vivo studies were conducted to evaluate its effects on cytochrome P450 (CYP) enzymes involved in the metabolism of cholesterol and xenobiotics in the rat liver. The effects of depleted uranium (DU) contamination on Sprague–Dawley were measured at 1 and 3 days after exposure. Biochemical indicators characterizing liver and kidney functions were measured in the plasma. The DU affected bile acid CYP activity: 7α-hydroxycholesterol plasma level decreased by 52% at day 3 whereas microsomal CYP7A1 activity in the liver did not change significantly and mitochondrial CYP27A1 activity quintupled at day 1. Gene expression of the nuclear receptors related to lipid metabolism (FXR and LXR) also changed, while PPARα mRNA levels did not. The increased mRNA levels of the xenobiotic-metabolizing CYP3A enzyme at day 3 may be caused by feedback up-regulation due to the decreased CYP3A activity at day 1. CAR mRNA levels, which tripled on day 1, may be involved in this up-regulation, while mRNA levels of PXR did not change. These results indicate that high levels of depleted uranium, acting through modulation of the CYP enzymes and some of their nuclear receptors, affect the hepatic metabolism of bile acids and xenobiotics.
Keywords: Depleted uranium; Cytochromes P450; Bile acids; Xenobiotics; Liver
Tissue uptake of DDT is independent of chylomicron metabolism by Natalie L. Trevaskis; Patrick Tso; Therese Rider; William N. Charman; Christopher J.H. Porter; Ronald Jandacek (pp. 196-200).
Aim: To determine whether DDT uptake from chylomicrons (CM) into tissues is coincident with CM core lipid uptake. Method: CM were collected from mesenteric lymph duct cannulated, male Sprague–Dawley rats administered olive oil containing 3H-Cholesterol (converted to cholesterol ester (CE) during absorption through the intestine) and 14C-DDT by oral gavage. The CM were suspended in normal saline and 400 μL (containing 0.11 μCi/mL 14C-DDT and 0.15 μCi/mL 3H-CE) was administered via the jugular vein to the recipient rats. The blood was sampled periodically over 30 min from the carotid artery and at the end of the experiment the adrenal glands, brain, fat, heart, liver and spleen were collected. The concentration of 14C-DDT and 3H-CE in whole blood samples and tissue samples was then determined. Results: DDT was removed from the whole blood and, therefore, CM at a significantly faster rate than CE (α=0.05). The tissue distribution of DDT was also different from that of CE, and DDT was particularly concentrated in the retriperitoneal fat and brain. For DDT, the values for VBdB and Cl were significantly higher compared with those determined for CE. Conclusion: DDT is absorbed predominantly via the intestinal lymphatic system in association with CM and accumulates in fatty tissues. This study furthers the understanding of the process of DDT uptake from CM into tissues and demonstrates that the uptake of DDT into tissues is faster than and independent of the uptake of CM core lipid (using CE as a marker). DDT was particularly concentrated in fatty tissues, accounting for its relatively high VBDB.
Keywords: Chylomicron; Clearance; DDT; Distribution; Lipoprotein
Tissue uptake of DDT is independent of chylomicron metabolism by Natalie L. Trevaskis; Patrick Tso; Therese Rider; William N. Charman; Christopher J.H. Porter; Ronald Jandacek (pp. 196-200).
Aim: To determine whether DDT uptake from chylomicrons (CM) into tissues is coincident with CM core lipid uptake. Method: CM were collected from mesenteric lymph duct cannulated, male Sprague–Dawley rats administered olive oil containing 3H-Cholesterol (converted to cholesterol ester (CE) during absorption through the intestine) and 14C-DDT by oral gavage. The CM were suspended in normal saline and 400 μL (containing 0.11 μCi/mL 14C-DDT and 0.15 μCi/mL 3H-CE) was administered via the jugular vein to the recipient rats. The blood was sampled periodically over 30 min from the carotid artery and at the end of the experiment the adrenal glands, brain, fat, heart, liver and spleen were collected. The concentration of 14C-DDT and 3H-CE in whole blood samples and tissue samples was then determined. Results: DDT was removed from the whole blood and, therefore, CM at a significantly faster rate than CE (α=0.05). The tissue distribution of DDT was also different from that of CE, and DDT was particularly concentrated in the retriperitoneal fat and brain. For DDT, the values for VBdB and Cl were significantly higher compared with those determined for CE. Conclusion: DDT is absorbed predominantly via the intestinal lymphatic system in association with CM and accumulates in fatty tissues. This study furthers the understanding of the process of DDT uptake from CM into tissues and demonstrates that the uptake of DDT into tissues is faster than and independent of the uptake of CM core lipid (using CE as a marker). DDT was particularly concentrated in fatty tissues, accounting for its relatively high VBDB.
