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Archives of Toxicology (v.86, #1)

The safety profile of imatinib in CML and GIST: long-term considerations by Eirini Thanopoulou; Ian Judson (pp. 1-12).

Imatinib mesylate is considered the standard first-line systemic treatment for patients with chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST) by targeting BCR-ABL and c-KIT tyrosine kinases, respectively. Indeed, imatinib has substantially changed the clinical management and improved the prognosis of both diseases. Treatment with imatinib is generally well tolerated, and the risk for severe adverse effects is low, generally occurring during the early phase of treatment and correlating with imatinib dose, phase of disease and patient’s characteristics. This article summarises recent data on safety profile of imatinib for the treatment of CML and GIST, including long-term side effects. Prolonged treatment with imatinib in both diseases demonstrates excellent tolerability. There are few significant concerns and those that have emerged, like cardiotoxicity, have far turned out to be exaggerated.

Keywords: Imatinib; CML; GIST; Safety; Toxicity

Highlight report: towards the replacement of in vivo repeated dose systemic toxicity testing by Jan G. Hengstler; Rosemarie Marchan; Marcel Leist (pp. 13-15).

Threshold of toxicological concern values for non-genotoxic effects in industrial chemicals: re-evaluation of the Cramer classification by H. Kalkhof; M. Herzler; R. Stahlmann; U. Gundert-Remy (pp. 17-25).

The TTC concept employs available data from animal testing to derive a distribution of NOAELs. Taking a probabilistic view, the 5th percentile of the distribution is taken as a threshold value for toxicity. In this paper, we use 824 NOAELs from repeated dose toxicity studies of industrial chemicals to re-evaluate the currently employed TTC values, which have been derived for substances grouped according to the Cramer scheme (Cramer et al. in Food Cosm Toxicol 16:255–276, 1978) by Munro et al. (Food Chem Toxicol 34:829–867, 1996) and refined by Kroes and Kozianowski (Toxicol Lett 127:43–46, 2002), Kroes et al. 2000. In our data set, consisting of 756 NOAELs from 28-day repeated dose testing and 57 NOAELs from 90-days repeated dose testing, the experimental NOAEL had to be extrapolated to chronic TTC using regulatory accepted extrapolation factors. The TTC values derived from our data set were higher than the currently used TTC values confirming the safety of the latter. We analysed the prediction of the Cramer classification by comparing the classification by this tool with the guidance values for classification according to the Globally Harmonised System of classification and labelling of the United Nations (GHS). Nearly 90% of the chemicals were in Cramer class 3 and assumed as highly toxic compared to 22% according to the GHS. The Cramer classification does underestimate the toxicity of chemicals only in 4.6% of the cases. Hence, from a regulatory perspective, the Cramer classification scheme might be applied as it overestimates hazard of a chemical.

Keywords: Cramer classification; TTC values; Industrial chemicals; Improvements; Repeated dose toxicity

Assessment of DNA integrity (COMET assay) in sperm cells of boron-exposed workers by Yalçın Duydu; Nurşen Başaran; Aylin Üstündağ; Sevtap Aydın; Ülkü Ündeğer; Osman Yavuz Ataman; Kaan Aydos; Yalçın Düker; Katja Ickstadt; Britta Schulze Waltrup; Klaus Golka; Hermann M. Bolt (pp. 27-35).

An extension of a male reproductive study conducted in a boric acid/borate production zone at Bandırma, Turkey, is presented. The relation between DNA-strand breaks (COMET assay, neutral and alkaline version) in sperm cells and previously described sperm quality parameters was investigated in boron-exposed males. A correlation between blood boron levels and mean DNA-strand breaks in sperm was weak, and DNA-strand breaks in sperm were statistically not different between control and exposed groups. Therefore, increasing boron exposures had no additional contribution in addition to already pre-existing DNA-strand breaks in the sperm cells. Weak but statistically significant correlations between DNA-strand breaks and motility/morphology parameters of sperm samples were observed in the neutral version of the COMET assay, while correlations between the same variables were statistically not significant in the alkaline version. A likely reason for these negative results, even in highly exposed humans, is that experimental exposures that had led to reproductive toxicity in animals were significantly higher than any boron exposures, which may be reached under realistic human conditions.

Keywords: Boric acid; Borax; Boron; COMET assay; Fertility; Sperm parameters; Male reproduction

Effects of salubrinal on cadmium-induced apoptosis in HK-2 human renal proximal tubular cells by Yuta Komoike; Hisako Inamura; Masato Matsuoka (pp. 37-44).

