Check out our New Publishers' Select for Free Articles

Archives of Toxicology (v.76, #1)

No Title by Peter M. Hoet; Goedele Roesems; Maurits G. Demedts; Benoit Nemery (pp. 1-7).

Cobalt metal (mCo) and hard metal, a mixture of cobalt and tungsten carbide (CoWC), are cytotoxic for alveolar macrophages and alveolar type II cells (AT-II). Although the exact mechanisms of toxicity are not entirely elucidated, evidence exists for an oxidant-mediated toxicity. In this study, we exposed primary cultures of rat AT-II, in vitro, to different forms of cobalt (mCo particles, CoWC particles, CoCl₂) and assessed changes in the activity of the hexose monophosphate shunt (HMS). Activation of the HMS occurs as an early response to (per)oxidative stress. Cobalt metal-containing particles (mCo and CoWC) when freshly immersed in medium, lead to an early concentration-dependent stimulation of the HMS in rat AT-II. The maximum stimulations of HMS (reached after 90 min) were 2.0±1.2, 2.9±0.4, 3.3±1.6 and 4.0±0.4 fold-increases for 15, 75, 300 and 1200 µg mCo/well, respectively. The observed time course of the activation by mCo particles clearly differed from that caused by paraquat (10^–5M), which is known to produce activated oxygen species after cyclic oxidation-reduction reactions. The comparable effect of peroxides (H₂O₂ and t-butyl hydroperoxide) on HMS and the inhibitory effects of catalase on the mCo-induced stimulation of the HMS strongly suggest the production of peroxides by freshly immersed mCo particles. However, we were not able to show a simple relationship between the stimulation of the HMS and the subsequent cell damage.

Keywords: Cobalt particle Cobalt ion Hard metal Type II pneumocyte Alveolar macrophage

No Title by Hideaki Shimada; Shizuka Yamaguchi; Hideyuki Murata; Masaki Otagiri; Yorishige Imamura (pp. 8-12).

Administration of cadmium (Cd) at a dose of 1.23 mg/kg (2.0 mg/kg as CdCl₂) markedly decreased the activity of an enzyme (acetohexamide reductase) catalysing the ketone-reduction of acetohexamide, an oral antidiabetic drug, in liver microsomes of male rats. However, the decreased enzyme activity was increased by repeated treatment with testosterone propionate (TP). When male rats were castrated and TP was given to the castrated ones, a similar decrease and increase, as described above, were observed in the microsomal enzyme activity. Cd exposure to male rats induced haemorrhage and atrophy of the testes and significantly diminished serum testosterone levels. There was no possibility that Cd accumulated in liver microsomes of male rats causing direct inhibition of the microsomal enzyme activity. We conclude that Cd exposure decreases androgen-dependent metabolism of acetohexamide in liver microsomes of male rats through its testicular toxicity. Cd exposure had no effect on acetohexamide reductase activity in liver cytosol of male rats.

Keywords: Acetohexamide Androgen-dependent metabolism Cadmiun Rat liver microsomes Testicular toxicity

No Title by Jürgen Pauluhn (pp. 13-22).

The object of this study was to compare the relative sensitivity of markers of exposure and effects in the lung of rats exposed to polymeric diphenyl-methane-4,4'-diisocyanate (pMDI) aerosol. Rats were repeatedly exposed to 12.9 mg pMDI/m³ (6 h/day, 5 days/week for 14 days; exposure was from days 0–17 followed by a post-exposure period to day 35). Markers of exposure were determined in bronchoalveolar lavage (BAL), blood (haemoglobin, plasma proteins), and urine on days 1, 4, 11, 18, 21, 28 and 35. Markers of effects were determined at the same time points and focused on changes in BAL constituents. In BAL, a maximum increase of total protein occurred following the first exposure and levelled off subsequently whilst BAL cell-related endpoints increased in a time-dependent manner. The kinetics of formation and elimination of adducts differed appreciably from one dosimeter to another. Whilst haemoglobin adducts were integrated by the cumulative exposures, the incremental yield of adduct formation appeared to be dependent on pulmonary as well as yet unknown erythrocyte-related factors. Plasma protein adducts attained a plateau after 1 week of exposure. MDI-related metabolite levels in urine did not show any time-dependent changes during the entire exposure period and declined rapidly during the post-exposure period. Thus, the kinetics of the fractional loading and clearance of pulmonary and extrapulmonary dosimeters did not parallel each other, nor was there a clear correlation with the markers of effects. In summary, it is concluded that biomonitoring is a powerful tool for the comparative dosimetry of well-defined exposure regimens. However, especially for irritant agents demonstrating portal-of-entry effects, markers related to 'total body burden' may not necessarily predict the absence or presence of local responses occurring within the target organ, namely the lung. In all compartments, dosimeters related to higher oligomers of MDI demonstrated low bioavailability, i.e. their recovery was appreciably lower than expected.

