The effect of xylene inhalation on the rat liver

In this study, 11,284 mg/m3 (2600 ppm) of xylene was administered for 8 hours a day to pregnant rats by means of inhalation, starting from the sixth day of their pregnancies. Furthermore, while a group of non-pregnant rats inhaled the same amount of xylene during the same period, the control group inhaled clean air. Consequently, in addition to the embryotoxic effects of xylene, the effects on the various tissues of the mothers and their litters were observed light and electron microscopes. No external anomalies were observed in any of the rats born at the end of the 21st day, and there were no macroscopic defects in their organs either. While following xylene inhalation no structural defects in the kidney and pancreas was found, expansions in the smooth endoplasmic reticulum of the liver tissues, increases in the lysosomes, and defective mitochondrion structures were found in the pregnant and non-pregnant rats. It was noticed that xylene in particular caused structural defects in the liver of the fetus. Compared to the control groups, increases were observed in the activities of the AST, ALT, ALP, and Arginase enzymes in the liver.     

Long-term study on workers occupationally exposed to ethylbenzene

Ethylbenzene is synthesized from benzene; subject to catalytic dehydrogenation it yields styrene, a raw material for the production of synthetic rubber and plastics. Long-term biomonitoring of occupational ethylbenzene exposures, carried out in the past 20 years in some 200 ethylbenzene-production workers, revealed this substance to pose little hazard to human health. As it turned out, mandelic acid concentrations in these workers' urine never exceeded 3.25 mmol.l-1 and none of the exposed showed damage to hematopoiesis and/or liver tissue. Over the last 10 years no case of malignancy has been recorded in this industrial facility belonging to a larger chemical complex where the overall incidence of cancer is about 3 times the national average. Today's low-level ethylbenzene exposures would make it fully justifiable if the present-day MAC limits, both whole-shift (200 mg.m-3) and peak (1,000 mg.m-3), were to be halved, i.e. to be lowered to 100 mg.m3 and 500 mg.m3 respectively. These newly recommended limit values are no more exceeded nowadays.     

Two generation reproduction study of ethylbenzene by inhalation in Crl-CD rats

BACKGROUND: This study was conducted to evaluate the potential adverse effects of ethylbenzene (EB) on reproductive capability from whole-body inhalation exposure of F0 and F1 parental animals. METHODS: Four groups of Crl:CD(SD)IGS BR rats (30/sex/group for F0 and 25/sex/group for F1) were exposed to 0, 25, 100, and 500 ppm EB for 6 hr/day for at least 70 consecutive days before mating. Inhalation exposure for the F0 and F1 females continued throughout mating, gestation through gestation day (GD) 20, and lactation days (LD) 5-21. On LD 1-4, females received EB in corn oil via oral gavage at dose levels of 26, 90, and 342 mg/kg/day (divided into three equal doses, approximately 2 hr apart), as calculated from a physiologically-based pharmacokinetic (PBPK) model to provide similar maternal blood area-under-concentration (AUC) as provided by inhalation. Pups were weaned on postnatal day (PND) 21 and exposure of the F1 generation started on PND 22. Estimates of internal exposure were determined by measuring EB concentrations in blood collected from F1 dams (4/group) and their culled pups 1 hr after the last gavage dose on PND 4. On PND 22, blood was collected from these same F1 dams and their weanlings for EB analysis 1 hr after a 6-hr inhalation exposure. The remainder of the F2 generation was not directly exposed. RESULTS: EB exposure did not affect survival or clinical observations. Male rats in the 500 ppm group in both generations gained weight more slowly than the controls. There were no indications of adverse effects on reproductive performance in either generation. Male and female mating and fertility indices, pre-coital intervals, spermatogenic endpoints, ovarian follicle counts, reproductive organ weights, lengths of estrous cycle and gestation, live litter size, pup weights, developmental landmarks, and postnatal survival were unaffected. No adverse exposure-related macroscopic pathology was noted at any level. CONCLUSIONS: Increased liver weights were found in the animals exposed to 500 ppm. F1 maternal whole blood EB concentrations of 0.49, 3.51, or 18.28 mg/L were found 1 hr after administration of a composite oral dose of 26, 90, or 342 mg/kg/day, respectively, but no detectable EB was found in blood samples of their F2 PND 4 culled pups. F1 maternal mean whole blood EB levels 1 hr after a 6-hr inhalation exposure on postpartum day (PPD) 22 was 0.11 mg/L (25 ppm), 0.56 mg/L (100 ppm), and 11 mg/L (500 ppm). For the offspring exposed with their dams on PND 22, F2 pup blood EB concentrations ranged from 0.017-0.039 mg/L (25 ppm), 0.165-0.465 mg/L (100 ppm), and 8.82-15.74 mg/L (500 ppm). Because decreased weight gain in the 500 ppm males was transient and no histopathological changes were associated with the increased liver weights in the 500 ppm male and female groups, these changes were not considered adverse. Therefore, for parental systemic toxicity, 100 ppm was considered a NOEL and 500 ppm a NOAEL in this study. The 500 ppm exposure concentration was considered a NOAEL for F0 and F1 reproductive toxicity and offspring developmental endpoints.     