Cadmium exposure is known to cause endoplasmic reticulum (ER) stress. In our current study, we examined the effects of salubrinal, a selective inhibitor of eukaryotic translation initiation factor 2 subunit α (eIF2α) dephosphorylation, on apoptotic cell death and ER stress-signaling events in HK-2 human renal proximal tubular cells exposed to cadmium chloride (CdCl₂). Using phase-contrast microscopy and a cell viability assay, we observed that salubrinal suppressed CdCl₂-induced cellular damage and cell death. Treatment with salubrinal reduced the number of TUNEL-positive cells and the cleavages of caspase-3 and poly(ADP-ribose) polymerase, but not the cleavage of light chain 3B, indicating protection from CdCl₂-induced apoptosis but not autophagy. Although eIF2α remained phosphorylated after CdCl₂ exposure to salubrinal-treated HK-2 cells, the expression of activating transcription factor 4 (ATF4) and the 78 kDa glucose-regulated protein (GRP78) was not increased. On the other hand, CdCl₂-induced expression of C/EBP homologous protein (CHOP) was reduced by salubrinal treatment. Expression of ATF4, an upstream regulator of GRP78 and CHOP, appeared to be a prerequisite for full protection by salubrinal against cadmium cytotoxicity, because CdCl₂-induced cellular damage was not fully suppressed in ATF4-deficient cells. Phosphorylated forms of mitogen-activated protein kinases (MAPKs), including c-Jun NH₂-terminal kinase (JNK), p38, and extracellular signal-regulated protein kinase (ERK), increased after CdCl₂ exposure, whereas salubrinal suppressed the phosphorylation of JNK and p38 but not ERK. These results suggest that salubrinal protects CdCl₂-exposed HK-2 cells from apoptosis by suppressing cell death signal transduction pathways.

Keywords: Salubrinal; Cadmium; Apoptosis; ER stress; HK-2 cells

Excretion kinetics of urinary 3-hydroxybenzo[a]pyrene following dietary exposure to benzo[a]pyrene in humans by Yeh-Chung Chien; Chun-Ting Yeh (pp. 45-53).

Urinary 3-hydroxy-benzo[a]pyrene (3-OHBaP) is considered as an exposure marker for assessing carcinogenic risks as it is a metabolite of benzo[a]pyrene (BaP). A controlled human study was conducted to examine the kinetics of urinary 3-OHBaP after consuming charcoal-barbecued meat. Two feeding experiments were performed, with meat doses of 15 and 30 g/kg (experiments 1 and 2, respectively). All voided urine over 7 days was collected and analyzed. The background urinary 3-OHBaP concentration was 0.002–0.085 ng/g creatinine, with large inter-individual (80–100%) and intra-individual of (90–100%) variations. The background amount of 3-OHBaP excreted by the current subjects was 40–50 pg/day. The amounts of urinary 3-OHBaP excreted within 12 h post-exposure increased significantly (P < 0.05) from background only in experiment 1. The proportion of the administered BaP dose that was excreted as urinary 3-OHBaP within 12 h post-exposure was 0.006 and 0.0012% in experiments 1 and 2, respectively. The excretion ratio declined as the dose increased. Urinary 3-OHBaP can be used to assess dietary exposure to BaP, but it may be not suitable for low-dose scenarios because of the low urinary excretion proportion and high variability of the background.

Keywords: Barbecued meats; PAH; 1-Hydroxypyrene; 3-Hydroxy-benzo[a]pyrene; Benzo[a]pyrene

Uptake of triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) and dicamba (3,6-dichloro-2-methoxybenzoic acid) from the apical membranes of the human intestinal Caco-2 cells by Osamu Kimura; Kensuke Tsukagoshi; Moriaki Hayasaka; Tetsuya Endo (pp. 55-61).

