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Archives of Toxicology (v.86, #10)

Estrogen receptors in human disease by C. Cadenas; H. M. Bolt (pp. 1489-1490).

Estrogen receptors and human disease: an update by Katherine A. Burns; Kenneth S. Korach (pp. 1491-1504).

A myriad of physiological processes in mammals are influenced by estrogens and the estrogen receptors (ERs), ERα and ERβ. As we reviewed previously, given the widespread role for estrogen in normal human physiology, it is not surprising that estrogen is implicated in the development or progression of a number of diseases. In this review, we are giving a 5-year update of the literature regarding the influence of estrogens on a number of human cancers (breast, ovarian, colorectal, prostate, and endometrial), endometriosis, fibroids, and cardiovascular disease. A large number of sophisticated experimental studies have provided insights into human disease, but for this review, the literature citations were limited to articles published after our previous review (Deroo and Korach in J Clin Invest 116(3):561–570, 2006) and will focus in most cases on human data and clinical trials. We will describe the influence in which estrogen’s action, through one of or both of the ERs, mediates the aforementioned human disease states.

Keywords: Estrogen; Estrogen receptors; Human disease; Cancer; Endometriosis; Fibroids; Ovary

The naturally occurring aliphatic isothiocyanates sulforaphane and erucin are weak agonists but potent non-competitive antagonists of the aryl hydrocarbon receptor by Ahmad F. Abdull Razis; Natalya Hanlon; Ewa Soltys; Veronika Krizova; Renato Iori; Kathryn E. Plant; Nick Plant; Costas Ioannides (pp. 1505-1514).

As the Ah receptor target gene products play a critical role in chemical carcinogenesis, antagonists are considered as potential chemopreventive agents. It is demonstrated in this paper that the isothiocyanates R,S-sulforaphane and erucin are non-competitive antagonists of the aryl hydrocarbon (Ah) receptor. Both isothiocyanates were poor agonists for the receptor and elevated CYP1A1 mRNA levels only modestly when incubated with precision-cut rat liver slices. In contrast, the classical Ah receptor agonist benzo[a]pyrene was a potent inducer of CYP1A1 mRNA levels, with this effect being effectively antagonized by the two isothiocyanates. In further studies, it was demonstrated that R,S-sulforaphane could both prevent the interaction of and displace already bound benzo[a]pyrene from the Ah receptor, but no concentration dependency was observed with respect to the isothiocyanate. Both erucin and R,S-sulforaphane antagonized the benzo[a]pyrene-mediated increase in the CYP1A-mediated O-deethylation of ethoxyresorufin in rat precision-cut liver slices. Of the two isomers of R,S-sulforaphane, the naturally occurring R-isomer was more effective than the S-isomer in antagonizing the activation of the Ah receptor by benzo[a]pyrene. Antagonism of the Ah receptor may be a major contributor to the established chemoprevention of aliphatic isothiocyanates.

Keywords: Isothiocyanates; Glucosinolates; Chemoprevention; Sulforaphane; Erucin; Ah receptor

Kupffer cells suppress perfluorononanoic acid-induced hepatic peroxisome proliferator-activated receptor α expression by releasing cytokines by Xuemei Fang; Shanshan Zou; Yuanyuan Zhao; Ruina Cui; Wei Zhang; Jiayue Hu; Jiayin Dai (pp. 1515-1525).