Biomonitoring of environmental pollution hazards from a nickel smelter waste dump

Longterm field exposure study was carried out on 10 rabbits placed for 6 months in a bioindication station located about 3 km downwind of a disposal site of nickel smelter waste dump. As revealed by the method of atomic absorption spectrophotometry, all of these animals showed elevated nickel and chromium levels in their body organs and hair. These findings were paralleled by histologic abnormalities in the lungs and liver tissues. Average dustfall values at the site of exposure did not exceed 5.5 g X m-2 X 30 d-1 during the period of observation. Dustfall deposits in this location contained nickel and chromium in amounts that were higher than in control locality. Analogous experiments on Wistar rats were carried out in a laboratory exposure chamber (exposure 4 h/day, 5 days/week, for a period of 6 months). After exposures to 50 mg X m-3 of metallic dust, lung parenchyma of rats was characterized by the presence of dust particles in various phases of phagocytosis as well as the presence of badly damaged or disintegrated alveolar macrophage cells, which pointed to metallic aerosol toxicity for biomembranes. The technique of air pollution biomonitoring on animals, correlated with the data on ambient air concentrations of the suspended particulate matter and its content of trace metals, appears to be a well suitable tool in establishing the potential air pollution hazards to the exposed populations living in the area of concern.     

Plasma corticosterone concentrations in the perinatal rat

1. Plasma corticosterone concentrations were determined in the foetal rat during the gestational period from day 18·5 to term and in postnatal rats over the first few hours after delivery. 2. The plasma corticosterone concentrations in foetal rats are as high as six times maternal values at day 19 of gestation and are approximately equal to maternal values from day 20 to term. 3. In postnatal rats the plasma corticosterone concentrations rise 3·5-fold on average within 5hr. of delivery. 4. The results are discussed in relation to the function of adrenal steroids in postnatal liver development.     

Changes in Proteasome Activity and Subunit Composition during Postnatal Development of Rat

The dynamics of the activities of 26S and 20S proteasomes in the rat liver and spleen have been studied during postnatal development from 1 to 90 days. The activities of proteasome forms both in spleen and in liver increased in adult animals as compared to one day rats. The activities of both proteasome forms in the liver did not differ significantly from those in the spleen at all stages of postnatal development. Using Western blot with monoclonal antibodies to Rpt6 subunit, we confirmed the presence of 26S proteasome in both organs at all stages of postnatal development. Studies with polyclonal antibodies to β1i (LMP2) subunit showed the appearance of the immune subunit in the spleen by day 9 and in the liver only by day 23 of postnatal development. This result suggests the earlier formation of the spleen as an organ with immune functions.__________Translated from Ontogenez, Vol. 36, No. 3, 2005, pp. 205–210.Original Russian Text Copyright © 2005 by Abramova, Astakhova, Sharova.     

Phenytoin induced oxidative stress in pre- and postnatal rat development - effect of vitamin E on selective biochemical variables

A pre- and postnatal study was carried out to investigate the effect of high dose (500 mg/kg) of the natural antioxidant vitamin E (VIT E) on biochemical variables in the model of chronic intrauterine hypoxia. Chronic hypoxia was induced by administration of the anticonvulsant phenytoin (PHT) during pregnancy. Rats were orally treated with PHT (150 mg/kg) from day 7 to 18 of gestation and VIT E prior to PHT orally on the same days. The activity of the lysosomal enzyme N-acetyl-ss-D-glucosaminidase (NAGA) and the level of glutathione (GSH) were used as markers of tissue damage. In the prenatal study PHT-induced embryofoetal toxicity was associated with an increase in NAGA activity and decrease of GSH level in maternal serum and heart and with an increase in NAGA activity in the placenta. Administration of VIT E did not inhibit the above given changes. PHT increased the activity of NAGA and decreased the level of GSH in foetal organs (liver, lungs, brain). VIT E did not reverse these changes. In the postnatal study, we did not find any significant differences in NAGA activity in the organs of 1-day-old pups. An increase of liver GSH level was found in PHT and VIT E+PHT groups of pups and in the group VIT E+PHT in the lungs. In conclusion, supplementation with a high-dose of VIT E failed to protect maternal, foetal and new-born rat organs from PHT induced changes of selective biochemical variables.     