We investigated whether the uptake of triclopyr (3, 5, 6-trichloro-2-pyridinyloxyacetic acid) and dicamba (3,6-dichloro-2-methoxybenzoic acid) across the apical membrane of Caco-2 cells was mediated via proton-linked monocarboxylic acid transporters (MCTs). The uptake of triclopyr from the apical membranes was fast, pH-, temperature-, and concentration dependent, required metabolic energy to proceed, and was competitively inhibited by monocarboxylic acids such as benzoic acid and ferulic acid (substrates of l-lactic acid-insensitive MCTs), but not by l-lactic acid. Thus, the uptake of triclopyr in Caco-2 cells appears to be mediated mainly via l-lactic acid-insensitive MCTs. In contrast, the uptake of dicamba (a benzoic acid derivative) was slow, and it was both pH- and temperature dependent. Coincubation with ferulic acid did not decrease the uptake of dicamba, although coincubation with benzoic acid moderately decreased it. The uptake of dicamba appears to be mediated mainly via passive diffusion, which is in contrast to the uptake of benzoic acid via MCTs. We speculate that the substituted groups in dicamba may inhibit uptake via MCTs.

Keywords: Triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid); Dicamba (3,6-dichloro-2-methoxybenzoic acid); Benzoic acid; Monocarboxylic acid transporter (MCT); Caco-2 cells

Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice by Tomohiko Nakagawa; Doni Hikmat Ramdhan; Naoki Tanaka; Hisao Naito; Hazuki Tamada; Yuki Ito; Yufei Li; Yumi Hayashi; Nozomi Yamagishi; Yukie Yanagiba; Toshifumi Aoyama; Frank J. Gonzalez; Tamie Nakajima (pp. 63-74).

Perfluorooctanoic acid is a ligand for peroxisome proliferator-activated receptor (PPARα). Ammonium perfluorooctanoate (APFO) at 0.1 and 0.3 mg/kg doses activated mouse PPARα, but not human PPARα. This study aimed to clarify whether milligram-order APFO can activate human PPARα, and the receptor is involved in APFO-induced chronic hepatic damage. Male Sv/129 wild-type (mPPARα), Pparα-null, and humanized PPARα (hPPARα) mice (8 weeks old) were divided into three groups. The first was treated with water and the other two with 1.0 and 5.0 mg/kg APFO for 6 weeks, orally, respectively. Both doses activated mouse and human PPARα to a similar or lower degree in the latter. APFO dose dependently increased hepatic triglyceride levels in Pparα-null and hPPARα mice, but conversely decreased those in mPPARα ones. APFO-induced hepatic damage differed markedly among the three genotyped groups: single-cell necrosis was observed in all genotyped mice; inflammatory cells and macrovesicular steatosis only in Pparα-null mice; and microvesicular steatosis and hydropic degenerations in hPPARα and Pparα-null mice. The molecular mechanism underlying these differences may be attributable to those of gene expressions involved in lipid homeostasis (PPARα, β- and ω-oxidation enzymes, and diacylglycerol acyltransferases) and uncoupling protein 2. Thus, milligram-order APFO activated both mouse and human PPARα in a different manner, which may reflect histopathologically different types of hepatic damage.

Keywords: Hepatic damage; Human; Mouse; Perfluorooctanoic acid; Peroxisome proliferator-activated receptor

Expression of hepatic and ovarian cytochrome P450 during estrous cycle in rats by Sang Yoon Lee; Soo Jin Oh; Kang Uk Yun; Hwan Mook Kim; Bong-Hee Kim; Kiho Lee; Sang Kyum Kim (pp. 75-85).

It is known that gender differences in drug metabolism are largely attributed to changes in sex and growth hormones. Serum concentrations of estradiol, progesterone, prolactin, follicle-stimulating hormone, and luteinizing hormone change markedly during the human menstrual cycle and the rat estrous cycle. However, little information is available regarding the effects of the human menstrual cycle or the rat estrous cycle on expression and activity of cytochrome P450 (CYP) isoforms. The present study was carried out to determine the expression and activity of CYP-dependent drug-metabolizing enzymes in the liver and ovary during the estrous cycle. The expression and activity of microsomal CYP isoforms (CYP1A1, CYP1A2, CYP1B1, CYP2B1, CYP2C11, CYP2C12, CYP2E1, CYP3A1, CYP3A2, and CYP4A), cytochrome b₅ and NADPH-dependent CYP reductase in the liver and ovary were measured in female rats in diestrus and proestrus. Our results indicated that hepatic and ovarian expression and activity of CYP isoforms, cytochrome b₅, and NADPH-dependent CYP reductase were not different between diestrus and proestrus, although serum estradiol concentration and uterus weight were markedly increased in the proestrus phase. These results suggest that the cytochrome P450-dependent system is not sensitive to changes in the estrous cycle, and further studies are warranted to determine the effects of the estrous cycle on in vivo metabolism of xenobiotics.