Kupffer cells (KCs) have been demonstrated to play a role in the regulation of intra-hepatic lipid metabolism through the synthesis and secretion of biologically active products. The involvement of KCs in the disturbance of lipid metabolism that induced by perfluorononanoic acid (PFNA), a known agonist of the peroxisome proliferator-activated receptor alpha (PPARα), was investigated in this study. Rats were exposed to PFNA or PFNA combined with gadolinium chloride, an inhibitor of KCs, for 14 days. PFNA exposure dose-dependently increased absolute and relative liver weights, induced triglyceride accumulation, up-regulated the expression of both SERBP-1c and PPARα, and stimulated the release of TNFα and IL-1β. Inactivation of KCs markedly lowered TNFα and IL-1β level, enhanced PFNA-induced expression of PPARα and its target genes, and reduced liver triglyceride levels. In vitro, PFNA-induced expression of PPARα in primary cultured hepatocytes was suppressed by recombinant rat TNFα and IL-1β. However, inhibition of the NF-κB pathway prevented this. Transient transfection and promoter analysis further revealed that these two cytokines and NF-κB were coordinately involved in the suppression of PPARα promoter activity. Our data demonstrate that TNFα and IL-1β released from KCs following PFNA exposure can suppress the expression of PPARα via NF-κB pathway, which partially contribute to the evident accumulation of triglycerides in rat liver.

Keywords: Peroxisome proliferator-activated receptors; NF-κB; Lipid metabolism; Hepatotoxicity; Perfluorinated compound

Melatonin attenuates gentamicin-induced nephrotoxicity and oxidative stress in rats by In-Chul Lee; Sung-Hwan Kim; Sang-Min Lee; Hyung-Seon Baek; Changjong Moon; Sung-Ho Kim; Seung-Chun Park; Hyoung-Chin Kim; Jong-Choon Kim (pp. 1527-1536).

The present study investigated the protective effects of melatonin (MT) against gentamicin (GM)-induced nephrotoxicity and oxidative stress in rats. We also investigated the effects of MT on induction of apoptotic cell death and its potential mechanisms in renal tissues in response to GM treatment. The following four experimental groups were evaluated: (1) vehicle control, (2) MT (15 mg/kg/day), (3) GM (100 mg/kg/day), and (4) GM&MT. GM caused severe nephrotoxicity as evidenced by increased serum blood urea nitrogen and creatinine levels, increased renal tubular cell apoptosis, and increased Bcl2-associated X protein and cleaved caspase-3 protein expression. Additionally, GM treatment caused an increase in levels of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) protein expression in renal tissues. The significant decreases in glutathione content, catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase, and glutathione reductase activities and the increase in malondialdehyde content indicated that GM-induced tissue injury was mediated through oxidative reactions. In contrast, MT treatment protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by the GM treatment. Histopathological studies confirmed the renoprotective effect of MT. These results indicate that MT prevents nephrotoxicity induced by GM in rats, presumably because it is a potent antioxidant, restores antioxidant enzyme activity, and blocks NF-κB and iNOS activation in rat kidney.

Keywords: Gentamicin; Nephrotoxicity; Melatonin; Protective effects; Rats

Autocrine effect of EGFR ligands on the pro-inflammatory response induced by PM_2.5 exposure in human bronchial epithelial cells by Kiran Ramgolam; Rodolphe Hamel; Mélina Rumelhard; Francelyne Marano; Armelle Baeza-Squiban (pp. 1537-1546).

Human exposure to PM_2.5 (particulate matter with an aerodynamic diameter below 2.5 μm) is known to be responsible for airway inflammation and may also induce airway remodelling. In respiratory epithelial cells exposed to PM_2.5, releases of pro-inflammatory cytokines such as granulocyte macrophage-colony stimulating factor (GM-CSF) and growth factor ligands of the epidermal growth factor receptor (EGFR) are increased. The present study aimed at determining the involvement of EGFR ligands by autocrine effects in PM_2.5-induced GM-CSF release. PM_2.5 exposure triggers GM-CSF release by human bronchial epithelial (HBE) cells. This release is dependent on EGFR activation by ligand binding as it is inhibited by AG1478, an inhibitor of EGFR tyrosine kinase activity as well as by a neutralizing anti-EGFR antibody. The use of conditioned medium from cells previously exposed to PM_2.5 demonstrates that PM_2.5-exposed cells release soluble EGFR ligands able to induce GM-CSF release by an autocrine manner. It was further demonstrated by inhibiting tumour-necrosis factor-alpha converting enzyme (TACE) that is involved in some EGFR ligand shedding. TAPI-2 and GM-6001, two TACE inhibitors, prevented the PM_2.5-induced GM-CSF release as well as the silencing of TACE by siRNA. We provide evidence that the pro-inflammatory response induced by PM_2.5 exposure on HBE cells, results from an autocrine effect of EGFR ligands released by TACE activity. This autocrine loop by eliciting and sustaining inflammation could contribute to exacerbation of airway remodelling in respiratory-compromised individuals.

