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PubMed2004

A comparison of x-ray detectors for mouse CT imaging.

There is significant interest in using computed tomography (CT) for in vivo imaging applications in mouse models of disease. Most commercially available mouse x-ray CT scanners utilize a charge-coupled device (CCD) detector coupled via fibre optic taper to a phosphor screen. However, there has been little research to determine if this is the optimum detector for the specific task of in vivo mouse imaging. To investigate this issue, we have evaluated four detectors, including an amorphous selenium (a-Se) detector, an amorphous silicon (a-Si) detector with a gadolinium oxysulphide (GOS) screen, a CCD with a 3:1 fibre taper and a GOS screen, and a CCD with a 2:1 fibre taper and both GOS and thallium-doped caesium iodide (CsI:Tl) screens. The detectors were evaluated by measuring the modulation transfer function (MTF), noise power spectrum (NPS), detective quantum efficiency (DQE), stability over multiple exposures, and noise in reconstructed CT images. The a-Se detector had the best MTF and the highest DQE (0.6 at 0 lp mm(-1)) but had the worst stability (45% reduction after 2000 exposure frames). The a-Si detector and the CCD with the 3:1 fibre, both of which used the GOS screen, had very similar performance with a DQE of approximately 0.30 at 0 lp mm(-1). For the CCD with the 2:1 fibre, the CsI:Tl screen resulted in a nearly two-fold improvement in DQE over the GOS screen (0.4 versus 0.24 at 0 lp mm(-1)). The CCDs both had the best stability, with less than a 1% change in pixel values over multiple exposures. The pixel values of the a-Si detector increased 5% over multiple exposures due to the effects of image lag. Despite the higher DQE of the a-Se detector, the reconstructed CT images acquired with the a-Si detector had lower noise levels, likely due to the blurring effects from the phosphor screen.

Algorithms↗
PubMed1999

Maternal pesticide exposure from multiple sources and selected congenital anomalies.

We explored the relation between various potential sources of maternal periconceptional pregnancy exposures to pesticides and congenital anomalies in offspring. Data were derived from a case-control study of fetuses and liveborn infants with orofacial clefts, neural tube defects, conotruncal defects, or limb anomalies, among 1987-1989 California births and fetal deaths. We conducted telephone interviews with mothers of 662 (85% of eligible) orofacial cleft cases, 265 (84%) neural tube defect cases, 207 (87%) conotruncal defect cases, 165 (84%) limb cases, and 734 (78%) nonmalformed controls. The odds ratio (OR) estimates did not indicate increased risk for any of the studied anomaly groups among women whose self-reported occupational tasks were considered by an industrial hygienist likely to involve pesticide exposures. Paternal occupational exposure to pesticides, as reported by the mother, revealed elevated ORs for only two of the cleft phenotypes [OR = 1.7 [95% confidence interval (CI) = 0.9-3.4] for multiple cleft lip with/without cleft palate and OR = 1.6 [95% CI = 0.7-3.4] for multiple cleft palate]. Use of pesticide products for household gardening, by mothers or by professional applicators, was associated with ORs > or =1.5 for most of the studied anomalies. Use of pesticide products for the control of pests in or around homes was not associated with elevated risks for most of the studied anomalies, although women who reported that a professional applied pesticides to their homes had increased risks for neural tube defect-affected pregnancies [OR = 1.6 (95% CI = 1.1-2.5)] and limb anomalies [OR = 1.6 (95% CI = 1.0-2.7)]. Having a pet cat or dog and treating its fleas was not associated with increased anomaly risk. Women who reported living within 0.25 miles of an agricultural crop revealed increased risks for offspring with neural tube defects [OR = 1.5 (95%CI = 1.1-2.1)]. For many of the comparisons, data were sparse, resulting in imprecise effect estimation. Despite our investigating multiple sources of potential pesticide exposures, without more specific information on chemical and level of exposure, we could not adequately discriminate whether the observed effects are valid, whether biased exposure reporting contributed to the observed elevated risks, or whether nonspecific measurement of exposure was responsible for many of the observed estimated risks not being elevated.