Keywords: Drug-metabolizing enzyme; Cytochrome P450; Estrous cycle; Liver; Ovary; Estradiol

Comparative analysis of phase I and II enzyme activities in 5 hepatic cell lines identifies Huh-7 and HCC-T cells with the highest potential to study drug metabolism by Jie Lin; Lilianna Schyschka; Ruben Mühl-Benninghaus; Jan Neumann; Liping Hao; Natascha Nussler; Steven Dooley; Liegang Liu; Ulrich Stöckle; Andreas K. Nussler; Sabrina Ehnert (pp. 87-95).

Primary human hepatocytes (hHeps) are still gold standard to perform human drug metabolism studies, but their availability is limited by donor organ scarcity. Therefore, hepatoma cell lines are widely used as alternatives, although their phases I and II drug-metabolizing activities are substantially lower compared with hHeps. The major advantage of these cell lines is immediate availability, standardized culture conditions and unlimited life span. Therefore, the aim of this study was to investigate the drug-metabolizing profile of five human hepatoma cell lines (HepG2, Hep3B, HCC-T, HCC-M and Huh-7) over a culture period of 10 passages. Fluorescent-based assays for seven different cytochrome P450 (CYP) isoforms and seven different phase II enzymes were performed and compared with enzymatic activities of hHeps. CYP activities were much lower in the cell lines (5–15% of hHeps), whereas phase II enzyme activities that are involved in buffering oxidative stress (e.g., Glutathione-S-transferase) reached levels comparable with hHeps. Furthermore, phases I and II enzyme activities in hepatoma cell lines vary strongly during culture time. Interestingly, the most constant results were obtained with Huh-7 cells. Huh-7 cells as well as HCC-T cells exhibited a drug-metabolizing profile closest to hHeps between passages two and four. Toxicity studies with Diclofenac, Paracetamol and Verapamil in both cell lines show dose–response characteristics and EC₅₀ values similar to hHeps. Therefore, we propose that due to the more consistent results throughout the passages, Huh-7 could be an alternative system to the limitedly available hHeps and frequently used HepG2 cell line in the study of drug metabolism.

Keywords: Drug development; Hepatocytes; Drug-induced liver damage; Hepatic cell lines

A potential role of calcium in apoptosis and aberrant chromatin forms in porcine kidney PK15 cells induced by individual and combined ochratoxin A and citrinin by Maja Šegvić Klarić; Davor Želježić; Lada Rumora; Maja Peraica; Stjepan Pepeljnjak; Ana-Marija Domijan (pp. 97-107).

The aim of this study was to establish the involvement of calcium signalling in genotoxicity, apoptosis and necrosis evoked by ochratoxin A (OTA) and citrinin (CTN) alone or in combination in porcine kidney PK15 cells. Cell proliferation test (MTT) and trypan blue assays (24 h) demonstrated that CTN (IC₅₀ = 73.5 ± 1.0, 75.4 ± 1.4 μM, respectively) was less toxic than OTA (IC₅₀ = 14.0 ± 2.4, 20.5 ± 1.0 μM, respectively). To test their cytotoxic interactions, two doses of single OTA (6 and 10 μM) and CTN (30 and 50 μM) and their combinations were applied. Combined treatment showed additive cytotoxic effects. OTA and CTN induced dose-dependent increase in cytosolic calcium level (assessed with Fura-2 AM). However, combined treatment did not provoke additional increase in calcium signal. The rate of apoptosis and necrosis (DAPI-antifade staining) was significantly higher after 12 h than 24 h, while the frequencies of micronuclei (MNs) and nuclear buds (NBs) were higher after 24 h than 12 h treatment. Combined exposure resulted in apoptotic and necrotic synergism, while genotoxic effects of OTA + CTN were noted as antagonistic or additive. Co-exposure of cells to calcium chelator BAPTA-AM significantly reduced CTN and OTA + CTN-evoked apoptosis. Twenty-four hour after co-exposure to BAPTA-AM and a single OTA and CTN, MNs significantly decreased while NBs dropped significantly after co-treatment with BAPTA-AM and OTA + CTN. In conclusion, disturbance of Ca²⁺ homeostasis caused by OTA and CTN plays a significant role in cell genotoxicity and death.