Keywords: Fine particles; Amphiregulin; Airway; TACE; 16HBE; Inflammation

Paraquat induces lung alveolar epithelial cell apoptosis via Nrf-2-regulated mitochondrial dysfunction and ER stress by Ya-Wen Chen; Yuan-Ting Yang; Dong-Zong Hung; Chin-Chuan Su; Kuo-Liang Chen (pp. 1547-1558).

Paraquat (1,1′-dimethyl-4,4′-bipyridinium chloride; PQ) is widely and commonly used as a herbicides in the world. PQ has been reported to be a major hazard because it causes lung injury. However, the molecular mechanisms underlying PQ-induced lung toxicity still need to be elucidated. Here, we found that PQ significantly decreases cell viability, increases sub-G1 hypodiploids DNA contents and caspase 3/7 activity in lung alveolar epithelial cell-derived L2 cells, which also caused mitochondrial dysfunction, and decreased the mRNA expression of Bcl-2 and increased that of Bax, Bak, and p53. Moreover, the protein expressions of Bax and Bak were increased in PQ-treated cells. In addition, when PQ was exposed to L2 cells, the expressions of ER stress-related signaling genes (including Grp78, CHOP, and caspase-12 mRNA) and proteins (including phospho-eIF-2α, CHOP, Grp78, calpain I and -II, and caspase-12) were significantly increased. PQ also decreased the protein expressions of pro-caspase-9/7/3. Next, we investigated the role of Nrf-2 in PQ-induced alveolar epithelial cell toxicity. In L2 cells, PQ induced Nrf-2 translocation from the cytosol to the nucleus. Cells transfected with Nrf-2 siRNA significantly reversed the PQ-induced toxicity, including depolarization of MMP, increased the Bax, Bak, p53 mRNAs expression, decreased the Bcl-2 mRNA expression, increased the caspase 3/7 activity, Grp78, CHOP, and caspase-12 mRNAs and protein expression, and decreased that of pro-caspase-3. Taken together, these results suggest that Nrf-2-regulated mitochondria and ER stress-related pathways are involved in the PQ-induced alveolar epithelial cell injury.

Keywords: Paraquat; Alveolar epithelial cell; Nrf-2; Apoptosis; Mitochondria dysfunction; ER stress

Similar distribution changes of GABAergic interneuron subpopulations in contrast to the different impact on neurogenesis between developmental and adult-stage hypothyroidism in the hippocampal dentate gyrus in rats by Ayako Shiraki; Hirotoshi Akane; Takumi Ohishi; Liyun Wang; Reiko Morita; Kazuhiko Suzuki; Kunitoshi Mitsumori; Makoto Shibutani (pp. 1559-1569).

