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Biomedical subjects

C Meredith

Publications and source records attributed to C Meredith.

At least 19 recordsLinked to original sources
PubMed2005

Detection of hypertension in the emergency department.

OBJECTIVES: To assess whether an emergency department (ED) is a suitable location for the targeted screening of hypertension. METHODS: This was a prospective targeted screening study based at the ED of an inner city teaching hospital. Non-acute subjects over 18 years were recruited consecutively from the "minors" section of the ED and invited to participate. All subjects had their blood pressure measured twice. A verbal numerical pain score (PS) out of 10 using a visual analogue scale was obtained. Those with a mean systolic blood pressure > 140 mmHg or a mean diastolic blood pressure > 90 mmHg (WHO JNC stage 1 hypertension) were invited for a subsequent follow up measurement. The primary outcome measure was the proportion of subjects with hypertension at follow up. The secondary outcome measure was the correlation between a subject's mid blood pressure (MBP) and their PS. RESULTS: In total, 765 subjects were tested, of whom 213 subjects were hypertensive at presentation (28.7%). After excluding those on anti-hypertensive medication (n = 43; 5.6%) and those who were non-UK residents (n = 44; 5.8%), 126 subjects were invited for follow up, of whom 51 subjects actually attended (40% attendance, 6.6% of study population). The MBP of those who re-attended was significantly lower than at presentation (p < 0.001); 39 subjects (5% of the study population, 76.4% of those attending follow up) remained hypertensive. There was no correlation between a subject's PS and their MBP (Pearson correlation coefficient = -0.02). A 10/10 PS was associated with an 8.4 mmHg rise in MBP compared to the mean MBP of subjects with PS 0-9 (p < 0.1). Of those originally presenting with PS > 5/10, 62% still had hypertension at follow up when the painful stimulus was significantly reduced (mean PS = 0.6). CONCLUSION: The ED provides an opportunity for identifying those individuals with hypertension who may otherwise remain undiagnosed. Caution is advised when diagnosing hypertension in those individuals suffering from anxiety and/or acute severe pain on presentation.

Adult↗
PubMed2003

Use of cultured precision-cut rat lung slices to study the in vitro induction of pulmonary cytochrome P450 forms.

1. The aim was to investigate the effects of some cytochrome P450 (CYP) enzyme inducers on CYP1A and CYP2B subfamily forms in cultured precision-cut rat lung slices. 2. Precision-cut lung slices were prepared from male Sprague-Dawley rats and cultured for 24 and/or 48 h in medium containing 0-20 micro g ml(-1) Aroclor 1254 (ARO), 0-50 micro M beta-naphthoflavone (BNF) and 0-50 micro M benzo(a)pyrene (BP). 3. Treatment with ARO, BNF and BP produced significant increases in lung slice whole homogenate 7-ethoxyresorufin O-deethylase activity. 4. Levels of CYP1A1 apoprotein were markedly increased in lung slice microsomes after treatment for 48 h with either 10 micro g ml(-1) ARO or 5 micro M BNF. In contrast, neither ARO nor BNF had any marked effect on levels of CYP2B1/2 apoprotein in 48-h cultured rat lung slice microsomes. 5. Real-time quantitative reverse transcription-polymerase chain reaction methodology (TaqMan) was used to quantify lung slice CYP1A1 and CYP2B1/2 mRNA levels. Rat lung slice CYP1A1 mRNA levels were increased up to 8.3-fold after treatment for 24 h with 2 and 10 micro g ml(-1) ARO, 0.5 and 5 micro M BNF, and 20 micro M BP. In contrast, treatment with 10 micro g ml(-1) ARO produced only a small 1.6-fold increase in CYP2B1/2 mRNA levels. 6. Precision-cut lung slices are a useful model in vitro system for the assessment of the effects of chemicals on pulmonary CYP forms.

Animals↗
PubMed2003

Studies on the induction of rat hepatic CYP1A, CYP2B, CYP3A and CYP4A subfamily form mRNAs in vivo and in vitro using precision-cut rat liver slices.