Keywords: Chylomicron; Clearance; DDT; Distribution; Lipoprotein
Identification of new single nucleotid polymorphisms (SNP) in alcohol dehydrogenase class IV ADH7 gene within a French population by Ahmed Abbas; Mathilde Lechevrel; François Sichel (pp. 201-205).
Many epidemiological studies have explored the possible link between the susceptibility to alcohol related cancers, such as oesophageal cancers, and genetic variants of alcohol dehydrogenases (ADHs). Alcohol dehydrogenase class IV ADH7 is mainly expressed in the upper aero-digestive tract and is involved in the first pass ethanol metabolism. As far as we know, no study has described single nucleotide polymorphisms (SNPs) within ADH7 exons in the Caucasian population. Therefore, in a pilot study, we used the denaturing high performance liquid chromatography (DHPLC) method to screen 49 oesophageal cancer cases for SNPs in the ADH7 gene. A total of 5 SNPs was observed in this study: one SNP in the 5′ non-translated regions of exon 1, two SNPs in introns 3 and 4 and two others SNPs in exons 3 and 4. The SNP located in the exon 1, which has never been described before, occurred in a reverse TATA box whereas the SNP of exon 3 was a non-silent polymorphism. Because these two SNPs could potentially affect the transcription and/or the enzyme activity, their distribution was evaluated in a representative sample of healthy Caucasians (n=89) recruited in Lower Normandy. Frequencies of heterozygous samples ranged from 11% (exon 3) to 28% (exon 1). No homozygous samples were found. In this pilot study, the DHPLC method was suitable for both SNP screening and genotyping and allowed the detection of five SNPs in the ADH7 gene, two of which have never been described before, among the European population.
Keywords: Alcohol dehydrogenase; Single nucleotide polymorphisms; Genotyping; Oesophageal cancer
Identification of new single nucleotid polymorphisms (SNP) in alcohol dehydrogenase class IV ADH7 gene within a French population by Ahmed Abbas; Mathilde Lechevrel; François Sichel (pp. 201-205).
Many epidemiological studies have explored the possible link between the susceptibility to alcohol related cancers, such as oesophageal cancers, and genetic variants of alcohol dehydrogenases (ADHs). Alcohol dehydrogenase class IV ADH7 is mainly expressed in the upper aero-digestive tract and is involved in the first pass ethanol metabolism. As far as we know, no study has described single nucleotide polymorphisms (SNPs) within ADH7 exons in the Caucasian population. Therefore, in a pilot study, we used the denaturing high performance liquid chromatography (DHPLC) method to screen 49 oesophageal cancer cases for SNPs in the ADH7 gene. A total of 5 SNPs was observed in this study: one SNP in the 5′ non-translated regions of exon 1, two SNPs in introns 3 and 4 and two others SNPs in exons 3 and 4. The SNP located in the exon 1, which has never been described before, occurred in a reverse TATA box whereas the SNP of exon 3 was a non-silent polymorphism. Because these two SNPs could potentially affect the transcription and/or the enzyme activity, their distribution was evaluated in a representative sample of healthy Caucasians (n=89) recruited in Lower Normandy. Frequencies of heterozygous samples ranged from 11% (exon 3) to 28% (exon 1). No homozygous samples were found. In this pilot study, the DHPLC method was suitable for both SNP screening and genotyping and allowed the detection of five SNPs in the ADH7 gene, two of which have never been described before, among the European population.