Hypothyroidism affects neurogenesis. The present study was performed to clarify the sensitivity of neurogenesis-related cellular responses in the hippocampal dentate gyrus between developmental and adult-stage hypothyroidism. An exposure study of methimazole (MMI) as an anti-thyroid agent at 0, 50, 200 ppm in the drinking water was performed using pregnant rats from gestation day 10 to postnatal day (PND) 21 (developmental hypothyroidism) and adult male rats by setting an identical exposure period from PND 46 through to PND 77 (adult-stage hypothyroidism). Offspring with developmental hypothyroidism were killed at PND 21 or PND 77, and animals with adult-stage hypothyroidism were killed at PND 77. Proliferation and apoptosis were unchanged in the dentate subgranular zone by either developmental or adult-stage hypothyroidism. With regard to precursor granule cells, a sustained reduction of paired box 6-positive stem or early progenitor cells and a transient reduction of doublecortin-positive late-stage progenitor cells were observed after developmental hypothyroidism with MMI at 50 and 200 ppm. These cells were unchanged by adult-stage hypothyroidism. With regard to γ-aminobutyric acid (GABA) ergic interneuron subpopulations in the dentate hilus, the number of parvalbumin-positive cells was decreased and the number of calretinin-positive cells was increased after both developmental and adult-stage hypothyroidism with MMI at 50 and 200 ppm. Fluctuations in GABAergic interneuron numbers with developmental hypothyroidism continued through to PND 77 with 200 ppm MMI. Considering the roles of GABAergic interneuron subpopulations in neurogenesis and neuronal differentiation, subpopulation changes in GABAergic interneurons by hypothyroidism may be the signature of aberrant neurogenesis even at the adult stage.

Keywords: Hypothyroidism; Hippocampal dentate gyrus; Impaired neurogenesis; γ-Aminobutyric acid (GABA) ergic interneurons; Parvalbumin (Pvalb)

Partition of metals in the maternal/fetal unit and lead-associated decreases of fetal iron and manganese: an observational biomonitoring approach by Ricarda S. Kopp; Michael Kumbartski; Volker Harth; Thomas Brüning; Heiko U. Käfferlein (pp. 1571-1581).

To systematically study the partition of environmental metals including lead, mercury, and cadmium and essential minerals such as iron, manganese, copper, and zinc in the maternal/fetal unit of healthy pregnant women, we analyzed blood and umbilical cord blood samples of 50 healthy mother/child pairs using a biomonitoring approach. The levels of essential minerals in healthy pregnant women were significantly different from those of the general population. The partition of essential minerals and environmental metals and their associations between maternal and umbilical cord blood were metal-specific. Lead entered the fetal environment nearly unaffected. The median fetal level was only 10 % lower than the corresponding maternal concentration (10.3 vs. 11.5 μg/l, P = 0.0038). Mercury accumulated in the fetal unit resulting in more than a threefold increase in fetal compared to maternal exposure (1.48 vs. 0.44 μg/l, P < 0.0001). In contrast, placental transfer of Cd was limited, and median fetal exposure was <0.1 μg/L. We finally used the data to assess the influence of exposures to environmental metals on fetal homeostasis of essential minerals because environmental metals such as lead are capable of interfering with normal cellular functions of essential minerals by mimicking their pathways. A subtle but systematic and dose-dependent effect of environmental exposure to lead on fetal homeostasis of manganese and iron in terms of reducing their concentrations in the fetal unit was found (P ≤ 0.039). The observed associations remained unaffected in the presence of mercury and cadmium. The results illustrate the need to establish specific normative levels of essential minerals in pregnant women. Additionally, the study provides initial insights into the mode-of-action of lead in the fetus at current environmental exposures.

Keywords: Biomonitoring; Lead; Essential minerals; Prenatal exposures; Blood

Cytotoxicity and genotoxicity of versicolorins and 5-methoxysterigmatocystin in A549 cells by Daniela Jakšić; Olivier Puel; Cécile Canlet; Nevenka Kopjar; Ivan Kosalec; Maja Šegvić Klarić (pp. 1583-1591).

