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Archives of Toxicology (v.85, #10)

Genotoxicity and carcinogenicity studies of antihistamines by Giovanni Brambilla; Francesca Mattioli; Luigi Robbiano; Antonietta Martelli (pp. 1173-1187).

This review provides a compendium of the results of genotoxicity and carcinogenicity assays performed on marketed antihistamines. Of the 70 drugs examined, 29 (41.4%) have at least one genotoxicity and/or carcinogenicity test result: 12 tested positive in at least one genotoxicity assay, six in at least one carcinogenicity assay, and four gave a positive response in both at least one genotoxicity assay and at least one carcinogenicity assay. Of 19 drugs with both genotoxicity and carcinogenicity data, eight were neither genotoxic nor carcinogenic, two were carcinogenic in at least one sex of mice or rats but tested negative in genotoxicity assays, five tested positive in at least one genotoxicity assay but were non-carcinogenic, and four gave a positive response in at least one genotoxicity assay and in at least one carcinogenicity assay. Only 12 (17.1%) of the 70 drugs examined have all data required by present guidelines for testing of pharmaceuticals, but it should be considered that a large fraction of them were developed and marketed prior the present regulatory climate.

Keywords: Antihistamines; Genotoxicity; Carcinogenicity

Quantitative cancer risk assessment for ethylene oxide inhalation in occupational settings by Ciriaco Valdez-Flores; Robert L. Sielken Jr; M. Jane Teta (pp. 1189-1193).

The estimated occupational ethylene oxide (EO) exposure concentrations corresponding to specified extra risks are calculated for lymphoid mortality as the most appropriate endpoint, despite the lack of a statistically significant exposure–response relationship. These estimated concentrations are for occupational exposures—40 years of occupational inhalation exposure to EO from age 20 to age 60 years. The estimated occupational inhalation exposure concentrations (ppm) corresponding to specified extra risks of lymphoid mortality to age 70 years in a population of male and female EO workers are based on Cox proportional hazards models of the most recent updated epidemiology cohort mortality studies of EO workers and a standard life-table calculation. An occupational exposure at an inhalation concentration of 2.77 ppm EO is estimated to result in an extra risk of lymphoid mortality of 4 in 10,000 (0.0004) in the combined worker population of men and women from the two studies. The corresponding estimated concentration decreases slightly to 2.27 ppm when based on only the men in the updated cohorts combined. The difference in these estimates reflects the difference between combining all of the available data or focusing on only the men and excluding the women who did not show an increase in lymphoid mortality with EO inhalation exposure. The results of sensitivity analyses using other mortality endpoints (all lymphohematopoietic tissue cancers, leukemia) support the choice of lymphoid tumor mortality for estimation of extra risk.

Keywords: Ethylene oxide; Excess cancer risk calculation for occupational inhalation exposure; NIOSH and UCC epidemiology data; Cox proportional hazards models; Lymphoid mortality

Genetic background of resistance to cadmium-induced testicular toxicity in inbred Wistar-Imamichi rats by Hideaki Shimada; Iori Hata; Takashi Hashiguchi; Yorishige Imamura (pp. 1195-1199).

We have previously reported that inbred Wistar-Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced testicular toxicity compared with inbred Fischer 344 (F344) rats. The present study was to elucidate the genetic background of resistance to Cd-induced testicular toxicity in WI rats. The genetic analysis of susceptibility to Cd-induced testicular toxicity was conducted by using Cd-resistant WI and Cd-sensitive F344 strains as the parental rats and by using the testicular hemoglobin level as the indicator. In the frequency distribution of testicular hemoglobin levels in parental, first filial (F₁) and second filial (F₂) rats treated with Cd at a dose of 2.0 mg/kg, F₁ rats had testicular hemoglobin levels intermediate to WI and F344 rats, and F₂ rats segregated into three groups of low, intermediate, and high phenotypes at the expected ratio. Furthermore, the backcross progeny between WI and F₁ or between F344 and F₁ segregated into two groups with the expected ratio. Based on a simple Mendelian genetic analysis, these segregation patterns lead us to conclude that two codominant alleles at a gene locus are responsible for the susceptibility to Cd-induced testicular toxicity in rats. This is the first report for the genetic analysis of susceptibility to Cd-induced testicular toxicity in inbred rat strains.