Keywords: Alcohol dehydrogenase; Single nucleotide polymorphisms; Genotyping; Oesophageal cancer
Tissue distribution and function of the Aryl hydrocarbon receptor repressor (AhRR) in C57BL/6 and Aryl hydrocarbon receptor deficient mice by Thorsten Bernshausen; Bettina Jux; Charlotte Esser; Josef Abel; Ellen Fritsche (pp. 206-211).
The Aryl hydrocarbon receptor repressor (AhRR) is a new member of bHLH-PAS proteins which is important in the regulation of cell growth and differentiation. The AhRR shares structural similarities with Aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT). The AhRR is thought to be involved in transcriptional control of AhR-regulated genes by sequestering ARNT. Most of the knowledge of regulation and function of the AhRR is from studies in cell lines. Here, we report the tissue distribution of AhRR in AhR deficient and wild type C57BL/6 mice. In addition, the inducibility of the AhRR and Cytochrome P450 (CYP) 1A1 in response to benzo(a)pyrene (B(a)P) (10 mg/kg bw i.p.) was investigated. The results show that the AhRR mRNA expression pattern in untreated C57BL/6 mice varies across tissues with high levels in hearts and brains. In other tissues, AhRR mRNA expression was low. In contrast to wild-type animals, the tissue levels in AhR−/− mice were about two to three orders of magnitude lower. Treatment of wild-type animals with B(a)P resulted in an induced AhRR expression in liver, spleen, lung and ovary. No significant induction of AhRR mRNA was found in brain and heart tissues, which have a constitutively high level of AhRR expression. Simultaneous measurements of CYP1A1 and AhRR mRNA expression do not strongly support the view that the AhRR tissue pattern triggers the tissue specific responsiveness of AhR-regulated genes to B(a)P treatment.
Keywords: AhRR; C57BL/6; AhR−/− ; CYP1A1
Tissue distribution and function of the Aryl hydrocarbon receptor repressor (AhRR) in C57BL/6 and Aryl hydrocarbon receptor deficient mice by Thorsten Bernshausen; Bettina Jux; Charlotte Esser; Josef Abel; Ellen Fritsche (pp. 206-211).
The Aryl hydrocarbon receptor repressor (AhRR) is a new member of bHLH-PAS proteins which is important in the regulation of cell growth and differentiation. The AhRR shares structural similarities with Aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT). The AhRR is thought to be involved in transcriptional control of AhR-regulated genes by sequestering ARNT. Most of the knowledge of regulation and function of the AhRR is from studies in cell lines. Here, we report the tissue distribution of AhRR in AhR deficient and wild type C57BL/6 mice. In addition, the inducibility of the AhRR and Cytochrome P450 (CYP) 1A1 in response to benzo(a)pyrene (B(a)P) (10 mg/kg bw i.p.) was investigated. The results show that the AhRR mRNA expression pattern in untreated C57BL/6 mice varies across tissues with high levels in hearts and brains. In other tissues, AhRR mRNA expression was low. In contrast to wild-type animals, the tissue levels in AhR−/− mice were about two to three orders of magnitude lower. Treatment of wild-type animals with B(a)P resulted in an induced AhRR expression in liver, spleen, lung and ovary. No significant induction of AhRR mRNA was found in brain and heart tissues, which have a constitutively high level of AhRR expression. Simultaneous measurements of CYP1A1 and AhRR mRNA expression do not strongly support the view that the AhRR tissue pattern triggers the tissue specific responsiveness of AhR-regulated genes to B(a)P treatment.
Keywords: AhRR; C57BL/6; AhR−/− ; CYP1A1
Early effects of iodine on DNA synthesis in sulfur mustard-induced skin lesions by Berta Brodsky; Sheetal Trivedi; Shyamal Peddada; Norris Flagler; Uri Wormser; Abraham Nyska (pp. 212-216).
Sulfur mustard (SM) is powerful alkylator and highly cytotoxic blisterogen in both humans and animals. This study in male guinea pigs shows that, at an early stage (5 h) after SM exposure, a marked increase occurred in epithelial nuclear vacuolation, epidermal thickening, and dermal acute inflammation. Topical iodine treatment reduced the severity of these parameters. The rate of DNA synthesis expressed by incorporation of bromodeoxyuridine was reduced upon topical treatment with iodine only or SM only by 46 and 72%, respectively. Iodine treatment following SM exposure exerted an effect similar to that of SM only, indicating that DNA synthesis is not directly involved in the mechanism of action of iodine-induced protection.