Aspergillus versicolor and A. flavus are primary colonizers in damp dwellings, and they produce sterigmatocystin (ST) and aflatoxin B1 (AFB₁), respectively. These hepatotoxic and carcinogenic mycotoxins and their precursors and derivates possess a furofuran ring, which has proven responsible for their toxicity. The aim of this study was to investigate the cytotoxicity and genotoxicity of versicolorin A (VER A) and versicolorin B (VER B), as the furofuran precursors of aflatoxins and ST, and of 5-methoxysterigmatocystin (5-MET-ST), a methoxy derivative of ST, in human adenocarcinoma lung cells A549. The IC₅₀ values of the tested compounds were obtained by the cell proliferation MTT test as follows: 109 ± 3.5 μM (VER A), 172 ± 4 μM (VER B) and 181 ± 2.6 μM (5-MET-ST). The comet assay and micronucleus test were used to assess their genotoxic potential after 24 h of treatment with concentrations corresponding to ½ and ¼ IC₅₀ in comparison with AFB₁ and ST, applied in concentrations corresponding to ½ IC₅₀, as previously determined in A549 cells. DNA damage parameters assessed by the comet assay were tail length, tail intensity and tail moment, while the level of DNA damage in the micronucleus test was evaluated by the number of formed micronuclei (MN), nuclear buds (NB) and nucleoplasmic bridges (NPB) in 1,000 binucleated cells. Considering the three comet parameters, all applied toxins exerted significant DNA damage compared to the control, while ST and VER B produced the highest DNA damage. All toxins provoked a statistically significant increase in MN, and a slightly decreased formation of NB and NPB. AFB₁, ST and 20 μM VER A showed a statistically significant increase in all three micronucleus parameters compared to the control, and the highest increase in the number of MN occurred in cells treated with 50 μM VER A. The differences between results obtained by the micronucleus test and comet assay could be explained by the fact that the micronucleus detects irreversible DNA damage, which is usually correlated with the previously determined cytotoxic potential of the AFB₁ precursors.

Keywords: Aflatoxins; Sterigmatocystin; Versicolorin A; Versicolorin B; 5-Methoxysterigmatocystin; Bisfuran ring; Comet assay; Micronucleus test; A549 cells

Possible involvement of genotoxic mechanisms in estragole-induced hepatocarcinogenesis in rats by Yuta Suzuki; Takashi Umemura; Daisuke Hibi; Tomoki Inoue; Meilan Jin; Yuji Ishii; Hiroki Sakai; Takehiko Nohmi; Tokuma Yanai; Akiyoshi Nishikawa; Kumiko Ogawa (pp. 1593-1601).

Estragole (ES) is a natural organic compound used frequently as a flavoring food additive. Although it has been reported to be tumorigenic and induce DNA adducts in the mouse liver, there have been no reports regarding ES hepatocarcinogenicity in rats. In the current study, we therefore examined potent carcinogenicity, DNA adduct formation and in vivo genotoxicity of ES in the livers of wild and reporter gene-carrying F344 rats. Males were administered 600 mg/kg bw ES by gavage and sequentially sacrificed at weeks 4, 8 and 16 for GST-P and PCNA immunohistochemistry and measurement of ES-specific DNA adducts by LC-MS/MS in the livers. GST-P-positive foci increased with time in ES-treated rats from week 4, PCNA-labeling indices being similarly elevated at both weeks 4 and 8. ES-specific DNA adducts such as ES-3′-N ²-dG, 3′-8-dG and 3′-N ⁶-dA were consistently detected, particularly at week 4. In a second study, male F344 gpt delta rats were administered 0, 22, 66, 200 or 600 mg/kg bw ES for 4 weeks. Gpt mutant frequency in the liver was increased in a dose-dependent manner, with significance at 200 and 600 mg/kg bw in good correlation with PCNA-labeling indices. Mutation spectra analysis showed A:T to G:C transitions to be predominantly increased in line with the formation of ES-3′-N ⁶-dA or 3′-8-dG. These results indicate that ES could be a possible genotoxic hepatocarcinogen in the rat, at least when given at high doses.

Keywords: Estragole; Rat; Hepatocarcinogenesis; Genotoxicity

Regulation of uterine AHR battery gene expression by 17β-Estradiol is predominantly mediated by estrogen receptor α by Felicitas Rataj; Frank Josef Möller; Maria Jähne; Oliver Zierau; Patrick Diel; Günter Vollmer; Georg Kretzschmar (pp. 1603-1612).