Adult↗
PubMed2002

Potentiation of 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123)-induced liver toxicity by ethanol in guinea-pigs.

HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane), a substitute for the banned chlorofluorocarbons (CFCs), is a structural analogue of the well-known hepatotoxicant halothane. The objectives of these experiments were to investigate (1) whether, like halothane, multiple exposure increases the risk of HCFC-123-induced liver toxicity, and (2) whether ethanol, a potent CYP2E1 inducer, potentiates the liver toxicity of HCFC-123. In experiment 1, male Hartley guinea-pigs were exposed twice a week to 5000 ppm HCFC-123 (4 h) during 3 weeks followed by 2 weeks recovery, and then re-exposed or not during 4 h to 5000 ppm HCFC-123. A group with a single exposure to 5000 ppm HCFC-123 and a control group were also included. In experiment 2, guinea-pigs received 5 or 10% ethanol in drinking water during 12 days before a single 4-h exposure to 5000 ppm HCFC-123. A group receiving 10% only, a group exposed once to 5000 ppm HCFC-123 but not pre-treated with ethanol and a control group were also included. In both experiments, the liver toxicity was assessed, 24 h post-exposure, by the serum activities of alanine aminotransferase (ALT) and isocitrate dehydrogenase (ICDH) as well as by histopathology. In experiment 2 the urinary excretion rate of the main metabolites trifluoroacetic acid (TFA) and chlorodifluoroacetic acid (CDFA) was assessed and CYP2E1 activity was measured by the chlorzoxazone metabolic ratio. Multiple exposure to 5000 ppm HCFC-123 did not cause greater liver damage than a single exposure (ALT, ICDH 3-fold control values). At this level of exposure the liver lesions were totally reversible within two weeks. Ethanol consumption produced CYP2E1 induction, increased urinary excretion of both HCFC-123 metabolites (more than 2-fold the rate measured in the non-induced group) and markedly increased the liver toxicity of HCFC-123 as shown by the serum liver enzyme activities (ALT 8.5-fold increase, ICDH 13-fold increase), and the histopathology. The necrosis was predominantly localised in the intermediate zone of the hepatic lobules with vacuolisation of the centrilobular zones. The effects associated with 10% ethanol pre-treatment were less marked than those observed with ethanol 5% and could be explained by the remaining blood ethanol levels causing an inhibition of HCFC-123 biotransformation. Significant correlations were obtained between the serum enzyme activities, the histopathology, the excretion rate of the metabolites and CYP2E1 activity. It can be concluded that (1) multiple exposure to HCFC-123 did not increase the liver toxicity of HCFC-123 in this experimental model, and (2) chronic ethanol consumption, known to be CYP2E1 inducer, strongly enhanced the biotransformation of HCFC-123 and its liver toxicity.

Administration, Inhalation↗
PubMed2004

Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet B-mediated responses by resveratrol in SKH-1 hairless mouse skin.