1. Real-time quantitative reverse transcription-polymerase chain reaction methodology (TaqMan(R)) was used to examine the induction of some selected rat hepatic cyto-chrome P450 (CYP) forms in vivo and in vitro using cultured precision-cut liver slices. 2. TaqMan primers and probe sets were developed for rat CYP1A1, CYP1A2, CYP2B1, CYP2B1/2, CYP3A1, CYP3A2 and CYP4A1 mRNAs. 3. To characterize the responsiveness of the rat CYP mRNA TaqMan primers and probe sets, rats were treated in vivo with a single intraperitoneal dose of 500 mg kg(-1) Aroclor 1254 (ARO) and with four daily oral doses of either 50 mg kg(-1) day(-1) dexamethasone (DEX) or 75 mg kg(-1) day(-1) methylclofenapate (MCP). Treatment with ARO produced 22 600-, 5480-, 648-, 52-, 47- and 9-fold increases in levels of CYP1A1, CYP2B1, CYP2B1/2, CYP1A2, CYP3A1 and CYP3A2 mRNA, respectively. DEX treatment produced 97-, 24-, 8- and 4-fold increases, respectively, in CYP3A1, CYP2B1, CYP2B1/2 and CYP3A2 mRNA levels, and MCP produced 339-, 126- and 25-fold increases, respectively, in CYP4A1, CYP2B1 and CYP2B1/2 mRNA levels. All three CYP inducers also increased microsomal CYP content and produced corresponding increases in CYP1A, CYP2B, CYP3A and CYP4A form marker enzyme activities. 4. Rat liver slices were cultured for 6 and 24 h in medium containing 0.1 micro M insulin and 0.1 micro M DEX, and also for 24 h in medium containing only 0.1 micro M insulin (DEX-free medium). Liver slices were cultured in control medium or in medium containing either 10 micro M beta-naphthoflavone (BNF), 10 micro g ml(-1) ARO, 500 micro M sodium phenobarbitone (NaPB), 20 micro M pregnenolone-16alpha -carbonitrile (PCN), 50 micro M Wy-14,643 (WY) or 50 micro M MCP. 5. With the exception of the effect of BNF on CYP1A1 mRNA levels, the induction of all the CYP mRNAs studied was greater after 24- than after 6-h treatment. Generally, the magnitude of induction of CYP mRNA levels was greater after 24 h in liver slices cultured in DEX-free than in DEX-supplemented medium. 6. Treatment of liver slices with BNF and ARO for 24 h in DEX-free medium produced 21- and 35-fold increases, respectively, and 38- and 37-fold increases, respectively, in CYP1A1 and CYP1A2 mRNA levels. NaPB, PCN, WY and MCP did not increase either CYP1A1 or CYP1A2 mRNA levels. 7. After 24 h, levels of CYP2B1/2 mRNA were increased 18-, 20-, 9-, 16- and 13-fold by treatment with ARO, NaPB, PCN, WY and MCP, respectively. PCN also produced 56- and 4-fold increases, respectively, in CYP3A1 and CYP3A2 mRNA levels. 8. Treatment with WY and MCP for 24 h produced 437- and 186-fold increases, respectively, in levels of CYP4A1 mRNA. None of the other CYP inducers studied had any effect on CYP4A1 mRNA levels. 9. The results demonstrate the utility of cultured precision-cut liver slices as an in vitro model system to evaluate the effects of xenobiotics on rat CYP1A, CYP2B, CYP3A and CYP4A form mRNA levels.

Animals↗
PubMed2002

Early onset chromosome 14-linked distal myopathy (Laing).

A dominantly inherited form of distal myopathy with onset in early childhood was first reported in a 4-generation Australian family in 1995. In the present report we provide further information on the clinical phenotype and natural history of this myopathy, and on the electromyogram and magnetic resonance imaging findings in affected individuals. The pattern of muscle involvement was similar to that in the 'tibial' forms of distal myopathy such as the Finnish (Udd) and Markesbery-Griggs types, with additional involvement of the finger extensors and of some more proximal limb and neck muscles. However, the age of onset was earlier than in these other myopathies and rimmed vacuoles were not found in biopsies from two affected individuals. Evidence of possible anticipation was found in one branch of the family. The gene locus for this myopathy had been mapped to 14q11.2-q13. The linkage region has been refined to a 24 cM region between D14S283 and D14S49 and mutations have been excluded in the PABP2 gene for oculopharyngeal muscular dystrophy which lies within this region.