Keywords: Bronchoalveolar lavage Diphenyl-methane-4,4'-diisocyanate (MDI) Biomonitoring Markers of exposure Adduct formation and elimination

No Title by G. Degen; P. Janning; P. Diel; H. Michna; H. Bolt (pp. 23-29).

Disposition and transplacental transfer of the phytoestrogen daidzein was studied in pregnant DA/Han rats on day 18 of gestation. Daidzein concentrations were determined by HPLC in maternal blood, maternal organs (liver, kidney, uterus), placenta and fetuses (liver and residual tissues) at specific times (5, 10, 20, 40 and 120 min) after intravenous administration of 10 mg/kg body weight. Early after injection, the majority of circulating daidzein was still in the aglycone form; at later time points the majority consisted of conjugates. The initially high isoflavone concentration in maternal plasma (about 25 µg/ml at 5 min) decreased rapidly within the first hour, and after 2 h total daidzein was below 1 µg/ml. Despite its efficient conjugation, daidzein was rapidly distributed in the organism: peak concentrations were attained 10 min after intravenous administration in all tissues analysed, with mean values of about 31 µg/g in maternal liver, 13 µg/g in kidneys and 5 µg/g in the uterus. Placenta contained about one-tenth the hepatic daidzein concentration, and fetal liver about 1/30 the peak concentration of maternal liver (i.e. 1.3 µg/g, which is one-third the placental concentration). Daidzein levels in tissues then declined in parallel with those in maternal blood. The data show that daidzein is transferred across the placenta of DA/Han rats to fetuses. This is indicative of a rapid transfer from the mother to the fetus, but also that efficient hepatic extraction of daidzein from the maternal blood occurs. Since dietary phytoestrogens account for a significant proportion of human exposure to potential endocrine modulators, and since the placenta does not represent a barrier to daidzein or related estrogenic isoflavones, the consequences of these exposures early in life should be examined and monitored carefully.

Keywords: Daidzein Phytoestrogen Plasma and tissue level Soy isoflavones Transplacental transfer

No Title by Khaled M. Ashry; Aqel W. Abu-Qare; Fathy R. Saleem; Yousef A. Hussein; Salah M. Hamza; Amal M. Kishk; Mohamed B. Abou-Donia (pp. 30-39).

Pregnant Sprague-Dawley rats (14–18 days of gestation) were treated with a single dose of 50 mg/kg (61% of oral LD₅₀ in female rats) of chlorpyrifos (0,0-diethyl-0-3,5,6-trichloro-2-pyridyl phosphorothioate) by oral gavage. Animals treated on day 18 of gestation were sacrificed at 1, 2, 4, 12 h after dosing. Animals treated on days 17, 16, 15, and 14 of gestation were sacrificed at 24, 48, 72, and 96 h after dosing, respectively. Maternal and fetal brain acetylcholinesterase (AchE) and plasma butyrylcholinesterase (BuChE) activities were significantly inhibited 1 h after treatment. Activity of fetal brain AChE and plasma BuChE recovered faster than that of the maternal enzymes. Peak inhibition of maternal spinal cord AChE and BuChE activities occurred 2 h and 1 h after dosing, respectively. Maternal spinal cord BuChE activity was totally recovered by 96 h compared to the partial recovery of spinal cord AChE activity. Maternal liver BuChE activity was significantly decreased within 1 h of dosing. The individual molecular forms (10S and 4S) of maternal and fetal brain AChE and BuChE activities were significantly decreased 1 h after treatment. Recovery of both forms of fetal brain AChE activity was much faster than the maternal forms. Activity of the 10S form of maternal control brain AChE was significantly higher than in the fetus control. The rapid recovery of cholinesterase enzymes in the fetus is attributed to the de novo synthesis of AChE enzymes in the fetus compared to the mother.