Multiple exposures to solar ultraviolet (UV) radiation cause critical damages that may lead to the development of several cutaneous disorders including skin cancer, the most frequently diagnosed malignancy in the USA. Therefore, efforts are needed to: (i) study the mechanism(s) of UV-mediated cutaneous damages, and (ii) design novel approaches for the management of skin cancer. 'Chemoprevention' via plant-based agents may be a useful approach for the management of neoplasia. Here, we evaluated the involvement of cell cycle regulatory molecules during resveratrol-mediated protection from multiple exposures of UVB (180 mJ/cm(2); on alternate days x 7 exposures) radiations in the SKH-1 hairless mouse skin. Resveratrol was topically applied on the skin of SKH-1 hairless mice at a dose of 10 micromol/mouse (in 0.2 ml acetone; 30 min prior to each UVB exposure). Studies were performed at 24 h following the last UVB exposure. Topical application of resveratrol resulted in significant decrease in UVB-induced bi-fold skin thickness, hyperplasia, and infiltration of leukocytes. The data from immunoblot and/or immunohistochemical analyses revealed that multiple exposure to UVB radiations causes significant upregulation in: (i) proliferating cell nuclear antigen (PCNA), a marker of cellular proliferation, and (ii) cyclin-dependent kinase (cdk)-2, -4 and -6, cyclin-D1, and cyclin-D2. Resveratrol treatment resulted in significant downregulation in UV-mediated increases in these critical cell cycle regulatory proteins. An interesting observation of this study was that resveratrol treatment resulted in a further stimulation of UVB-mediated increases in cyclin kinase inhibitor WAF1/p21 and tumor suppressor p53. Further, resveratrol was also found to cause significant decreases in UVB-mediated upregulation of: (i) the mitogen-activated protein kinase kinase, and (ii) the 42 kDa isotype of mitogen-activated protein kinase (MAPK). Thus, our data suggested that the antiproliferative effects of resveratrol might be mediated via modulation in the expression and function of cell cycle regulatory proteins cyclin-D1 and -D2, cdk-2, -4 and -6, and WAF1/p21. Our data further suggest that the modulation of cki-cyclin-cdk network by resveratrol may be associated with inhibition of the MAPK pathway. We suggest that resveratrol may be useful for the prevention of UVB-mediated cutaneous damages including skin cancer.

Administration, Topical↗
PubMed2001

Human immunodeficiency virus-1 specific and natural cellular immunity in HIV seronegative subjects with multiple sexual exposures to virus.

The probability of HIV infection by sexual contact, although it varies greatly, appears to be lower than that of infection by other routes of exposure. The aim of this study was to evaluate immunological determinants involved in protection against HIV infection in subjects with multiple and repeated sexual exposures to the virus. Twenty-two subjects were studied for CD8+ cell anti-HIV suppression activity and serum neutralizing activity against the HIV strain of their own partners, beta-chemokine production, and natural killer cell activity. CD8+ cell anti-HIV activity and neutralizing activity of sera were found in 13 (76%) and 12 (70.5%) out of 17 HIV-1 negative subjects, respectively. Six individuals had a relevant immune response against HIV: three subjects with a high CD8+ cell antiviral suppression activity and three individuals with sera neutralizing activity titer >1:10. These last three subjects had the highest beta-chemokine levels, a very prolonged period of multiple sexual intercourse (>6 years) and a seropositive partner with a high viral load. A partial reduction of neutralizing activity titer was observed when pre-incubating the sera with anti-beta-chemokine neutralizing antibodies. A spontaneous natural killer cell activity was suppressed in the majority of HIV-1 negative subjects with sexual exposure in comparison with normal individuals. The protection from sexual HIV transmission appears to be the result of a network of different humoral and cellular factors.

Adult↗
PubMed2003

Neurotoxicity and immunotoxicity assessment in CBA/J mice with chronic Toxoplasma gondii infection and multiple oral exposures to methylmercury.

The present study was conducted to determine the effect of multiple low doses of methylmercury (MeHg) on the course of a chronic Toxoplasma gondii infection. Four groups of 6-wk-old female CBA/J mice either were fed 25 T. gondii tissue cysts of the ME-49 strain or were vehicle control. Six weeks later, half of each group was orally gavaged with 8-mg/kg body weight doses of MeHg on days 0, 2, 4, 7, 10, and 13, totaling 4 experimental groups. Mice were killed on day 17 or 18 after MeHg exposure. Flow cytometric analysis of lymphocyte subpopulations in the thymus demonstrated a significant increase in the percentage of CD4- CD8+ T-cells in mice exposed to MeHg with a concurrent T. gondii infection. Groups of mice exposed to MeHg showed a decrease in total thymic cellularity and cellularity of all T-cell subpopulations when compared with control mice, but viability of these cells was unaffected. Splenic cell viability was decreased in mice exposed to MeHg, but alterations in T-cell subpopulations were not noted. These data indicate that multiple low doses of MeHg may not exacerbate chronic toxoplasmosis, but MeHg-induced effects on the immune system were evident.

Animals↗
PubMed1997

Evaluation of the metabolism and hepatotoxicity of styrene in F344 rats, B6C3F1 mice, and CD-1 mice following single and repeated inhalation exposures.

