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Archives of Toxicology (v.84, #1)

Arsenic: metabolism and transport mechanisms in human hepatocytes by Hermann M. Bolt; Joanna D. Stewart (pp. 1-2).

Metabolism of arsenic in human liver: the role of membrane transporters by Zuzana Drobná; Felecia S. Walton; David S. Paul; Weibing Xing; David J. Thomas; Miroslav Stýblo (pp. 3-16).

Metabolism of inorganic arsenic (iAs) is one of the key factors determining the character of adverse effects associated with exposure to iAs. Results of previous studies indicate that liver plays a primary role in iAs metabolism. This paper reviews these results and presents new data that link the capacity of human hepatocytes to metabolize iAs to the expression of specific membrane transporters. Here, we examined relationship between the expression of potential arsenic transporters (AQP9, GLUT2, P-gp, MRP1, MRP2, and MRP3) and the production and cellular retention of iAs and its methylated metabolites in primary cultures of human hepatocytes exposed for 24 h to subtoxic concentrations of arsenite. Our results show that the retention of iAs and methylarsenic metabolites (MAs) by hepatocytes exposed to sub-micromolar concentrations of arsenite correlates negatively with MRP2 expression. A positive correlation was found between MRP2 expression and the production of dimethylarsenic metabolites (DMAs), specifically, the concentration of DMAs in culture media. After exposures to high micromolar concentrations of arsenite which almost completely inhibited MAs and DMAs production, a positive correlation was found between the expression of GLUT2 and cellular retention of iAs and MAs. MRP3, AQP9, or P-gp expression had no effect on the production or distribution of iAs, MAs, or DMAs, regardless of the exposure level. Hepatocytes from seven donors used in this study did not contain detectable amounts of MRP1 protein. These data suggest that MRP2 plays an important role in the efflux of DMAs, thus, regulating kinetics of the methylation reactions and accumulation of iAs and MAs by human hepatocytes. The membrane transport of iAs by high-capacity GLUT2 transporters is not a rate-limiting step for the metabolism of arsenite at low exposure level, but may play a key role in accumulation of iAs after acute exposures which inhibit iAs methylation.

Keywords: Arsenic; Human liver; Membrane transport

Association of XPD/ERCC2 G 23591 A and A 35931 C polymorphisms with skin lesion prevalence in a multiethnic, arseniasis-hyperendemic village exposed to indoor combustion of high arsenic coal by Guo-fang Lin; Hui Du; Ji-gang Chen; Hong-chao Lu; Wei-chao Guo; Klaus Golka; Jian-hua Shen (pp. 17-24).

More than 2,000 arsenic-related skin lesions (as at 2002) in a few villages of China’s Southwest Guizhou Autonomous Prefecture represent a unique case of endemic arseniasis related with indoor combustion of high-arsenic coal. The skin lesion prevalence was significantly higher in ethnic Han villagers than in ethnic Hmong villagers. This study was focused on a possible involvement of XPD/ERCC2 G 23591 A and A 35931 C polymorphisms in risk modulation of skin lesions and in the body burden of As in this unique case of As exposure. G 23591 A and A 35931 C were genotyped by a PCR-based procedure. Total As contents in hair and urine samples as well as environmental samples of the homes of the two ethnic clans were analysed. A significant higher presentation of A/A 35931 (homozygous wild) genotype in both clans was found in skin lesion patients, compared with their asymptomatic fellow villagers (67.1 vs. 46.3%, OR 2.36, 95% CI 1.35–4.14, P = 0.002). Interestingly, the population frequencies of the A/A 35931 genotype did not show significant differences between ethnic Han villagers and their Hmong neighbours (47.1 vs. 45.5%). Very low frequencies of homozygous and heterozygous variant genotypes of G 23591 A were recorded in the residents in target village. G/A 23591 and A/A 23591 were detected only in 3.2% (8/244) and 0.8% (2/244) of the villagers, respectively. The polymorphic status at the locus of A 35931 C might modulate the risk for arsenic-related skin lesions in the investigated groups.