Clonogenic hemopoietic cells (CFU-S) in mouse pre- and postnatal ontogeny

Content of three classes of clonogenic haemopoietic cells (CFU-S-7, CFU-S-11 and CFU-S-ep) was determined in haemopoietic organs of mouse during embryogenesis (10, 14 and 18 day) and postnatal ontogenesis (2, 3 and 7 day, 1, 2, 3 and 18 month). CFU-S-7 and CFU-S-11 that from big splenic colonies on 7th and 11th days of transplantation are present in liver, spleen and bone marrow at all developmental stages. However their concentration and CFU-S-7 CFU-S-11 ratio change in haemopoietic organs. CFU-S-ep that form small colonies on 11th day are observed before birth in liver and spleen and 1 week after birth there and also in bone marrow but are practically absent from haemopoietic organs of older animals. Thus, CFU-S compartment structure is characterized by definite ratio of its subpopulations. It seems to reflect functional state of haemopoietic system during development.     

Acrylonitrile inhalation in rats: I. Effect on intermediary metabolism

In male Wistar rats the inhalation exposure to acrylonitrile (AN), 280 mg X m-3, 8 hours a day for five days significantly decreased the serum concentration of cholesterol and triglycerides, but the liver concentrations of phospholipids, and esterified fatty acids were unchanged. The liver microsomal protein and cytochrome P-450 content decreased significantly. On the other hand the levels of glucose, lactate and pyruvate in the blood and brain significantly increased up to 250% of controls. A microscopic examination of the lungs, liver, kidneys and adrenals did not show structural changes and the numbers and enzyme activities of alveolar macrophages were also unaffected. In single 12-hour inhalation exposures the elevation of blood glucose was proportional to the inhaled concentration of AN (average concentrations 57, 125, or 271 mg X m-3); the effect was significant at the lowest AN concentration and was intensified in the glucose tolerance test. The elevation of blood glucose proved to be the most sensitive and dose-related indicator of AN exposure of those observed.     

Acrylonitrile inhalation in rats: II. Excretion of thioethers and thiocyanate in urine

In male Wistar rats, the inhalation exposure to acrylonitrile (AN), 271 mg X m-3, 8 hours a day, 5 days a week, did not affect protein sulfhydryl concentration in liver and blood and decreased glutathione concentration in the liver, but not in the brain at the end of the fifth exposure. The urinary excretion of the main AN metabolites, thioethers (AN-mercapturic acids) and thiocyanate was proportional to the inhaled AN concentration (57, 125, 271 mg X m-3, respectively) in a single exposure for 12 hours, and their mutual ratio was greatly different from that after injection of AN. The results revealed that the urinary excretion of thioethers is a very sensitive and dose-related indicator of exposure to AN and extrapolation of the results indicates that the exposure to AN concentration below 10 mg X m-3 could thus be demonstrated.     

Ontogeny of integumental calcium in relation to surface area and skin water content in the perinatal rat.

Calcium is an important regulator of epidermal differentiation and skin biomechanics in many vertebrate species. In this study, we measured total epidermal calcium in the perinatal Sprague-Dawley rat. Values ranged from 12 to 15 mg per 100 g of tissue. These levels were elevated compared with dermis and other soft (nonbone) organs, including brain, kidney, heart, and liver. Administration of radioactive calcium to the pregnant rat resulted in high rates of 45Ca2+ localization in the fetal epidermis 24 h later. From gestational day 20 to postnatal day 3, the epidermis showed progressive dehydration with water content decreasing from 79 to 73%. Dermal hydration over the same period decreased from 91 to 81%. In the neonatal rat (age 0-3 days), linear regression analysis of surface area vs. body weight on a log-log plot yielded a slope of 1.04. This finding contrasts with an expected slope of 0.67 based on simple surface area-to-volume relationships and differs from the empirical 0.75-power law observed in adult bioenergetics. In summary, these results show the perinatal rat is encapsulated by a continuous differentially hydrated calcium-rich epidermal envelope that increases in surface area over the early postnatal period directly as the first power of body mass.     