Styrene is used for the manufacture of plastics and polymers. The metabolism and hepatotoxicity (mice only) of styrene was compared in male B6C3F1 mice, CD-1 mice, and F344 rats to evaluate biochemical mechanisms of toxicity. Rats and mice were exposed to 250 ppm styrene for 6 h/day for 1 to 5 days, and liver (mice only) and blood were collected following each day of exposure. Mortality and increased serum alanine aminotransferase (ALT) activity were observed in mice but not in rats. Hepatotoxicity in B6C3F1 mice was characterized by severe centrilobular congestion after one exposure followed by acute centrilobular necrosis. Hepatotoxicity was delayed by 1 day in CD-1 mice, and the increase in ALT and degree of necrosis was less than observed for B6C3F1 mice. Following exposure to unlabeled styrene for 0, 2, or 4 days, rats and mice were exposed to [7-14C]-styrene (60 microCi/mmol) for 6 h. Urine, feces, and expired air were collected for up to 48 h. Most styrene-derived radioactivity was excreted in urine. The time-course of urinary excretion indicates that rats and CD-1 mice eliminated radioactivity at a faster rate than B6C3F1 mice following a single 250 ppm exposure, consistent with a greater extent of liver injury for B6C3F1 mice. The elimination rate following 3 or 5 days of exposure was similar for rats and both mouse strains. Following three exposures, the total radioactivity eliminated in excreta was elevated over that measured for one exposure for both mouse strains. An increased excretion of metabolites on multiple exposure is consistent with the absence of ongoing acute necrosis following 4 to 5 daily exposures. These data indicate that an induction in styrene metabolism occurs after multiple exposures, resulting in an increased uptake and/or clearance for styrene.

Administration, Inhalation↗
PubMed1994

Teratogen exposure: lack of morphological abnormalities by detailed fetal sonography.

Teratogen exposures cause 1-2% of congenital abnormalities. Our anecdotal experience was that detailed fetal sonograms conducted for the indication of teratogen exposure failed to demonstrate significant morphological abnormalities. We reviewed our experience to see how often such examinations yielded positive results. Records from 11 September 1989 to 13 September 1993 were reviewed. All women referred for detailed fetal sonography for the sole indication of exposure to drugs, toxins, or infectious agents and with a sonographic age of 16-24 menstrual weeks were included. All exposures were included in the study, even those without known teratogenic potential. Patients previously diagnosed with a morphological abnormality or with an abnormal level of maternal serum alpha-fetoprotein were excluded.A total of 125 women with 126 singleton pregnancies comprised the study population. Ten women had multiple exposures. Including the multiple exposures, there was a total of 138 exposures, 104 to drugs and other toxins (45 of which were not known human teratogens), and 34 to infections. The only significant morphological abnormality found was a duplicated kidney in a woman with parvovirus exposure. While parvovirus is a cause of anemia and hydrops, it is not a known human teratogen. We therefore assume that this was a coincidental association. We conclude that teratogen exposure is a low-yield indication for detailed fetal sonography.

Journal Article↗
PubMed1975

Asbestos exposure and multiple primary tumors.

Recently we observed 5 patients with multiple primary tumors who also had a history of occupational asbestos exposure. Two patients had a lung carcinoma and a colon carcinoma and 3 others had 2 distinct pulmonary carcinomas. Most of the attending physicians were unaware of the patient's occupational risk for asbestos exposure and the resultant health hazards. Therefore, we review the uses of asbestos and occupations at risk for asbestos exposure.

Adenocarcinoma↗
PubMedDate not supplied

Covalent binding of xenobiotics to specific proteins in the liver.