Keywords: Cadmium; Testicular toxicity; Susceptibility; Strain difference; Genetic analysis; Inbred rat

Absorption and metabolism of the food contaminant 3-chloro-1,2-propanediol (3-MCPD) and its fatty acid esters by human intestinal Caco-2 cells by Thorsten Buhrke; Rüdiger Weißhaar; Alfonso Lampen (pp. 1201-1208).

3-Chloro-1,2-propanediol (3-MCPD) fatty acid esters are formed upon thermal processing of fat-containing foods in the presence of chloride ions. Upon hydrolytic cleavage, these substances could release free 3-MCPD. This compound is toxicologically well characterised and displayed cancerogenic potential in rodent models. Recently, serious contaminations of different food products with 3-MCPD fatty acid esters have been reported. In regard to a risk assessment, the key question is to which degree these 3-MCPD fatty acid esters are hydrolysed in the human gut. Therefore, the aim of the present project was to examine the hydrolysis of 3-MCPD fatty acid esters and the resulting release of free 3-MCPD by using differentiated Caco-2 cells, a cellular in vitro model for the human intestinal barrier. Here, we show that 3-MCPD fatty acid esters at a concentration of 100 μM were neither absorbed by the cells nor the esters were transported via a Caco-2 monolayer. 3-MCPD-1-monoesters were hydrolysed in the presence of Caco-2 cells. In contrast, a 3-MCPD-1,2-diester used in this study was obviously absorbed and metabolised by the cells. Free 3-MCPD was not absorbed by the cells, but the substance migrated through a Caco-2 monolayer by paracellular diffusion. From these in vitro studies, we conclude that 3-MCPD-1-monoesters are likely to be hydrolysed in the human intestine, thereby increasing the burden with free 3-MCPD. In contrast, intestinal cells seem to have the capacity to metabolise 3-MCPD diesters, thereby detoxifying the 3-MCPD moiety.

Keywords: 3-MCPD; 3-MCPD fatty acid ester; Food contaminant; Risk assessment; Caco-2

The association between bladder cancer and a single nucleotide polymorphism (rs2854744) in the insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) gene by Mohammad Reza Safarinejad; Nayyer Shafiei; Shiva H. Safarinejad (pp. 1209-1218).

Insulin-like growth factors (IGF) regulate growth and development and enhance cellular proliferation. IGF-binding protein-3 (IGFBP-3) inhibits IGF action by competitively binding IGFs that prevents their binding to the IGF cell surface receptor. Altered expression and serum levels of IGFBP-3 are associated with a number of malignancies. Study addressing the effect of IGFBP-3 gene polymorphism on bladder cancer is lacking. The aim of this study was to examine the effect of -202 A/C polymorphism of IGFBP-3 gene on development of bladder transitional cell carcinoma (TCC) and its correlation with serum concentration of IGF-1 and IGFBP-3 and with clinicopathological characteristics. One single nucleotide polymorphism (rs2854744) was genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR–RLFP) technique. One hundred and sixty-two bladder cancer patients were genotyped for this SNP. The genotypes were compared with those of a random sample of 324 age-matched controls of the general population. Serum levels of IGF-I and IGFBP-3 were also determined. We found statistically significant differences in the genotypic distribution between the cases and the control subject (χ² = 6.43, df = 2.0, P = 0.028). Using CC genotype as a reference, the odds ratio for the subjects with AC genotype was 1.76 (95% CI: 1.27–2.84; P = 0.038). We detected a significantly decreased risk of bladder cancer associated with the AA genotype (adjusted OR = 0.48; 95% CI = 0.24–0.64; P = 0.001) compared with the CC genotype. This decreased risk was more pronounced for invasive bladder cancer. Age-adjusted mean serum IGFBP-3 levels were lowest in the individuals with the CC genotype. We found a positive correlation between age-adjusted serum IGFBP-3 levels and circulating IGF-1 concentrations (16% difference in IGFBP-3 in top vs. bottom tertiles of IGF-1, P for trend = 0.001), which was comparable across genotypes at the -202 IGFBP-3 locus (interaction term, F = 0.10, P = 0.87). Genetic polymorphism of the IGFBP-3 gene may be involved in the etiology of bladder TCC, and our results need further confirmation by larger studies.