The aryl hydrocarbon receptor (AHR) is known to mediate the cellular response to numerous xenobiotics including dioxin. Surprisingly AHR knockout mice provide evidence for the involvement of the AHR signalling cascade in estrogen regulated physiological functions of the female reproductive system. Several studies already aimed to investigate the impact of the AHR mediated xenobiotic response pathway on estrogen receptor (ER) signalling, whereas on contrary availability of data describing the effect of 17β-Estradiol (E2) on the AHR signalling cascade is rather limited. In this study we observed an inhibitory effect of E2 treatment on uterine Ahr, Arnt, Arnt2, Ahrr, Cyp1a1, Ugt1 and Nfe2l2 gene expression in ovariectomized Wistar rats, whereas Cyp1b1, Nqo1 and Gsta2 displayed an increased transcription. The usage of the ER selective agonists, 16α-LE₂ (ERα selective) and 8β-VE₂ (ERβ selective), enabled us to distinguish between ER subtype specific responses. On mRNA level the observed changes in gene expression were mainly mediated by ERα except for the expression of Nqo1. In most cases the activation of ERβ caused effects opposite to the ones observed following activation of ERα. Despite the significant changes in AHR mRNA levels immunohistochemical staining uterine tissue section did not reveal changes of the AHR protein level. Taken together our results validate, support and extend the hypothesis of uterine crosstalk between AHR and ER signalling pathways. Furthermore they give an insight into how the AHR and its related genes may participate in E2 dependent uterine physiological processes and provide another potential mechanism of action for xenoestrogens.

Keywords: Aryl hydrocarbon receptor; Estrogen receptor; ARNT; 17β-Estradiol; ER selective agonists; Uterus

7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide by Eric V. Patridge; Emma S. E. Eriksson; Philip G. Penketh; Raymond P. Baumann; Rui Zhu; Krishnamurthy Shyam; Leif A. Eriksson; Alan C. Sartorelli (pp. 1613-1625).

Here, we report on 7-nitro-4-(phenylthio)benzofurazan (NBF-SPh), the most potent derivative among a set of patented anticancer 7-nitrobenzofurazans (NBFs), which have been suggested to function by perturbing protein–protein interactions. We demonstrate that NBF-SPh participates in toxic redox-cycling, rapidly generating reactive oxygen species (ROS) in the presence of molecular oxygen, and this is the first report to detail ROS production for any of the anticancer NBFs. Oxygraph studies showed that NBF-SPh consumes molecular oxygen at a substantial rate, rivaling even plumbagin, menadione, and juglone. Biochemical and enzymatic assays identified superoxide and hydrogen peroxide as products of its redox-cycling activity, and the rapid rate of ROS production appears to be sufficient to account for some of the toxicity of NBF-SPh (LC₅₀ = 12.1 μM), possibly explaining why tumor cells exhibit a sharp threshold for tolerating the compound. In cell cultures, lipid peroxidation was enhanced after treatment with NBF-SPh, as measured by 2-thiobarbituric acid-reactive substances, indicating a significant accumulation of ROS. Thioglycerol rescued cell death and increased survival by 15-fold to 20-fold, but pyruvate and uric acid were ineffective protectants. We also observed that the redox-cycling activity of NBF-SPh became exhausted after an average of approximately 19 cycles per NBF-SPh molecule. Electrochemical and computational analyses suggest that partial reduction of NBF-SPh enhances electrophilicity, which appears to encourage scavenging activity and contribute to electrophilic toxicity.

Keywords: Benzofurazan; Reactive oxygen species; Oxidative stress; Electrochemistry; Electrophilic stress

Effect of fluoride toxicity on cardiovascular systems: role of oxidative stress by Ercan Varol; Simge Varol (pp. 1627-1627).

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Archives of Toxicology (v.86, #10)