Chemicals that cause toxicity though a direct mechanism, such as acetaminophen, covalently bind to a select group of proteins prior to the development of toxicity, and these proteins may be important in the initiation of the events that lead to the hepatotoxicity. Disruption of the cell is measured by release of intracellular proteins such as alanine aminotransferase and occurs late in the time course following a hepatotoxic dose of a direct toxin. Prior to this disruption, there appears to be a large number of proteins covalently modified by a reactive metabolite. There are at least two possible mechanisms that may cause the toxicity. First, some critical protein is a target of the reactive metabolite. Disruption of the enzymatic function (or a critical pathway for a regulatory protein) may lead directly to cell death. With the direct hepatotoxin acetaminophen, there is a decrease in the activity of several of the early target proteins, but how this disruption of critical proteins leads to the toxicity is still unclear. The early targets appear to be proteins with accessible nucleophilic sulfhydryl groups, and usually the target has a high concentration of the protein within the cell. It is possible that the binding to some of these proteins represents a detoxification protecting more critical targets within the cell. A second mechanism for the direct toxicity is that more and more proteins become targets in the time course following administration of a direct toxin, and eventually the cells machinery is overwhelmed. The cell can then no longer function, or there is a disruption the redox balance within the cell due to the decreased function of numerous proteins. In contrast to the direct-acting toxins, the chemical-protein conjugates that initiate toxicity through an activation of the immune system appear to have a limited number of target proteins and are localized within one subcellular fraction. Halothane produces adducts almost exclusively in the microsomal fraction, and these adducts appear to be limited to selective proteins with high concentrations in this fraction. The substitution level is an important factor in the development of an immune response. Halothane hepatitis patients' antibodies primarily recognize proteins with a high substitution level. For halothane and diclofenac, the proteins are accessible to the immune system through exposure on the plasma membrane. Trichloroethylene binds primarily to a 50-kDa microsomal protein, and preliminary evidence has been presented which indicates that a trichloroethylene-protein conjugate is released into the blood following exposure, where contact with the immune system can occur. In order to elicit an immune response the immune system requires multiple exposure to the chemical-protein conjugates. With halothane hepatitis and with diclofenac hepatitis, as well as occupational and environmental exposure to trichloroethylene, there are multiple exposures leading to repeat presentation of the protein adducts to the immune system; this situation is not generally found with acetaminophen overdose patients. In summary, direct toxicants such as acetaminophen covalently bind to selected targets which may be critical to the development of hepatotoxicity, and they later form adducts with numerous proteins which may overwhelm the cell's capacity to maintain homeostasis, leading to loss of vital function and cell death (Fig.3). In contrast, indirect toxicants that elicit an immune-mediated toxicity such as halothane, and possibly diclofenac and trichloroethylene, appear to have a limited number of protein targets with a high substitution level, and the immune system is exposed repeatedly to the modified proteins.

Animals↗
PubMed2001

Esterase inhibition in SH-SY5Y human neuroblastoma cells following exposure to organophosphorus compounds for 28 days.

Esterase inhibition was determined in SH-SY5Y human neuroblastoma cells grown in serum-free media and exposed to 10(-11) to 10(-7) M concentrations of organophosphorus (OP) compounds for 28 days. To examine metabolic activation in these exposures, pairs of pro- and active toxicants were studied, including chlorpyrifos and its oxon, parathion and paraoxon, and tri-ortho-tolyl phosphate and phenyl saligenin phospahte. Inhibition of acetylcholinesterase was greater in cells treated for 28 days with all active organophosphorus compounds than it was in cells treated only once with the same concentration of a given OP compound. The protoxicants chlorpyrifos and parathion produced acetylcholinesterase inhibition after multiple exposures although no inhibition was seen following a single exposure to these agents. Exacerbation of neurotoxic esterase inhibition by multiple exposures to the test compounds was not as pronounced as that of acetylcholinesterase. Exposure to the test compounds for 28 days did not significantly enhance esterase inhibition produced by a subsequent exposure to 10(-9) M chlorpyrifos-oxon. The results indicate that in vitro methods can be used to study the effect of multiple OP exposures on esterase activity.

Acetylcholinesterase↗
PubMed1997

Protective and therapeutic immunity against leukemia induced by irradiated B7-1 (CD80)-transduced leukemic cells.