Keywords: Insulin-like growth factor-binding protein 3; Polymorphism; Urogenital cancer; Bladder neoplasms; Genetic variation

Molecular characterization of an acidic phospholipase A₂ from Bothrops pirajai snake venom: synthetic C-terminal peptide identifies its antiplatelet region by Sabrina S. Teixeira; Lucas B. Silveira; Franco M. N. da Silva; Daniela P. Marchi-Salvador; Floriano P. Silva Jr; Luiz Fernando M. Izidoro; André L. Fuly; Maria A. Juliano; Camila R. dos Santos; Mário T. Murakami; Suely V. Sampaio; Saulo L. da Silva; Andreimar M. Soares (pp. 1219-1233).

This paper describes a biochemical and pharmacological characterization of BpirPLA₂-I, the first acidic Asp49-PLA₂ isolated from Bothrops pirajai. BpirPLA₂-I caused hypotension in vivo, presented phospholipolytic activity upon artificial substrates and inhibitory effects on platelet aggregation in vitro. Moreover, a synthetic peptide of BpirPLA₂-I, comprising residues of the C-terminal region, reproduced the antiplatelet activity of the intact protein. A cDNA fragment of 366 bp encompassing the mature form of BpirPLA₂-I was cloned by reverse transcriptase-PCR of B. pirajai venom gland total RNA. A Bayesian phylogenetic analysis indicated that BpirPLA₂-I forms a clade with other acid Asp49-PLA₂ enzymes from the Bothrops genus, which are characterized by the high catalytic activity associated with anticoagulant or hypotensive activity or both. Comparison of the electrostatic potential (EP) on the molecular surfaces calculated from a BpirPLA₂-I homology model and from the crystallographic models of a group of close homologues revealed that the greatest number of charge inversions occurred on the face opposite to the active site entrance, particularly in the Ca²⁺ ion binding loop. This observation suggests a possible relationship between the basic or acid character of PLA₂ enzymes and the functionality of the Ca²⁺ ion binding loop.

Keywords: Snake venom; Acidic phospholipase A₂ ; Biochemical and pharmacological characterization; Bothrops pirajai ; Antiplatelet domain

Sub-chronic effect of perfluorooctanesulfonate (PFOS) on the balance of type 1 and type 2 cytokine in adult C57BL6 mice by Guang-Hui Dong; Miao-Miao Liu; Da Wang; Li Zheng; Zai-Fu Liang; Yi-He Jin (pp. 1235-1244).

As a ubiquitous and highly persistent environmental contaminant, the clear mechanisms to explain any perfluorooctanesulfonate (PFOS)-induced immunotoxicity are still unknown. This study here sought to examine the ability of PFOS to potentially perturb T-helper (T_H)-1 and T_H-2 cell cytokine secreting activities, as well as to cause shifts in antibody isotype levels, and possible mechanisms involved in PFOS-induced immunotoxicity. Adult male C57BL/6 mice were exposed to PFOS daily via gavage for 60 days [0, 0.5, 1, 5, 25, or 50 mg/kg total administered dose (TAD)]. One day after the final exposure, the ex vivo production of the T_H1-type cytokines (IL-2 and IFN-γ), T_H2-type (IL-4), and IL-10 cytokines by isolated splenocytes, serum levels of immunoglobulin (Ig) were assessed via ELISA or ELISPOT. The results showed that IL-4 secretion was increased at exposure ≥5 mg PFOS/kg TAD in a dose-dependent manner. PFOS exposure increased IL-10 but decreased IL-2 and IFN-γ formation markedly at 50 mg PFOS/kg TAD. Serum levels of sheep red blood cells (SRBC)-specific IgM synthesis decreased significantly with PFOS exposure in a dose-related manner; serum SRBC-specific IgG, IgG1, and IgE levels increased with 50 mg PFOS/kg TAD regimens. These results indicated that, after a long-term exposure to PFOS, a host’s immune state is likely to be characterized by a shift toward a more T_H2-like state that, in turn, may lead to enhancement of their humoral response and suppression of their cellular response at levels of upper range for occupationally exposed workers or approximately 150-fold for general human population.