Creatine biosynthesis enzymes in the postnatal development of rats: the role of cyclo-3',5'-AMP and glucagon in the postnatal induction of liver guanidine acetate-N-methyltransferase]

The activity of enzymes of creatin biosynthesis in the rat liver and kidneys has been studied during the postnatal development. The activity of transamidinase of kidneys (E.C. 2.1.4.1.) increases gradually and linearly up to the 20th day after birth, then decreases on the 12th--25th days and increases again up to the level characteristic of the adult organism. The activity of guanidine acetate-N-methyl transferase (E.C. 2.1.1.2.) is rather high during the first days of postnatal development, then decreases and from the 15th day on increases again attaining the maximal level by the 23rd--25th day. The second period of the increase in the enzyme activity begins on the 29th--30th day of postnatal development. The results obtained suggest that the sharp increase of activity of guanidine acetate-N-methyl transferase of the rat liver during the early postnatal development is realized with the participation of cyclic 3',5'-AMP which appears to mediate the glucagon action.     

Postnatal development of rat pups after maternal exposure to diethanolamine

BACKGROUND: Diethanolamine (DEA), a widely used surfactant, was administered to pregnant mice at the oral LD10 resulting in failure of pups to grow and thrive through postnatal day (PND) 3 [National Toxicology Program, 1987; York et al., Teratology 37:503-504, 1988]. The toxicity profile for DEA differs among rodent species. This study investigated DEA-induced postnatal toxicity in a second species. METHODS: Timed-mated Sprague-Dawley rats were dosed (0, 50, 125, 200, 250, or 300 mg DEA/kg/day, p.o.) on gestational days (GD) 6-19. Dams and pups were monitored for body weight, feed/water intake, clinical signs, litter size, and sex ratio. At necropsy (PND 21), maternal liver and kidney weights and number of uterine implantation sites were recorded. RESULTS: The high-dose group was terminated early due to excessive toxicity. The estimated maternal LD10 was 218 mg/kg/day. Maternal effects included decreased body weight and relative feed intake (>or=200 mg/kg/day), transiently reduced relative water intake (125 and 250 mg/kg/day), and increased absolute kidney weight (>or=125 mg/kg/day). Postimplantation loss (PND 0) and pup mortality (PND 0-4) were increased (>or=200 and >or=125 mg/kg/day, respectively). Pup body weight was reduced (>or=200 mg/kg/day) as late as PND 21. CONCLUSIONS: This study demonstrates reduced postnatal growth and survival in a second species after gestational exposure to DEA, persistence of toxic effects through the end of lactation, possibly due to long elimination half-life, and maternal and developmental toxicity no-observed-adverse-effect level (NOAELs) (50 mg/kg/day) and lowest-observed-adverse-effect level (LOAELs) (125 mg/kg/day) for oral DEA exposure during embryo/fetal development in the rat.     

The effect that nickel,copper, and zinc salts have on seed germination and initial ontogenesis of water parsnip (<Emphasis Type="Italic">Sium latifolium</Emphasis> L.) and wood club-rush (<Emphasis Type="Italic">Scirpus silvaticus</Emphasis> L.)

The effect that nickel, copper, and zinc sulfates have on seed germination and the initial stages of the ontogenesis of water parsnip and wood club-rush has been investigated. Nickel and copper in the concentration range of 250–500 mg/l and zinc at a concentration of 500 mg/l were the most toxic for water parsnip seeds, while, for the wood club-rush seeds, maximum toxicity was observed at Ni and Cu concentrations ranging from 50 to 500 mg/l and at Zn concentrations of 250–500 mg/l. The development of water parsnip seedlings was normal at Ni concentrations of 1–25 mg/l, Cu concentrations of 1–10 mg/l, and Zn concentrations up to 50 mg/l; the development of wood club-rush seedlings was normal at a Ni concentration of 1 mg/l, and Cu and Zn concentrations of 1–25 mg/l. A further increase in the concentration caused photosynthesis suppression, slower growth of the vegetation organs, and their subsequent necrosis. Water parsnip is more resistant to the toxicants.     

Cyclic variations in nitrogen uptake rate of soybean plants: effects of external nitrate concentration

Net uptake of NO3- by non-nodulated soybean plants [Glycine max (L.) Merr. cv. Ransom] growing in flowing hydroponic cultures containing 0.5, 1.0 and 10.0 mol m-3 NO3- was measured daily during a 24-d period of vegetative development to determine if amplitude of maximum and minimum rates of net NO3- uptake are responsive to external concentrations of NO3-. Removal of NO3- from the replenished solutions during each 24-h period was determined by ion chromatography. Neither dry matter accumulation nor the periodicity of oscillations in net uptake rate was altered by the external NO3- concentrations. The maxima of the oscillations in net uptake rate, however, increased nearly 3-fold in response to external NO3- concentrations. The maxima and minima, respectively, changed from 4.0 and 0.6 mmol NO3- per gram root dry weight per day at an external solution level of 0.5 mol m-3 NO3- to 15.2 and -2.7 mmol NO3- per gram root dry weight per day at an external solution level of 10.0 mol m-3 NO3-. The negative values for minimum net uptake rate from 10.0 mol m-3 NO3- solutions show that net efflux was occurring and indicate that the magnitude of the efflux component of net uptake was responsive to external concentration of NO3-.     