B7 molecules provide an important co-stimulatory signal for T cell receptor/CD3-mediated T cell activation via binding to their cognate receptors, CD28 and CTLA-4. We have introduced B7-1 (CD80) into M1 cells, spontaneously occurring mouse myelocytic leukemic cells, and assessed its potential to induce antitumor immunity to leukemia cells. Syngeneic, immunocompetent SL mice receiving two independent B7-1-transduced monoclonal sublines, M1-B7-1/F/clone F20 and M1-B7-1/F/clone F7, were rejected in 57% and 43% of SL mice, respectively. In vivo depletion of T cell subsets showed that both CD4+ and CD8 T cells were indispensable for the B7-1-dependent anti-leukemic immunity. Although a single exposure of irradiated monoclonal M1-B7/1/F cells was not fully effective, multiple exposures induced protective immunity against subsequent challenge with parental M1 cells. Furthermore, multiple vaccinations with irradiated monoclonal M1-B7-1/F/clone F7 cells could cure 67% of mice previously injected with a lethal number of M1 cells. These results emphasize that multiple exposures of irradiated B7-1-transduced myeloid leukemic cells can induce protective and therapeutic immunity against leukemia and that B7-1-mediated gene therapy may have therapeutic efficacy for patients with acute myelocytic leukemia.

Animals↗
PubMed1988

[Subcellular mechanisms of the action of weak extra-low frequency electromagnetic fields on the cerebral cortex].

Electron microscopic examinations of the cerebral cortex in rabbits and rats after exposure to weak extra-low electromagnetic fields has detected ultrastructural changes whose degree in different nerve tissue elements was dependent on the duration of irradiation. Single exposure to weak extra-low electromagnetic field resulted only in the glial response of the neocortex, while multiple exposure resulted alternately in the response of glial cells or neuronal bodies. Three days after a single exposure and within 15 days after multiple exposure to electromagnetic field a complete repair of the nervous tissue was observed. No destructive or pathological alterations have been found which suggests the functional character of the reactions induced. Neuro-morphological alterations are of a similar character when induced by weak extra-low electromagnetic fields or other biophysical effects which points to common subcellular mechanisms of nonspecific adaptive reactions.

Animals↗
PubMed1990

Multiple small exposures of filtered mid-UV radiation increase the resistance of Chinese hamster cells to far-UV, mid-UV and filtered mid-UV radiation.

The response of Chinese hamster cells (V79-MI2G) to multiple, low doses of filtered mid-UV radiation (wavelengths longer than 300 nm) were examined over an exposure period of 30 days. Cell survival and the induction of mutation at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus using resistance to 6-thioguanine (TG) were the endpoints in this study. With increasing total accumulated dose given at 500 J/m2/day as a single short exposure, an increased resistance to cell killing was observed. This increase in resistance to cell killing was accompanied by a gradual decrease in sensitivity to the induction of mutants resistant to 6-TG. Above total accumulated doses of 5000 J/m2 the frequency of 6-TG resistance did not increase. After multiple doses of filtered mid-UV radiation the cells became more resistant to subsequent challenges with acute doses of far-UV, mid-UV or filtered mid-UV. The increased resistance to the cell killing action and to the mutation induction by UV suggests that during exposure to low, multiple doses of filtered mid-UV radiation the cells become adapted to the damaging effects of filtered mid-UV radiation.

Adaptation, Physiological↗
PubMed1979

Arsenic exposure in multiple environmental media in children near a smelter.

A nationwide survey of heavy-metal exposure in children living near primary nonferrous metal smelters demonstrated high urine arsenic levels in children living near a copper smelter in Ajo, Arizona. Airborne smelter emissions and drinking water were the apparent sources of exposure. To determine whether increased arsenic absorption had produced adverse health effects, we conducted an evaluation of 132 Ajo children 5 to 18 years old and compared results with those of 47 children from a comparison town with low arsenic exposure. Environmental testing showed that Ajo's municipal water supply contained arsenic in concentrations of 0.09 mg/l (the EPA standard is 0.05 mg/l); arsenic concentrations in dust averaged 342.2 microgram/g. Urine arsenic levels in Ajo children correlated positively with amount of tap-water consumed (r = .32, p less than. 0002) and with distance of residence from the smelter (r = .20, p less than .02). Tap-water drinkers had significantly higher urine arsenic levels than bottled water drinkers (t = 4.21 p less than .001). Mean urine arsenic levels were significantly higher for children in Ajo (4.75 microgram/100 ml) than for children in the comparison town (1.17 microgram/100 ml). Hair arsenic levels correlated poorly with arsenic exposure. Despite the study population's chronic exposure to elevated environmental levels of arsenic, no clinical or hematologic abnormalities attributable to arsenic were found.