Adolescent↗
PubMed2001

Biogeography and ecological setting of Indian Ocean hydrothermal vents.

Within the endemic invertebrate faunas of hydrothermal vents, five biogeographic provinces are recognized. Invertebrates at two Indian Ocean vent fields (Kairei and Edmond) belong to a sixth province, despite ecological settings and invertebrate-bacterial symbioses similar to those of both western Pacific and Atlantic vents. Most organisms found at these Indian Ocean vent fields have evolutionary affinities with western Pacific vent faunas, but a shrimp that ecologically dominates Indian Ocean vents closely resembles its Mid-Atlantic counterpart. These findings contribute to a global assessment of the biogeography of chemosynthetic faunas and indicate that the Indian Ocean vent community follows asymmetric assembly rules biased toward Pacific evolutionary alliances.

Animals↗
PubMed2001

Food allergy--towards predictive testing for novel foods.

The risks associated with IgE-mediated food allergy highlight the need for methods to screen for potential food allergens. Clinical and immunological tests are available for the diagnosis of food allergy to known food allergens, but this does not extend to the evaluation, or prediction of allergenicity in novel foods. This category, includes foods produced using novel processes genetically modified (GM) foods, and foods that might be used as alternatives to traditional foods. Through the collation and analysis of the protein sequences of known allergens and their epitopes, it is possible to identify related groups which correlate with observed clinical cross-reactivities. 3-D modelling extends the use of sequence data and can be used to display eptiopes on the surface of a molecule. Experimental models support sequence analysis and 3-D modelling. Observed cross-reactivities can be examined by Western blots prepared from native 2-D gels of a whole food preparation (e.g. hazelnut, peanut), and common proteins identified. IgEs to novel proteins can be raised in Brown Norway rat (a high IgE responder strain) and the proteins tested in simulated digest to determine epitope stability. Using the CSL serum bank, epitope binding can be examined through the ability of an allergen to cross-link the high affinity IgE receptor and thereby release mediators using in vitro cell-based models. This range of methods, in combination with data mining, provides a variety of screening options for testing the potential of a novel food to be allergenic, which does not involve prior exposure to the consumer.

Allergens↗
PubMed2000

Preliminary evaluation of an in vitro test for assessment of excitotoxicity by measurement of early gene (c-fos mRNA) levels.

Using primary cultures of mouse cerebellar granule cells as an in vitro model system, it has been demonstrated that different profiles of temporal expression of the c-fos proto-oncogene are observed under non-excitotoxic and excitotoxic conditions. A ratio has been derived previously for the steady-state level of c-fos mRNA after 30 min and 240 min which suggests that a 240 min/30 min ratio of greater than 1 correlates with excitotoxicity, whereas a ratio of less than 1 correlates with a non-excitotoxic outcome. Moreover, a positive correlation is seen with abrogation of excitotoxicity in response to selective excitatory amino acid receptor antagonists. This test, proposed as a specific biomarker for excitotoxicity is undergoing prevalidation. Excitotoxicity is defined as neuronal cell death mediated by hyperactivation of glutamate receptor subtypes and therefore might be expected to be prevented by selective glutamate receptor antagonists. In preliminary evaluation studies, we have conducted work under the direction of the European Center for Validation of Alternate Methods (ECVAM) using compounds specified by ECVAM that have been subdivided into four groups based on known or presumed actions. These groups comprise: Group 1-endogenous/synthetic excitotoxins; Group 2-environmental, putative excitotoxins; Group 3-neurotoxic but non-excitotoxic compounds, and Group 4-non-toxic compounds. The results of this study support the proposal that the c-fos mRNA time-ratio test is a specific biomarker of excitotoxicity. Just as importantly, this test has the potential for application in screening newly-designed EAA receptor antagonists in the search for clinically relevant drugs to treat a variety of neuropathologies.