Estrogenic effect of propylparaben (propylhydroxybenzoate) in rainbow trout Oncorhynchus mykiss after exposure via food and water

The estrogenic effect of propylparaben was investigated in a rainbow trout Oncorhynchus mykiss test system. Propylparaben was administered orally to sexually immature rainbow trout every second day for up to 10 days in doses between 7 and 1830 mg kg(-1) 2 d(-1) and in the water at 50 and 225 microg l(-1) for 12 days. Plasma vitellogenin was measured before and during the exposures and the concentrations of propylparaben in liver and muscle were determined at the end of experiments. Increases in average plasma vitellogenin levels were seen at oral exposure to 33 mg propylparabenkg(-1) 2 d(-1); the most sensitive fish responded to 7 mg kg(-1). The ED(50) values for increase in vitellogenin synthesis were 35, 31 and 22 mg kg(-1) 2 d(-1) at day 3, 6 and 11, respectively. Exposure to 225 microg propylparabenl(-1) increased vitellogenin synthesis, but exposure to 50 microg l(-1) did not. Propylparaben showed little tendency to bioaccumulation in rainbow trout; less than 1 per thousand of the total amount of propylparaben administered orally at 1830 mg kg(-1) 2 d(-1) over the 10-d experimental period was retained in muscle and liver 24 h after the end of the experiment. Exposure to 225 microg propylparabenl(-1) for 12 d led to concentrations of 6700 and 870 microg propylparabenkg(-1) liver and muscle, respectively. Half lives for propylparaben were 8.6 h in liver and 1.5 h in muscle.     

Benzofuranyl ureas with potent cardiovascular teratogenicity in rats

Studies of embryo-fetal development in rats were conducted with two 5-lipoxygenase inhibitors. SB-202235 (1,000 mg/kg/day) or SB-210661 (50, 100, or 500 mg/kg/day) was administered orally by gavage to female rats on days 6-17 postcoitus (pc) or days 7-16 pc. SB-202235 (1,000 mg/kg/day) and SB-210661 (100 mg/kg/day) reduced maternal body weight gain for the treatment period by 16% and 21%, respectively, relative to controls. SB-202235 (1,000 mg/kg/day) or SB-210661 (50 or 100 mg/kg/day), did not affect numbers of resorptions, dead or live fetuses/litter, but 500 mg/kg/day of SB-210661 caused 100% embryo lethality. SB-202235 (1,000 mg/kg/day) and SB-210661 (50 and 100 mg/kg/day) reduced fetal body weight by 15-30% and produced extensive cardiovascular malformations, as well as diaphragmatic hernias. SB-210661 also caused thymic abnormalities and cryptorchidism. Cardiovascular defects included abnormalities in aorticopulmonary septation, the aortic arch, pulmonary trunk, and ventricular septal defects are discussed relative to comparable human syndromes of cardiovascular malformation.     

m-Octopamine: Normal Occurrence with p-Octopamine in Mammalian Sympathetic Nerves

The development of a radiochemical enzyme assay for p-octopamine in 1969 led to its identification in a large number of invertebrate nerve systems and in mammalian sympathetic nerves. The original method by which p-octopamine was measured has now been found to be nonspecific; however, modifications of this procedure can determine both m- and p-octopamine. We recently developed a new specific method for the unequivocal identification and quantitative determination in tissue of the six octopamine and synephrine isomers. With this method--negative chemical ionization gas chromatography-mass spectrometry--the more physiologically active m-octopamine has been found in association with p-octopamine in 10 organs of the rat. m-Octopamine is present in concentrations equal to those of p-octopamine in heart, spleen, and liver and in concentrations from 30 to 60% of p-octopamine in adrenals, vas deferens, brain, kidney, large intestine, bladder, and lungs. In vivo inhibition of monoamine oxidase markedly increased the concentrations of both m- and p-octopamine in all organs examined. Both amines were virtually absent from all organs except the adrenals following chemical sympathectomy with 6-hydroxydopamine, thereby establishing that m- and p-octopamine are localized within sympathetic nerve endings.