Keywords: Perfluorooctanesulfonate; Type 1 cytokine; Type 2 cytokine; Immunoglobulin

Silencing of tissue factor by antisense deoxyoligonucleotide prevents monocrotaline/LPS renal injury in mice by Mohamed Sadek Abdel-Bakky; Mohamed A. Hammad; Larry A. Walker; Mohammad K. Ashfaq (pp. 1245-1256).

Tissue factor (TF) is involved in monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity. It is not known whether MCT/LPS can cause renal toxicity and whether TF is involved in this toxicity. Thus, the present study was undertaken to investigate the potential renal toxicity after MCT/LPS co-treatment and the involvement of TF in this toxicity. MCT was delivered to ND4 male mice (200 mg/kg) per os followed 4 h later by treatment with LPS ip (6 mg/kg) to investigate its effect on kidney. We injected TF antisense oligonucleotide (TF-AS) intravenously (i.v) in mice prior to LPS treatment, to block TF, and measured their blood urea nitrogen (BUN), creatinine (CRE), alkaline phosphatase (ALP), and potassium. In MCT/LPS co-treated group, fibrin was detected on the glomerular capillary lumina, distal tubules of renal cortex, and the necrotic tubules of renal medulla. An elevation of BUN, creatinine, and the BUN/creatinine ratio was seen in mice with MCT/LPS co-treatment, compared to animals receiving LPS or MCT alone. Simultaneously, an aggressive tubular necrosis was seen in the medullary tubules in the same group which may account for the oliguria observed in these animals. Fourfold inductions in the plasma TF level was detected at 10 h after MCT/LPS co-treatment which increased to 18-fold at 24 h. Increased blood level of leptin, interleukin-6 (IL-6) and downregulation of tubular chemokine (C-X-C motif) ligand 16 (CXCL16) are characteristic features in MCT/LPS co-treated animal. On the other hand, mice injected with TF-AS in the presence of MCT/LPS co-treatment showed no elevation of the blood BUN, creatinine, potassium, and normal levels of the proinflammatory molecules. TF-AS injection significantly prevented glomerular and tubular fibrin deposition, tubular necrosis, and improvement of the animal survivability. Renal toxicity involving TF can be prevented successfully by the use of TF-AS.

Keywords: Tissue factor antisense; Monocrotaline; Lipopolysaccharide; Renal toxicity

Effect of diindolylmethane on Ca²⁺ movement and viability in HA59T human hepatoma cells by Jin-Shiung Cheng; Su-Shung Shu; Chun-Chi Kuo; Chiang-Ting Chou; Wei-Lun Tsai; Yi-Chien Fang; Li-Ni Kuo; Jeng-Hsien Yeh; Wei-Chuan Chen; Jau-Min Chien; Ti Lu; Chih-Chuan Pan; He-Hsiung Cheng; Kuo-Liang Chai; Chung-Ren Jan (pp. 1257-1266).

The effect of diindolylmethane, a natural compound derived from indole-3-carbinol in cruciferous vegetables, on cytosolic Ca²⁺ concentrations ([Ca²⁺]_i) and viability in HA59T human hepatoma cells is unclear. This study explored whether diindolylmethane changed [Ca²⁺]_i in HA59T cells. The Ca²⁺-sensitive fluorescent dye fura-2 was applied to measure [Ca²⁺]_i. Diindolylmethane at concentrations of 1–50 μM evoked a [Ca²⁺]_i rise in a concentration-dependent manner. The signal was reduced by removing Ca²⁺. Diindolylmethane-induced Ca²⁺ influx was not inhibited by nifedipine, econazole, SK&F96365, and protein kinase C modulators but was inhibited by aristolochic acid. In Ca²⁺-free medium, treatment with the endoplasmic reticulum Ca²⁺ pump inhibitors thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) inhibited or abolished diindolylmethane-induced [Ca²⁺]_i rise. Incubation with diindolylmethane inhibited thapsigargin or BHQ-induced [Ca²⁺]_i rise. Inhibition of phospholipase C with U73122 reduced diindolylmethane-induced [Ca²⁺]_i rise. At concentrations of 10–75 μM, diindolylmethane killed cells in a concentration-dependent manner. The cytotoxic effect of diindolylmethane was not reversed by chelating cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid. Propidium iodide staining data suggest that diindolylmethane (25–50 μM) induced apoptosis in a concentration-dependent manner. Collectively, in HA59T cells, diindolylmethane induced a [Ca²⁺]_i rise by causing phospholipase C-dependent Ca²⁺ release from the endoplasmic reticulum and Ca²⁺ influx via phospholipase A₂-sensitive channels. Diindolylmethane induced cell death that may involve apoptosis.