Animals↗
PubMed2000

Interleukin-10 is an unequivocal Th2 parameter in the rat, whereas interleukin-4 is not.

Exposure of Wistar rats to the immunotoxic compounds hexachlorobenzene (HCB), bis(tri-n-butyltin)oxide, and benzo(a)pyrene was previously found to affect mRNA expression of interleukin (IL)-2, IL-2R alpha-chain, and interferon (IFN)-gamma, the prototypic Th1 cytokine. In contrast, the mRNA expression of IL-4, the prototypic Th2 cytokine, was unaffected. This latter finding suggested that the IL-4 mRNA expression may not be an unequivocal parameter for Th2 responses in the rat. In order to obtain such a parameter the present study was performed, consisting of two types of experiments. Expression and production of IL-4 as well as IL-10, a second Th2 cytokine, were measured. First, Lewis (Th1 prone) and Brown Norway (BN; Th2 prone) rats were exposed to HCB. Exposure was previously found to increase the serum immunoglobulin (Ig)E levels, an IL-4-dependent response, in BN but not Lewis rats, and in Lewis rats to aggravate experimental allergic encephalomyelitis (EAE), severity being inversely related to IL-10 levels. Secondly, BN rats were infected with Trichinella spiralis, an infection previously found to induce IL-4 production. HCB exposure did not affect IL-4 mRNA expression in either strain, while IL-4 production was decreased in Lewis and unaffected in BN rats. In Lewis rats both the mRNA expression and the production of IL-10 were decreased. The T. spiralis infection induced IL-4 and IL-10 mRNA expression, as well as IL-10 production. In contrast, the IL-4 production was strongly reduced. Thus, both the IL-10 mRNA expression and production correlated with the EAE development and T. spiralis infection. In HCB exposed Lewis rats and T. spiralis infected BN rats the IL-4 mRNA expression correlated with IgE levels and T. spiralis infection, respectively, whereas the IL-4 production lacked correlation in all cases. Collectively, these results suggest that IL-10 is an unequivocal Th2 parameter in the rat, whereas IL-4 is not.

Animals↗
PubMed1999

Historical Genetics: The Parentage of Chardonnay, Gamay, and Other Wine Grapes of Northeastern France.

The origins of the classic European wine grapes (Vitis vinifera) have been the subject of much speculation. In a search for parental relationships, microsatellite loci were analyzed in more than 300 grape cultivars. Sixteen wine grapes that have long been grown in northeastern France, including 'Chardonnay', 'Gamay noir', 'Aligoté', and 'Melon', have microsatellite genotypes consistent with their being the progeny of a single pair of parents, 'Pinot' and 'Gouais blanc', both of which were widespread in this region in the Middle Ages. Parentage analysis at 32 microsatellite loci provides statistical support for these relationships.

Journal Article↗
PubMed1999

In vitro exposure effects of cyclosporin A and bis(tri-n-butyltin)oxide on lymphocyte proliferation, cytokine (receptor) mRNA expression, and cell surface marker expression in rat thymocytes and splenocytes.

Rat thymocytes and splenocytes were exposed in vitro to the model compounds Cyclosporin A (CsA), an immunosuppressive drug, and bis(tri-n-butyltin)oxide (TBTO), an immunotoxic environmental contaminant. The lymphocyte transformation test (LTT), cytokine (receptor) mRNA expression (RT-PCR and dot blot hybridisation), and flow cytometry were evaluated as assays for in vitro immunotoxicity, at dose levels that did not show effects on viability, this being the aim of the study. LTT and RT-PCR proved useful assays. Lymphocyte transformation was suppressed by both compounds, while IL-2 mRNA expression was suppressed by CsA but not by TBTO, and both compounds suppressed IL-2R mRNA expression in splenocytes but not in thymocytes. Furthermore, the data obtained suggest that antiproliferative effects may be more relevant than apoptosis induction for TBTO induced thymus atrophy.