Keywords: Indoor combustion; Arsenic; Skin lesion; XPD/ERCC2 ; Body burden

Biomarkers of organophosphorus nerve agent exposure: comparison of phosphylated butyrylcholinesterase and phosphylated albumin after oxime therapy by Robert W. Read; James R. Riches; Jacqueline A. Stevens; Sarah J. Stubbs; Robin M. Black (pp. 25-36).

Organophosphorus nerve agents inhibit the activity of cholinesterases by phosphylation of the active site serine. In addition, sarin, cyclosarin, soman and tabun have been shown to phosphylate a tyrosine residue in albumin. Therapies against nerve agent poisoning include the use of oximes to reactivate inhibited cholinesterases by displacement of the phosphyl moiety and hence detectable levels of adducts with cholinesterases may be reduced. Adducts with tyrosine have been shown to be persistent in the guinea pig in the presence of oxime therapy. Plasma samples obtained from an animal study aimed at improving therapy against nerve agent poisoning were used to compare the suitability of tyrosine and butyrylcholinesterase (BuChE) adducts as biomarkers of nerve agent exposure after treatment with therapeutic oximes. Under the terms of the project licence, these samples could be collected only on death of the animal, which occurred within hours of exposure or when culled at 23 or 24 days. Tyrosine adducts were detected in all samples collected following intra-muscular administration of twice the LD₅₀ dose of the respective nerve agent. Aged BuChE adducts were detected in samples collected within a few hours after administration of soman and tabun, but not after 23 or 24 days. No BuChE adducts were detected in animals exposed to sarin and cyclosarin where samples were collected only after 23 or 24 days.

Keywords: Biomarkers; Nerve agents; Phosphylated butyrylcholinesterase; Phosphylated tyrosine; Oxime therapy

Use of two validated in vitro tests to assess the embryotoxic potential of mycophenolic acid by Kathrin Eckardt; Ralf Stahlmann (pp. 37-43).

Mycophenolate mofetil is a widely used immunosuppressive drug that recently has been categorized as a human teratogen. Animal experiments indicate a teratogenic potential of the drug, but so far, it has not been studied in embryotoxicity in vitro assays. The aim of this study was to evaluate the in vitro embryotoxic potential of mycophenolic acid and investigate the ability of such tests to detect its embryotoxic potential. We used two validated assays: the rat whole embryo culture and the murine embryonic stem cell test. Rat embryos cultured from gestational day 9.5 for 48 h with the drug showed dysmorphogenic development already at a concentration of 250 μg mycophenolic acid/l medium. At concentrations of 750 μg/l and more, all rat embryos exhibited malformations. The main effects were defective yolk sac blood circulation, neural tube defects (open cranial neural pore), malformations of the head with missing eye anlagen and heart anomalies. Moreover, the exposed embryos showed a concentration-dependent decrease in protein content, crown-rump length, number of somites and morphological score. The murine embryonic stem cell test was slightly more sensitive. Proliferation and differentiation of the ES-D3-cells were significantly impaired at concentrations of 31 and 125 μg mycophenolic acid/l medium, respectively. In the differentiation assay, at a concentration of 125 μg mycophenolic acid/l medium and more, the number of wells with differentiated cardiomyocytes significantly decreased. Additionally, a cytotoxicity assay with balb/c 3T3 mouse fibroblasts was used to compare the proliferation and vitality of embryonic cells with adult cells. In the balb/c 3T3 cytotoxicity assay, the number of vital mouse fibroblasts significantly decreased at a mycophenolic acid concentration of 62 μg/l and more. In conclusion, by using the two validated in vitro tests, we showed that mycophenolic acid exhibits a pronounced embryotoxic potential at cytotoxic concentrations. This result from validated in vitro tests is of special interest, because it supports the use of the tests to detect human teratogens.