Keywords: Ca²⁺ ; Diindolylmethane; HA59T; Hepatoma

The difference of glutathione antioxidant system in newly weaned and young mice liver and its involvement in isoline-induced hepatotoxicity by Qing-Ning Liang; Yu-Chen Sheng; Ping Jiang; Li-Li Ji; Yu-Ye Xia; Yang Min; Zheng-Tao Wang (pp. 1267-1279).

Cellular glutathione antioxidant system plays important roles in counteracting hepatotoxins-induced oxidative stress injury. The present study was designed to observe the differences of this system in newly weaned and young mice liver and its involvement in the susceptibility to isoline-induced liver injury. Our results showed that liver reduced glutathione (GSH) amounts were higher in newly weaned mice than young mice. Glutamate-cysteine ligase (GCL) activity was higher in newly weaned mice due to the higher expression of catalytic subunit of GCL (GCLC) protein and mRNA. However, the activities of glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) were higher in young mice liver, which might be due to the higher expression of GR, GPx-1, and GST-Pi proteins. Next, the results of AST analysis and histopathological evaluation showed that newly weaned mice demonstrated more severe liver injury induced by isoline. Furthermore, liver GSH amounts and the activities of GR, GPx, and GST were all lower in newly weaned mice than young mice after treated with isoline. Depletion of cellular GSH by d,l-buthionine-(S, R)-sulfoximine (BSO) aggravated isoline-induced cytotoxicity, while N-acetyl-l cysteine (NAC) ameliorated such cytotoxicity. Furthermore, the inhibitors of GR, GPx, and GST all aggravated isoline-induced cytotoxicity. In conclusion, our results demonstrated the differences of glutathione antioxidant system between newly weaned and young mice liver. Meanwhile, our results also revealed age-dependent liver injury induced by isoline for the first time, which might be due to the different responses of glutathione antioxidant system to isoline between newly weaned and young mice.

Keywords: Glutathione antioxidant system; Isoline; Age-dependent difference; Hepatotoxicity; Oxidative stress

Developmental exposure to methylmercury and 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) affects cerebral dopamine D1-like and D2-like receptors of weanling and pubertal rats by Teresa Coccini; Elisa Roda; Anna F. Castoldi; Diana Poli; Matteo Goldoni; Maria Vittoria Vettori; Antonio Mutti; Luigi Manzo (pp. 1281-1294).

MeHg (0.5 mg/kg/day) and/or PCB153 (5 mg/kg/day) effects, administered orally to rat dams (GD7-PND21), were explored in PND21 and PND36 offspring brain in terms of density (Bmax) and affinity (Kd) of dopamine D1-like (D1-Rs) and D2-like receptors (D2-Rs), by saturation binding studies. D1-Rs decreased density in both cortex and striatum (15–30%) by MeHg and PCB153, either alone or combined, without additivity in PND21 males. Changes disappeared by PND36. In females, only MeHg caused a 15% Bmax decrease in striatum. D2-Rs enhanced density (23–50%) and reduced affinity in cortex to a similar extent by all treatments in both weanling and pubertal males. Affinity was also decreased in females by all types of exposure at both ages, while density was enhanced by PCB153 only in a delayed manner (PND36). No changes were detected in striatum. In MeHg and MeHg + PCB153 pup cortex, Hg concentrations ranged, on PND21, between 0.25 and 0.89 and 0.94–1.40 μg/g tissue, respectively, and were 5- to sixfold lower 2 weeks later. PCB153 levels, in PCB153 ± MeHg treated rats, were about 15 μg/g tissue (PND21) and 4–8 μg/g tissue (PND36). In striatum, the Hg and PCB153 concentrations were similar to those in cortex. Brain kinetics trend also applied to blood PCB153 or Hg levels. Perinatal exposure to MeHg and/or PCB153 affects D1- and D2-Rs in a gender-, time-, and brain area-dependent manner. Combined treatment does not exacerbate the neurochemical effects of the individual compounds.