Animals↗
PubMed1999

Autosomal dominant distal myopathy not linked to the known distal myopathy loci.

The distal myopathies are clinically, pathologically and genetically heterogenous. Thus far, seven types of distal myopathy have been linked to four chromosome loci. We recently examined four affected members from three generations of an autosomal dominant distal myopathy kindred. A muscle biopsy was performed on the index case. Muscle histopathology showed non-specific myopathic findings including increased variation in fiber size and increased internalized nuclei. No abnormal inclusions or vacuoles were present. Microsatellite markers for the four distal myopathy loci on chromosomes 2, 9 and 14 were studied on affected and several unaffected family members. Affected patients developed distal weakness in anterior foreleg muscles followed by progressive distal upper and proximal lower extremity involvement. Chromosome 2, 9 and 14 regional markers were informative and demonstrated recombinations with affected individuals in the pedigree. The resulting LOD scores obtained from the multipoint analyses gave no evidence of positive linkage to any of the regions and positively excluded (LOD score less than -2) all, or virtually all, of the candidate regions examined. This autosomal dominant distal myopathy family does not show evidence of linkage to any of the known distal myopathy loci, suggesting the existence of at least one more distal myopathy locus. Furthermore, the clinical and pathological features appear distinct from other previously described but genetically-undetermined autosomal dominant distal myopathies.

Adult↗
PubMed1999

Allergy to bovine beta-lactoglobulin: specificity of immunoglobulin E generated in the Brown Norway rat to tryptic and synthetic peptides.

BACKGROUND: Animal models which reflect the induction and development of food-allergic reactions are important in the identification of allergenic potential of food proteins and peptides. A number of rat strains, including PVG, Hooded Lister and Brown Norway have been shown to produce immunoglobulin (Ig) E antibodies to food proteins as well as to inhaled allergens. Previous work in our laboratory using the Brown Norway (BN) rat has shown that specific IgE is produced following administration of ovalbumin and milk products via both enteral and parenteral route; this has allowed us to rank ovalbumin, lactoferrin and bovine serum albumin in terms of their inherent allergenic potential and has enabled us to demonstrate that milk protein allergens recognized by the systemically-sensitized animal are consistent with those recognized by sera from cow's milk-allergic patients (the most common allergens recognized were beta-lactoglobulin and the alpha, beta and kappa-caseins). OBJECTIVE: To demonstrate that the BN rat model can be used to identify the major IgE-binding peptides from beta-lactoglobulin, a known human food allergen, and that those IgE-binding peptides are similar to those recently identified using sera from cow's milk-allergic patients. METHODS: BN rats were exposed to beta-lactoglobulin or to semiskimmed milk via the intraperitoneal route in the presence of the adjuvant carrageenan. Specific IgE raised against beta-lactoglobulin was determined by a direct enzyme immunoassay using acetyl-cholinesterase substrate; specific IgG responses were also monitored. Overlapping synthetic peptides and tryptic peptides were used within the ELISA to identify the major and minor IgE-binding immunoreactive sequences. RESULTS: In terms of comparative immunogenicity, there appeared to be sequences that were predominantly IgE- or IgG-reactive. IgE-dominant regions were amino acid sequences 21-40, 41-60, 107-117 and 148-168 whereas sequences 1-24, 67-77, 82-92, 85-95 and 117-127 appeared more selective for IgG antibody recognition. An increased capacity to induce specific IgE was observed when the allergen was present in the context of whole food. CONCLUSIONS: These studies provide evidence that the immune system of the BN rat and humans - at least in the case of milk allergens - is recognizing similar protein allergens and indeed, at the molecular level, similar peptide epitopes.

Animals↗
PubMed1999

Injury rates in Shotokan karate.