Keywords: Mycophenolic acid; Teratogenicity; Whole embryo culture; Embryonic stem cell test; Cytotoxicity test

Bisabololoxide A, one of the main constituents in German chamomile extract, induces apoptosis in rat thymocytes by Ikuko Ogata; Takuya Kawanai; Erika Hashimoto; Yumiko Nishimura; Yasuo Oyama; Hakaru Seo (pp. 45-52).

German chamomile (Matricaria recutita L.), one of the popular ingredients in herbal teas, has been traditionally used for medicinal purposes. Bisabololoxide A (BSBO) is one of the main constituents in this herb. BSBO is supposed to be principle in some bioactivities of German chamomile such as anti-inflammatory, gastrointestinal, and antipruritic actions. Although the use of German chamomile has spread, the information related to toxicity of BSBO is very limited. In present study, the cytotoxic effect of micromolar BSBO was cytometrically examined on rat thymocytes by using appropriate fluorescent dyes. When the cells were incubated with BSBO for 24 h, BSBO at concentrations of 30 μM or more significantly increased populations of dead cells, shrunken cells, and cells with phosphatidylserine exposed on membrane surface. Both cell shrinkage and externalization of membrane phosphatidylserine are general features in an early stage of apoptosis. In addition, BSBO significantly increased population of cells containing hypodiploid DNA, and the increase was completely attenuated by Z-VAD-FMK, a pan-inhibitor for caspases, indicating an involvement of caspase activation. Thus, it is likely that the type of cell death induced by BSBO is apoptosis. The significant changes in cellular parameters of rat thymocytes by BSBO were not observed when the concentration was 10 μM or less. Furthermore, the short incubation (3 h) of cells even with 30–100 μM BSBO did not significantly affect the cells. Therefore, it may be suggested that BSBO is practically safe when German chamomile is conventionally used.

Keywords: Bisabololoxide A; German chamomile (Matricaria recutita L.); Cytotoxicity; Thymocytes; Apoptosis

Cypermethrin exposure during puberty disrupts testosterone synthesis via downregulating StAR in mouse testes by Hua Wang; Qun Wang; Xian-Feng Zhao; Ping Liu; Xiu-Hong Meng; Tao Yu; Yan-Li Ji; Heng Zhang; Cheng Zhang; Ying Zhang; De-Xiang Xu (pp. 53-61).

Cypermethrin is a widely used synthetic pyrethroid insecticide. Previous studies showed that cypermethrin significantly decreased the fertility and reduced the number of implantation sites and viable fetuses in females impregnated by males exposed to cypermethrin. As yet, little is known about the mechanism of cypermethrin-induced reproductive toxicity. In the present study, we investigated the effects of cypermethrin exposure during puberty on steroidogenesis in mice. Young male mice were administered with cypermethrin (25 mg/kg) by gavage daily from postnatal day (PND) 35 to PND70. Results showed that the level of serum and testicular testosterone (T) was markedly decreased in cypermethrin-treated mice. Additional experiment showed that cypermethrin exposure during puberty markedly downregulated mRNA level of steroidogenic acute regulatory protein (StAR) in testes. Correspondingly, protein level of testicular StAR was significantly decreased in cypermethrin-treated mice. Cypermethrin exposure during puberty did not affect the number of Leydig cells in testes. Although cypermethrin exposure during puberty did not affect the weight of testes and epididymides, the number of sperm in the cauda epididymides was significantly decreased in cypermethrin-treated mice. Taken together, these results indicate that cypermethrin exposure during puberty significantly disrupts T synthesis via downregulating the expression of testicular StAR. The decreased T synthesis might be associated with cypermethrin-induced impairment in spermatogenesis in mice.

Keywords: Cypermethrin; Pyrethroid; Testes; Steroidogenesis; Testosterone; Steroidogenic acute regulatory protein (StAR)

Histochemical study of intestinal mucins after administration of silver nanoparticles in Sprague–Dawley rats by Gil Nam Jeong; Un Bock Jo; Hyeon Yeol Ryu; Yong Soon Kim; Kyung Seuk Song; Il Je Yu (pp. 63-69).