Keywords: Nephrotoxins; Genotoxicity; Necrosis; BAPTA-AM; Mycotoxin synergism

The anabolic steroid methandienone targets the hypothalamic–pituitary–testicular axis and myostatin signaling in a rat training model by Stephanie Mosler; Carlos Pankratz; Alexis Seyfried; Marion Piechotta; Patrick Diel (pp. 109-119).

There is increasing evidence that the biological activity of myostatin (MSTN), a negative regulator of muscle growth, is affected by training but also anabolic steroids. In this study, we analyzed the effects of the frequently abused anabolic steroid methandienone (Md) on the hypothalamic–pituitary–testicular axis and androgen-sensitive tissues in intact rats performing a treadmill training to simulate the situation of abusing athletes. The anabolic effects were correlated with the expression of members of the MSTN signaling cascade. Md treatment resulted in a significant stimulation of anabolic activity of the levator ani muscle, which was further increased by training, while prostate and seminal vesicle weights decreased in conformance with hormone concentrations of LH and testosterone. In gastrocnemius muscle, mRNA expression of genes of the MSTN signaling cascade (MSTN, Smad7 and MyoD) was reduced by training but not after Md treatment, in soleus muscle MSTN and its inhibitors, follistatin (FLST) and Smad-7 were only affected after training in combination with Md treatment. In summary, our data demonstrate that Md treatment of intact rats results in anabolic effects which are enhanced in combination with physical activity. Interestingly, the anabolic activity on the levator ani was increased in combination with training, although the levator ani muscle was not specifically stimulated by our training protocol. In the m. gastrocnemius and soleus, the anabolic effects correlate with changes in the expression patterns of genes involved in MSTN signaling. Our data provide evidence that the decrease in the weight of androgen-sensitive sexual glands, observed after Md treatment, is caused by a suppression of endogenous testosterone synthesis. These observations provide new insights into the molecular mechanisms of the interaction between anabolic steroids, training and MSTN signaling during skeletal muscle adaptation.

Keywords: Myostatin; Methandienone; Follistatin; Doping; Anabolic steroid

Urban particulate matter activates Akt in human lung cells by Todd L. Watterson; Brett Hamilton; Randy S. Martin; Roger A. Coulombe Jr. (pp. 121-135).

The normally picturesque Cache Valley in northern Utah is frequently reported to have the worst particulate (PM) air pollution in the United States. Numerous epidemiological studies conducted elsewhere have associated PM exposure to a variety of cardiovascular diseases and early mortality. We have previously shown that Cache Valley PM (CVPM) is pro-inflammatory, through a variety of mechanisms involving the release of inflammatory cytokines, unfolded protein response, ER stress, and C-reactive protein (CRP). This study was undertaken to determine whether Cache Valley PM (CVPM) would activate Akt, an upstream mechanism common to these events. Human lung (BEAS-2B) cells were treated with either fine (PM_2.5) or coarse (PM₁₀) particles (12.5 and 25 μg/ml) for periods up to 24 h. PM-exposed cells exhibited Akt activation as evidenced by phosphorylation at Thr³⁰⁸ and Ser⁴⁷³. Events downstream of Akt activation such as NF-κB activation were observed at 1 and 24 h, but IκB phosphorylation occurred only at 24 h, indicating that mechanisms of PM-mediated NF-κB activation are time dependent. Akt and NF-κB related inflammatory cytokine IL-1α, and IL-6 and the chemokine IL-8 were upregulated in treated cells at 6 and 24 h. The calpain inhibitor leupeptin limited Akt phosphorylation to Ser⁴⁷³ and reduced release of IL-1α, IL-6, and IL-8, indicating that calpain or similar protease(s) are involved in PM-induced activation of Akt and subsequent release of inflammatory cytokines. Our data indicate that PM activates Akt, which may play a role in the pro-inflammatory response to PM exposure.

Keywords: Akt; Particulate air pollution; PM_2.5 ; LPS; Leupeptin; PTEN; Cytokine

Lung deposition and toxicological responses evoked by multi-walled carbon nanotubes dispersed in a synthetic lung surfactant in the mouse by Carole Ronzani; Coralie Spiegelhalter; Jean-Luc Vonesch; Luc Lebeau; Françoise Pons (pp. 137-149).