OBJECTIVE: To document the injury rate in three British Shotokan karate championships in consecutive years. In these tournaments strict rules governed contact, with only "light" or "touch" contact allowed. Protective padding for the head, hands, or feet was prohibited. METHODS: Prospective recording of injuries resulting from 1770 bouts in three national competitions of 1996, 1997, and 1998. Details of ages and years of karate experience were also obtained. RESULTS: 160 injuries were sustained in 1770 bouts. The overall rate of injury was 0.09 per bout and 0.13 per competitor. 91 (57%) injuries were to the head. The average age of those injured was 22 years, with an average of nine years of experience in karate. CONCLUSIONS: The absence of protective padding does not result in higher injury rates than in most other series of Shotokan karate injuries. Strict refereeing is essential, however, to maintain control and minimise contact.

Adolescent↗
PubMed1998

Altered cytokine (receptor) mRNA expression as a tool in immunotoxicology.

Molecular immunotoxicology is aimed at analysing exposure effects on the temporal expression of important immunoregulatory genes. Cytokines play key roles in the immune system and thus molecular immunotoxicology has focused on the analysis of cytokine (expression) levels. These targets offer important new avenues to explore both in terms of mechanistic understanding of immunotoxicity and in terms of developing new assays and tests for predicting the immunotoxic potential of novel compounds. Effects on cytokine levels can be analysed on two different levels, these being mRNA and protein. The choice essentially depends on the aim of the study. Proteins comprise the biological activity so they are a more direct measure than mRNA. mRNA on the other hand, measures at a specific point in time within a tissue or organ, whereas protein is measured in a body fluid, possibly as a spill-over from tissue, or in a supernatant as a summation over a culture period. mRNA levels are assayed using Northern or dot blotting that both comprise hybridisation and using reverse transcription-polymerase chain reaction (RT-PCR). Although the latter technique has both enormous sensitivity and relative ease of operation as important advantages, it requires much more effort in terms of quantitation. References to the nucleic acid sequences of human, murine, and rat cytokines and their receptors are presented (with accession numbers). Examples in which molecular techniques were successfully employed to assess immunotoxicity and (in some cases) understand mechanisms of action are also presented.

Animals↗
PubMed1998

Calcium influx via L-type voltage-gated channels mediates the delayed, elevated increases in steady-state c-fos mRNA levels in cerebellar granule cells exposed to excitotoxic levels of glutamate.

The altered kinetics of steady-state c-fos mRNA production in cultured cerebellar granule cells under excitotoxic conditions was investigated in neurons subjected to depolarising stimuli, namely, high KCl and L-glutamate (Glu), in which Ca2+ influx occurs by differing routes. Increases in intracellular-free calcium levels ([Ca2+]i) stimulated by nontoxic or toxic levels of Glu were blocked by selective N-methyl-D-aspartate (NMDA) receptor antagonism; were blocked only partially by the L-type channel blocker, nifedipine; and were unaffected by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptor antagonists. Glu-induced cell death was prevented only by NMDA receptor blockade. Exposure of cells to nontoxic levels of Glu resulted in a transient increase in c-fos mRNA levels, whereas an excitotoxic dose produced a delay in the appearance of c-fos mRNA but a subsequent, progressive, and sustained (>4 hr) increase. An excitotoxic dose of Glu in combination with either nifedipine or selective NMDA receptor antagonists resulted in the normal, transient increase of c-fos mRNA levels. Chronic exposure to 55 mM KCl caused no cytotoxicity, although it resulted in a delayed, elevated increase in c-fos mRNA levels that was unaffected by NMDA receptor blockade but reverted to the normal, transient profile of c-fos mRNA formation when it was coadministered with nifedipine. The KCl-induced increase in [Ca2+]i levels was inhibited dramatically by nifedipine but was unaffected by any of the ionotropic Glu receptor antagonists. The results support the notion that the appearance of a delayed but elevated increase in steady-state c-fos mRNA levels following exposure to excitotoxic doses of Glu is mediated specifically by calcium influx via L-type voltage-gated channels.

Animals↗
PubMed1998

Effects of in vivo exposure to bis(tri-n-butyltin)oxide, hexachlorobenzene, and benzo(a)pyrene on cytokine (receptor) mRNA levels in cultured rat splenocytes and on IL-2 receptor protein levels.