Adolescent↗
PubMed1999

Effect of multiple antigenic exposures in the gut on oral tolerance and induction of antibacterial systemic immunity.

We have analyzed oral tolerance of microbial antigens in an experimental model in which mice are treated orally with a single small dose of soluble antigen and challenged systemically with the antigen in complete Freund's adjuvant. We found that, while oral administration of sonicated extracts of either Leishmania major, Leishmania donovani, or Staphylococcus aureus was tolerogenic, as was administration of the nominal antigen ovalbumin or conalbumin, oral administration of Escherichia coli or Salmonella typhimurium sonicated extract was not. Since E. coli is an enteric commensal that colonizes the intestine soon after birth, these data suggested that lack of demonstrable oral tolerance may be related to the frequency of oral exposure to an antigen. In support of this, we found that multiple oral doses of ovalbumin or S. aureus or L. donovani antigens did not increase systemic hyporesponsiveness beyond that achieved with a single oral dose. We have also tested the ability of mice fed with sonicates of the tolerogenic S. aureus or the nontolerogenic S. typhimurium to clear a subsequent systemic infection with the homologous bacteria and found that, while clearance of S. aureus was unaffected by prior feeding, clearance of S. typhimurium was actually enhanced. The data suggest that frequent oral antigenic exposure may eventually lead to induction of systemic immunity in tolerant mice.

Administration, Oral↗
PubMedDate not supplied

[Ultrastructure of the sinusoidal endothelial and Kupffer cells during multiple stress exposure: morphometric research].

Structural changes in endotheliocytes and Kupffer cells of the mouse liver induced by multiple stressing actions testify to the hypertrophy of these cells and to the increase in the number of their ultrastructures. Manifestations of these processes in cells of each type are characterized by a number of peculiarities which permit considering them as two different cell types.

Animals↗
PubMedDate not supplied

In vivo formation of (+)-anti-benzo[a]pyrene diol-epoxide-plasma albumin adducts in fish.

Benzo[a]pyrene (BaP), a procarcinogenic polycyclic aromatic hydrocarbon (PAH), is bioactivated to BaP diol-epoxides (BPDEs) that can form adducts with DNA and blood proteins. We report here for the first time the in vivo formation of adducts between BPDE and plasma albumin (Alb) from two fish species experimentally exposed to BaP. Brook trout (Salvelinus fontinalis) received either a single i.p. dose (10 mg/kg) or two separate i.p. doses (25 mg/kg; 7 days apart) of BaP, and blood was collected 2 (single exposure) or 3 (multiple exposure) days post-treatment. Arctic charr (Salvelinus alpinus) received 10 i.p. doses (3 mg/kg; a single dose every 6 days), and blood was collected 2 days after the second, sixth, and 10th injections. BPDE-Alb adducts were measured by an improved HPLC/fluorescence method developed to detect and quantify BaP-tetrols released after acid hydrolysis of adducted Alb. HPLC/fluorescence chromatograms of Alb from BaP-treated fish revealed only BaP-tetrol I-1, thus indicating the formation of adducts exclusively via the (+)-anti-BPDE metabolite. Levels of (+)-anti-BPDE-Alb adduct ranged from 0.68 to 19.6 ng of tetrol I-1 per gram of Alb. Notably, adduct level was not related to BaP dose and there was no accumulation of adducts with repeated exposure, which may indicate a very short half-life (< 2 days) of plasma Alb in fish. The data suggest that BPDE-Alb adducts in fish could be useful as a non-destructive biomarker of recent exposure to bioactivated BaP.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