Keywords: Sulfur mustard; Skin lesions; Iodine; DNA synthesis
Early effects of iodine on DNA synthesis in sulfur mustard-induced skin lesions by Berta Brodsky; Sheetal Trivedi; Shyamal Peddada; Norris Flagler; Uri Wormser; Abraham Nyska (pp. 212-216).
Sulfur mustard (SM) is powerful alkylator and highly cytotoxic blisterogen in both humans and animals. This study in male guinea pigs shows that, at an early stage (5 h) after SM exposure, a marked increase occurred in epithelial nuclear vacuolation, epidermal thickening, and dermal acute inflammation. Topical iodine treatment reduced the severity of these parameters. The rate of DNA synthesis expressed by incorporation of bromodeoxyuridine was reduced upon topical treatment with iodine only or SM only by 46 and 72%, respectively. Iodine treatment following SM exposure exerted an effect similar to that of SM only, indicating that DNA synthesis is not directly involved in the mechanism of action of iodine-induced protection.
Keywords: Sulfur mustard; Skin lesions; Iodine; DNA synthesis
The antioxidative and antihistaminic effect of Nigella sativa and its major constituent, thymoquinone on ethanol-induced gastric mucosal damage by Mehmet Kanter; Omer Coskun; Hamdi Uysal (pp. 217-224).
The aim of this study was to assess the possible protective effects of Nigella sativa (NS) and its constituent, thymoquinone (TQ) on ethanol-induced gastric mucosal damage in an experimental model. Forty male rats aged four months were divided into four groups (each group containing ten animals); the control group received physiologic saline (10 ml kg−1) and the ethanol group had taken 1 ml (per rat) absolute alcohol by gavage. The third and fourth groups also received NS (500 mg kg−1) and TQ (10 mg kg−1) by gavage 1 h before alcohol administration, respectively. Both drugs (NS and TQ) could protect the gastric mucosa against the injurious effect of absolute alcohol and promote ulcer healing as evidenced from the ulcer index values. Gastric damage was confirmed histomorphometrically by significant increases in the number of mast cells (MC) and gastric erosions in ethanol treated rats. The NS treatment significantly decreased the number of MC and reduced the area of gastric erosions. Likewise, TQ treatment was also able to reduce the number of MC and the gravity of gastric mucosal lesions, but to lesser extent compared to NS. Gastric tissue histamine levels and myeloperoxidase activities were found to be increased in ethanol treated rats, and NS or TQ treatment reversed these increases. Results obtained from this study suggest that both drugs, particularly NS could partly protect gastric mucosa from acute alcohol-induced mucosal injury, and these gastroprotective effects could be due to their antiperoxidative, antioxidant and antihistaminic effects.
Keywords: Nigella sativa ; Thymoquinone; Ulcer; Antioxidant; Antihistaminic; Rat
The antioxidative and antihistaminic effect of Nigella sativa and its major constituent, thymoquinone on ethanol-induced gastric mucosal damage by Mehmet Kanter; Omer Coskun; Hamdi Uysal (pp. 217-224).
The aim of this study was to assess the possible protective effects of Nigella sativa (NS) and its constituent, thymoquinone (TQ) on ethanol-induced gastric mucosal damage in an experimental model. Forty male rats aged four months were divided into four groups (each group containing ten animals); the control group received physiologic saline (10 ml kg−1) and the ethanol group had taken 1 ml (per rat) absolute alcohol by gavage. The third and fourth groups also received NS (500 mg kg−1) and TQ (10 mg kg−1) by gavage 1 h before alcohol administration, respectively. Both drugs (NS and TQ) could protect the gastric mucosa against the injurious effect of absolute alcohol and promote ulcer healing as evidenced from the ulcer index values. Gastric damage was confirmed histomorphometrically by significant increases in the number of mast cells (MC) and gastric erosions in ethanol treated rats. The NS treatment significantly decreased the number of MC and reduced the area of gastric erosions. Likewise, TQ treatment was also able to reduce the number of MC and the gravity of gastric mucosal lesions, but to lesser extent compared to NS. Gastric tissue histamine levels and myeloperoxidase activities were found to be increased in ethanol treated rats, and NS or TQ treatment reversed these increases. Results obtained from this study suggest that both drugs, particularly NS could partly protect gastric mucosa from acute alcohol-induced mucosal injury, and these gastroprotective effects could be due to their antiperoxidative, antioxidant and antihistaminic effects.