Keywords: Chlorpyrifos Cholinesterase enzymes Pregnancy Rats

No Title by Antti Mäkitie; Ulla Pirvola; Ilmari Pyykkö; Hisataka Sakakibara; Vesa Riihimäki; Jukka Ylikoski (pp. 40-47).

The effect of inhaled styrene on the structure and function of the auditory organ of the male Wistar rat was studied. The animals were exposed either to 600, 300 or 100 ppm styrene (12 h/day, 5 days/week, for 4 weeks). Auditory sensitivity was tested prior to and after the exposure by auditory brain stem audiometry (ABR) at frequencies of 1.0, 2.0, 4.0 and 8.0 kHz. Inner ear morphological changes were studied by light- and electron-microscopy. Exposure to 600 ppm styrene caused a 3 dB hearing loss only at the highest test frequency (8 kHz). Quantitative morphological analysis of cochlear hair cells (cytocochleograms) showed that 600 ppm styrene caused a severe outer hair cell (OHC) loss particularly in the third OHC row of the upper basal and lower middle coil. The inner hair cells were usually intact. Exposure to lower styrene concentrations (100 and 300 ppm) caused no unequivocal functional deficit or hair cell damage. We conclude that there appears to be a concentration threshold for styrene ototoxicity in rats (between 300 and 600 ppm).

Keywords: Styrene Solvent Hearing loss Inner ear Ototoxicity

No Title by Mei-Ling Yang; Yashang Lee; Tien-Shang Huang; Fung-Jou Lu (pp. 48-54).

A unique peripheral vascular disease named “Blackfoot disease” (BFD) is endemic on the southwest coast of Taiwan. Clinically, the signs and symptoms of BFD are similar to those of arteriosclerosis and Buerger disease. Humic acid has been proposed as a causative factor in BFD; however, the relationship between humic acid and atherosclerotic-like plaque associated with BFD remains unclear. In this study, we investigated the effects of humic acid extracted from Blackfoot disease-endemic well water (BFD-HA) on cultured C3H10T1/2 fibroblasts, a murine embryonic cell line. Our present data demonstrate that C3H10T1/2 cells were arrested at the G₁ phase and subsequently differentiated to adipocytes after treatment with BFD-HA. The adipocyte differentiation of C3H10T1/2 cells induced by BFD-HA was also accompanied with increased glycosaminoglycan production. These results suggest that a large lipid accumulation of arterial blood vessels in BFD patients may be linked in part to the adipocyte differentiation of vascular fibroblasts induced by BFD-HA.

Keywords: Adipocyte differentiation Blackfoot disease Humic acid

No Title by Lada Rumora; Sanja Kovačić; Ružica Rozgaj; Ivana Čepelak; Stjepan Pepeljnjak; Tihana Žanić Grubišić (pp. 55-61).

Fumonisins, mycotoxins produced by certain strains of Fusarium moniliforme, could induce various diseases in animals and are suspected human carcinogens. Fumonisin B₁ (FB₁), the most commonly found fumonisin, has been characterised as a tumour initiator and a tumour promoter, a mitogen and an anti-proliferative agent. In this study we examined the cytotoxicity and genotoxicity of FB₁ in rabbit kidney RK13 cells. To evaluate the effects of FB₁ on survival of this cell line we analysed cell viability, membrane integrity, DNA fragmentation and overall morphology of the cells. The genotoxic potential of FB₁ was estimated by monitoring the ability of this mycotoxin to induce micronuclei in RK13 cells. Exposure to FB₁ caused a significant increase in micronucleus frequency in a concentration- and in a time-dependent manner. Nanomolar concentrations of FB₁ decreased cell viability after 24 h and even more so after 48 h of exposure. The morphological changes observed suggested that an increased number of RK13 cells were dying by the process of apoptosis. However, FB₁ also induced impairments of cell and mitochondrial membrane integrity, as assessed by lactate dehydrogenase and glutamate dehydrogenase leakage. These results could imply that nanomolar concentrations of FB₁ induced apoptosis, which subsequently may proceed to secondary necrosis. In summary, our observations suggest that FB₁ is genotoxic and cytotoxic to RK13 cells.

Keywords: Fumonisin B1 Apoptosis Micronucleus assay RK13 cells

No Title by P. Ulrich; O. Grenet; J. Bluemel; H. Vohr; C. Wiemann; O. Grundler; W. Suter (pp. 62-62).

Sections

Personal tools

Archives of Toxicology (v.76, #1)

Sections

Personal tools

Local resources

Archives of Toxicology (v.76, #1)