Keywords: Development; Neurotoxicity; Polychlorobiphenyls; Food contaminants; Mixture

Combined analysis of chromosomal aberrations and glutathione S-transferase M1 and T1 polymorphisms in pathologists occupationally exposed to formaldehyde by Alfredo Santovito; Tiziana Schilirò; Sergio Castellano; Piero Cervella; Maria Paola Bigatti; Giorgio Gilli; Roberto Bono; Massimiliano DelPero (pp. 1295-1302).

The formaldehyde (FA) genotoxic potential in occupationally exposed individuals is conflicting. A relevant indoor-air FA pollution was found in hospitals and scientific institutions where FA is used as a bactericide and tissue preservative. In the present study, we evaluated the frequency of chromosomal aberrations (CAs) in peripheral blood lymphocytes from workers in pathology wards who have been exposed to FA, compared with a group of unexposed subjects. The subjects were also analyzed for the GSTM1 and GSTT1 metabolic gene polymorphisms. The exposed subjects showed a significant increase in the frequency of CA per cell and in the percentage of cells with aberrations compared to control subjects. The different GST genotypes did not affect the level of cytogenetic damage since CA frequencies were not statistically different between the GST “null” genotypes and the GST “positives”. The generalized linear models showed that the number of CAs and cells with CAs increased with age, but, independent of age, it was significantly higher in the experimental rather than in the control group. Cubic-spline regression confirmed the linear relationship between CAs and age, but it provided evidence for a non-linear relationship between CAs and the number of years of FA exposure. Similar results were observed when the model included the number of cells with CAs as dependent variables. Our results demonstrate that air FA induces CAs even consequently to low levels of daily exposure, indicating an increased risk of genetic damage for workers exposed to this air pollutant.

Keywords: Biomonitoring; Toxicology; Exposure monitoring; Formaldehyde; Polymorphisms

Distinct DNA methylation patterns of lysophosphatidic acid receptor genes during rat hepatocarcinogenesis induced by a choline-deficient l-amino acid-defined diet by Kyoko Okabe; Mai Hayashi; Ikuma Yoshida; Kazuki Nishimura; Nobuyuki Fukushima; Toshifumi Tsujiuchi (pp. 1303-1310).

Altered expressions of lysophosphatidic acid (LPA) receptor genes have been reported in tumor cells of human and rats. Recently, we detected the frequent mutations of LPA receptor-1 (LPA1) gene in rat hepatocellular carcinomas (HCCs) induced by a choline-deficient l-amino acid-defined (CDAA) diet. In this study, the DNA methylation patterns of LPA receptor genes and their expression levels during rat hepatocarcinogenesis induced by the CDAA diet were investigated. Six-week-old F344 male rats were continuously fed with the CDAA diet, and animals were then killed at 7 days and 2, 12, 20, and 75 weeks, respectively. Genomic DNAs were extracted from livers and HCCs for the assessment of methylation status by bisulfite sequencing, comparing to normal livers. The livers of rats fed the CDAA diet were unmethylated in LPA1 and LPA2 genes as well as normal livers. In LPA3 gene, although normal livers were unmethylated, the livers at 7 days and 2 and 12 weeks weakly or moderately methylated and those at 20 weeks markedly methylated. Moreover, 4 HCCs were completely methylated in LPA3 gene. Expression levels of LPA receptor genes in the livers of rats fed the CDAA diet and HCCs were correlating with DNA methylation status. These results indicate that DNA methylation status of the LPA3 gene was disturbed in the livers of rats fed the CDAA diet and established HCCs, suggesting that alterations of the LPA receptor genes might be involved during rat hepatocarcinogenesis induced by the CDAA diet.

Keywords: LPA receptor; CDAA diet; Hepatocarcinogenesis; Methylation; Rat

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Archives of Toxicology (v.85, #10)