To investigate the effects of silver nanoparticles on the histological structure and properties of the mucosubstances in the intestinal mucosa, Sprague–Dawley rats were divided into four groups (10 rats in each group): vehicle control, low-dose group (30 mg/kg), middle-dose group (300 mg/kg), and high-dose group (1,000 mg/kg), and administered silver nanoparticles (60 nm) for 28 days, following OECD test guideline 407 and using GLP. The control sections contained no silver nanoparticles; however, the treated samples showed luminal and surface particles and the tissue also contained silver nanoparticles. A dose-dependent increased accumulation of silver nanoparticles was observed in the lamina propria in both the small and large intestine, and also in the tip of the upper villi in the ileum and protruding surface of the fold in the colon. The silver nanoparticle-treated rats exhibited higher numbers of goblet cells that had released their mucus granules than the controls, resulting in more mucus materials in the crypt lumen and ileal lumen. Moreover, cell shedding at the tip of the villi was frequent. Lower amounts of neutral and acidic mucins were found in the goblet cells in the silver nanoparticle-treated rats, plus the amount of sialomucins was increased, while the amount of sulfomucins was decreased. In particular, in the colon of the silver nanoparticle-treated rats, sialyated mucins were detected in the lamina propria, the connective tissue under the epithelia. Therefore, the present results suggest that silver nanoparticles induce the discharge of mucus granules and an abnormal mucus composition in the goblet cells in the intestines.

Keywords: Silver nanoparticles; Mucins; Intestines; Histochemistry; Intestinal goblet cells

Effect of gestational and lactational exposure to perfluorooctanesulfonate on calcium-dependent signaling molecules gene expression in rats’ hippocampus by Xiaohui Liu; Wei Liu; Yihe Jin; Wenguang Yu; Faqi Wang; Li Liu (pp. 71-79).

Perfluorooctanesulfonate (PFOS) is an environmental contaminant found in human and animal tissues worldwide. The developing nervous system is thought to be particularly sensitive to PFOS by the fact that PFOS can cross blood–brain and placental barriers. Effect of gestational and lactational exposure to PFOS on central nervous system (CNS) in Wistar rats was investigated by the cross-foster model built with PFOS at 0 or 3.2 mg/kg food. Real-time reverse transcription-polymerase chain reaction was employed to evaluate the gene expression of calcium-dependent signaling molecules in rats’ hippocampus which are critical to the function of CNS. The expression of calcium-related signaling molecules, such as N-methyl-d-aspartate receptor subtype-2B (NR2B), calmodulin (CaM), Ca²⁺/calmodulin-dependent kinase II α (CaMKIIα) and cAMP-response element-binding (CREB) were increased in the PFOS exposure group at postnatal day 1 (PND 1). The decreased NR2B in the prenatal PFOS exposure group, the decreased CaM in the pre-/postnatal PFOS exposure group, the increased CaMKIIα in the whole-life PFOS exposure group and the increased CREB in the prenatal/whole-life PFOS exposure group was observed at PND 7. At PND 35, rats exhibited the decreased NR2B in the pre-/postnatal and the whole-life PFOS exposure group, and the decreased CaM in the postnatal PFOS group. The results indicate that perinatal exposure to PFOS during the critical period of development of the brain may have neurotoxic effect on CNS by mediating the molecules of calcium signaling pathway.

Keywords: Developmental neurotoxicity; Gestation; Lactation; PFOS; Hippocampus

Acknowledgement to referees (pp. 81-81).

Erratum to: Cypermethrin exposure during puberty disrupts testosterone synthesis via downregulating StAR in mouse testes by Hua Wang; Qun Wang; Xian-Feng Zhao; Ping Liu; Xiu-Hong Meng; Tao Yu; Yan-Li Ji; Heng Zhang; Cheng Zhang; Ying Zhang; De-Xiang Xu (pp. 83-83).

Erratum to: Use of two validated in vitro tests to assess the embryotoxic potential of mycophenolic acid by Kathrin Eckardt; Ralf Stahlmann (pp. 85-85).

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Archives of Toxicology (v.84, #1)