Analysis of cytokine (receptor) mRNA levels has been suggested to be a sensitive technique for predicting the immunomodulatory potential of drugs and chemicals. Furthermore, this type of analysis is thought to be important in unraveling mechanisms of immunotoxicity. To study these issues, male Wistar rats were exposed to the immunotoxic environmental contaminants bis(tri-n-butyltin) oxide (TBTO; 5, 20, or 80 mg/kg diet for 6 weeks), hexachlorobenzene (HCB; 50, 150, or 450 mg/kg diet for 6 weeks), or benzo(a)pyrene (B(a)P; 3, 10, 30, or 90 mg/kg body wt for 5 weeks by a daily (5 times a week) oral intubation). Spleen cells were cultured with Con A and analyzed by dot blot hybridization for IL-2, IFN-gamma, IL-2 receptor alpha-chain (IL-2R alpha; CD25), and IL-4 mRNA levels. In addition, spleen and thymus sections of TBTO-exposed animals were assayed immunohistochemically for CD25 expression. Exposure to TBTO resulted in a dose-dependent decrease in IL-2R alpha mRNA levels from 5 mg/kg, a dose-dependent increase in IFN-gamma mRNA levels from 20 mg/kg, and increased IL-2 mRNA levels at 80 mg/kg diet. Exposure to HCB resulted in a dose-dependent increase in IL-2 and IFN-gamma mRNA levels from 150 mg/kg and increased IL-2R gamma mRNA levels at 450 mg/kg diet. Exposure to B(a)P resulted in a dose-dependent increase in IL-2 and IFN-gamma mRNA levels from 10 mg/kg and increased IL-2R alpha mRNA levels at 90 mg/kg body wt. No effects were seen on IL-4 mRNA levels. Spleen and thymus sections of TBTO-exposed animals showed reduced CD25 expression from 5 mg/kg diet. These results show that (1) the correlation between altered cytokine (receptor) mRNA levels and functional endpoints is variable, depending on the type of functional endpoint tested and the compound studied, (2) these assays are among the most sensitive ones for TBTO and HCB immunotoxicity, and among the more sensitive ones for B(a)P immunotoxicity, and (3) for TBTO, these assays provide a possible clue to a mechanism for thymus atrophy, resulting from exposure to this compound: reduced IL-2R expression may impede thymocyte maturation, resulting in thymus atrophy.

Animals↗
PubMed1998

Immunotoxicology: extrapolation from animal to man--estimation of the immunotoxicologic risk associated with TBTO exposure.

Bis(tri-n-butyltin)oxide (TBTO) has been shown to be immunotoxic in rodents, resulting in decreased resistance to infections. The no-effect level assessed by estimating effects on host resistance in rats has been found to lie between 0.5 and 5.0 mg TBTO/kg food (0.025 and 0.25 mg/kg body weight). For risk assessment such animal data need to be extrapolated to the human situation. In risk assessment procedures uncertainty factors are used to account for interspecies variation (extrapolation from animal to man) and for variation within the human species. For both factors a value of 10 is often used, based on international guidelines. Hence, exposures below 0.00025 mg/kg body weight should not pose a risk for the human population. In the present study we have taken an alternative approach. We have produced dose-response curves for the effect of TBTO exposure on resistance to Trichinella spiralis. To extrapolate this curve to the human situation, we produced additional dose response data concerning in vitro effects of TBTO exposure on the mitogen responsiveness of both rat lymphoid cells and human blood cells. Using regression analyses of these dose-response data, we calculated a factor that accounts for interspecies variation (IEV) and a factor that accounts for intraspecies variation (IAV) within the human samples. Using these factors, we estimated the dose that decreases resistance in man to an infection. We choose 10% increase of the infectious load as a reference point which in our view is of biological significance. Based on these considerations, we estimated the dose that may affect resistance in adult humans at 0.04 mg/kg body weight. Pre- and postnatal exposure will probably result in effects at lower concentrations, due to the vulnerability of the developing immune system.

Adult↗