Keywords: Nigella sativa ; Thymoquinone; Ulcer; Antioxidant; Antihistaminic; Rat
Male reproductive toxicity of four bisphenol antioxidants in mice and rats and their estrogenic effect by Osamu Takahashi; Shinshi Oishi (pp. 225-241).
Male mice and rats were fed a diet containing four bisphenol antioxidants, 2,2′-methylenebis(4-ethyl-6-tert-butylphenol) (ME), 2,2′-methylenebis(4-methyl-6-tert-butylphenol) (MM), 4,4′-butylidenebis(3-methyl-6-tert-butylphenol) (BM), or 4,4′-thiobis(3-methyl-6-tert-butylphenol) (TM) at levels of 0.06–0.25% for 2 months. BM and TM decreased epididymal, seminal vesicular, prostate and preputial weights, and injured seminiferous tubules in mice in a dose-dependent fashion. BM and TM also reduced sex accessory organ weights and sperm production capacity in rats, but MM and ME were more toxic to rats than BM and TM. ME and MM did not bind ERα up to 10−3 M, while BM and TM competitively bound ERα against β-estradiol (E2). Fifty percent inhibitory concentrations (IC50 s) of BM, TM, and bisphenol A (positive control) against E2-binding were 7.3×10−6 M, 1.8×10−5 M, and 1.4×10−5 M, respectively. When ovariectomized (OVX) mice were sc administered TM at doses of 60 and 300 mg/kg/day for 4 days, or when OVX mice were fed BM in the diet at a level of 0.25% for 2 months, uterine weight was significantly increased. These results suggest that BM and TM are weakly toxic, possibly through an estrogenic mechanism to male reproductive organs in mice as well as rats, while MM and ME may be the direct testicular toxins in rats but not mice.
Keywords: Testis; Epididymis; Prostate gland; Estrogen; Uterus
Male reproductive toxicity of four bisphenol antioxidants in mice and rats and their estrogenic effect by Osamu Takahashi; Shinshi Oishi (pp. 225-241).
Male mice and rats were fed a diet containing four bisphenol antioxidants, 2,2′-methylenebis(4-ethyl-6-tert-butylphenol) (ME), 2,2′-methylenebis(4-methyl-6-tert-butylphenol) (MM), 4,4′-butylidenebis(3-methyl-6-tert-butylphenol) (BM), or 4,4′-thiobis(3-methyl-6-tert-butylphenol) (TM) at levels of 0.06–0.25% for 2 months. BM and TM decreased epididymal, seminal vesicular, prostate and preputial weights, and injured seminiferous tubules in mice in a dose-dependent fashion. BM and TM also reduced sex accessory organ weights and sperm production capacity in rats, but MM and ME were more toxic to rats than BM and TM. ME and MM did not bind ERα up to 10−3 M, while BM and TM competitively bound ERα against β-estradiol (E2). Fifty percent inhibitory concentrations (IC50 s) of BM, TM, and bisphenol A (positive control) against E2-binding were 7.3×10−6 M, 1.8×10−5 M, and 1.4×10−5 M, respectively. When ovariectomized (OVX) mice were sc administered TM at doses of 60 and 300 mg/kg/day for 4 days, or when OVX mice were fed BM in the diet at a level of 0.25% for 2 months, uterine weight was significantly increased. These results suggest that BM and TM are weakly toxic, possibly through an estrogenic mechanism to male reproductive organs in mice as well as rats, while MM and ME may be the direct testicular toxins in rats but not mice.
Keywords: Testis; Epididymis; Prostate gland; Estrogen; Uterus