In the present work, we elaborated a synthetic lung surfactant composed of dipalmitoyl phosphatidylcholine (DPPC), phosphatidylglycerol, cholesterol and bovine serum albumin (BSA), as a vehicle to study the lung toxicity of pristine multi-walled carbon nanotubes (MWCNT). MWCNT were dispersed in surfactant, saline or saline containing DPPC, BSA, Pluronic^® F68 or sodium dodecyl sulfate, for comparison. Dispersions were characterized visually, and by light microscopy, dynamic light scattering and transmission electronic microscopy (TEM). Deposition of surfactant-dispersed MWCNT in the lung of BALB/c mice upon single or repeated administrations was analyzed by histology and TEM. Inflammation and airway remodeling were assessed in bronchoalveolar lavage fluid (BALF) or lung tissue of mice by counting cells and quantifying cytokines, tumor growth factor (TGF)-β1 and collagen, and by histology. We found that the elaborated surfactant is more effective in dispersing MWCNT when compared to the other agents, while being biocompatible. Surfactant-dispersed MWCNT distributed all throughout the mouse airways upon single and repeated administrations and were observed in alveolar macrophages and epithelial cells, and in infiltrated neutrophils. Mice that received a single administration of MWCNT showed neutrophil infiltrate and greater concentrations of tumor necrosis factor (TNF)-α, keratinocyte-derived chemokine (KC) and interleukin (IL)-17 in BALF when compared to controls. After repeated MWCNT administrations, increases in macrophage number, KC and TGF-β1 levels in BALF, and collagen deposition and mucus hyperplasia in lung tissue were observed. Altogether, the elaborated lung surfactant could be a valuable tool to further study the toxicological impact of pristine MWCNT in laboratory animals.

Keywords: Carbon nanotubes; Dispersion; Surfactant; Lung; Deposition; Toxicity

Endocrine-mediated effects of 4,4’-(hexafluoroisopropylidene)diphenol in SD rats, based on a subacute oral toxicity study by Takaaki Umano; Ryota Tanaka; Kanji Yamasaki (pp. 151-157).

The purpose of this study was to investigate the endocrine-mediated effects of 4,4’-(hexafluoroisopropylidene)diphenol according to OECD test guideline no. 407. The estrogenic properties of this chemical have already been shown on uterotrophic assay, and this chemical is classified as a low-production volume chemical in REACH program. Rats were orally gavaged with 0, 10, 30, and 100 mg/kg/day of test chemical for at least 28 days, beginning at 8 weeks of age. In the 100 mg/kg group of male rats, endocrine-mediated effects, atrophic changes in the mammary glands and testicular Leydig cells, decreased accessory sex organ weights, and hypertrophy of the adrenal zona fasciculata with increased organ weights were seen; there was dysfunction of the estrous cycle in the 30 and 100 mg/kg groups, and increased serum T4 values were observed in the 100 mg/kg groups of both sexes. In addition, we also noted other findings, such as reduced body weight gains in the 30 and/or 100 mg/kg groups of both sexes, dilatation of the large intestinal lumen in the 100 mg/kg groups of both sexes, decreased hematopoiesis in the bone marrow and spleen, and decreased white blood cell counts in the 100 mg/kg group of male rats. Our results demonstrate that in a repeated-dose toxicity study, 4,4’-(hexafluoroisopropylidene)diphenol has various endocrine-mediated effects and its NOAEL (no observed adverse effect level) is 10 mg/kg/day.

Keywords: Estrogenic effects; Endocrine; 4,4’-(Hexafluoroisopropylidene)diphenol; Rat; OECD test guideline no 407

Sertoli cells proliferate in adult rats with prenatal exposure to 3,3′,4,4′,5-pentachlorobiphenyl by Shin Wakui; Tomoko Muto; Yoshihiko Suzuki; Hiroyuki Takahashi; Hiroshi Hano (pp. 159-162).

Sertoli cells play a critical role in spermatogenesis, and in adults, they are terminally differentiated with loss of proliferative activity. This study revealed Sertoli cell proliferation in 17-week-old Sprague–Dawley rats whose dams had been intragastrically administered 250 ng of 3,3′,4,4′,5-pentachlorobiphenyl/kg on days 13–19 postconception. Immunohistochemical evidence of proliferating cell nuclear antigen (PCNA) expression and electron microscope observation of mitotic figures confirmed the proliferation. Because the serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone concentrations were similar to those of vehicle-treated rats, a direct endocrine cause for the observed effects was unlikely.

Keywords: Rats; Testis; Sertoli cell proliferation; Prenatal PCB126 exposure

Acknowledgements to referees (pp. 163-164).

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Archives of Toxicology (v.86, #1)