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C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) develop neurological symptoms and die 6--7-day post-inoculation in the absence of high parasitemia. The effects of chronic intake of a high-fat diet on this process are largely unknown. In this study, we assessed the effect of a high-fat diet on the host-parasite response to malarial infection. Mice were fed ad libitum with either standard or a high-fat diet for 8 weeks and afterwards were infected with PbA. PbA-infected mice feeding a standard diet presented blood parasitemia, hepatic and cerebral histopathological alterations, and hepatic injury with increased hemozoin deposition in the liver. By contrast, these changes were not observed in the malaria high-fat diet group. In addition, mice fed a high-fat diet did not develop the expected neurological symptoms of cerebral malaria and were resistant to death. Taken together, our results indicate that chronic ingestion of high-fat diet prevents the development of experimental malaria induced by PbA injection, suggesting a relationship between a high-fat diet and malaria, which is an interesting subject for further study in humans.

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide, CAP) is an important ingredient in spicy foods consumed throughout the world. Vinblastine (VBL) is a naturally occurring alkaloid prescribed to cancer patients. Many cancer patients treated with VBL were taking CAP at the same time. This study attempted to investigate the effect of CAP on the pharmacokinetics of VBL, which is the substrate of CYP3A, P-gp, and Mrp2. CAP, cyclosporine (CsA) or olive oil was given to rats for seven consecutive days, and on the seventh day, VBL (1.3 mg/kg) was administered intravenously. CsA was used as a CYP3A1/2 and transporter inhibitor, and olive oil was used as a vehicle. The results showed that pretreatment of rats with CAP (3.0 mg/kg) for seven consecutive days resulted in an increase in the AUC0-t of VBL of about 29.8% (P < 0.05) compared with the control group. Moreover, CAP decreased the CL of VBL to 75.5% (P < 0.05). At this time, CYP3A1/2 and Mrp2/Abcc2 in the liver was decreased at the mRNA and protein levels. These results demonstrate that chronic ingestion of CAP will increase systemic exposure and reduce clearance of VBL in rats. The food-drug interaction between CAP and VBL appears to be due to modulation of CYP3A1/2 and Mpr2 expression by CAP.

The widespread occurrence of microplastics (MPLs) and nanoplastics (NPLs), collectively abbreviated as M/NPLs, has markedly affected the ecosystem and has become a global threat to human health. Multiple investigations have shown that the chronic ingestion of M/NPLs negatively affects gut barrier function but the mechanism remains unclear. Herein, this research has investigated the toxic effects of pristine polystyrene (PS) M/NPLs, negatively charged carboxylated polystyrene M/NPLs (PS-COOH) and positively charged aminated polystyrene M/NPLs (PS-NH2) of two sizes (70 nm and 5 μm in diameter) in mice. Gavage of these PS M/NPLs for 28 days caused obvious injuries to the gut tract, leading to the decreased expression of tight junction proteins. The toxicity of the M/NPLs was ranked as PS-NH2 > PS-COOH > pristine PS. Oral administration of these M/NPLs resulted in marked gut microbiota dysbiosis. The M/NPLs-enriched genera generally contained opportunistic pathogens which are accompanied by a deteriorated intestinal barrier function, while most M/NPLs-decreased bacteria were beneficial microbes with known tight junction-promoting functions, implicating an important indirect toxic effect of gut microbiota dysbiosis in M/NPLs-induced gut barrier dysfunction. In conclusion, this research highlights the importance of gut microbiota in the toxicity of M/NPLs exposure on gut barrier function, providing novel insights into the adverse effects of M/NPLs exposure on human health.

Objective: The aim of this study was to determine sucralose and acesulfame-potassium (ace-K) pharmacokinetics in breast milk following maternal ingestion of a diet soda. Methods: Thirty-four exclusively breast-feeding women (14 normal-weight, 20 obese) consumed 12 ounces of Diet Rite Cola, sweetened with 68-mg sucralose and 41-mg ace-K, before a standardized breakfast meal. Habitual non-nutritional sweeteners intake was assessed via a diet questionnaire. Breast milk was collected from the same breast before beverage ingestion and hourly for 6 hours. Results: Owing to one mother having extremely high concentrations, peak sucralose and acesulfame-potassium concentrations following ingestion of diet soda ranged from 4.0 to 7387.9 ng/mL (median peak 8.1 ng/mL) and 299.0 to 4764.2 ng/mL (median peak 945.3 ng/mL), respectively. Conclusions: Ace-K and sucralose transfer into breast milk following ingestion of a diet soda. Future research should measure concentrations after repeated exposure and determine whether chronic ingestion of sucralose and acesulfame-potassium via the breast milk has clinically relevant health consequences.

The ingestion of microplastics (plastic particles Echinogammarus marinus, using food consumption, growth, and moulting as endpoints. Amphipods were fed a gelatinous algal feed spiked with microbeads (8 μm) in concentrations of ~0.9, 9 and 99 microplastics/g for 35 days. E. marinus was also analysed for retention of microplastics, and egestion rate was calculated in a separate high-dose feeding experiment. No significant effects were found in the food consumption or growth assays. There was no accumulation of microplastics in the gut, with only one microbead recorded internally in three (8%) of the exposed amphipods. The low number is likely linked to gastrointestinal functions, allowing for easy egestion of indigestible items. This assumption was supported by the observation that after high-dose exposure, 60 % of E. marinus egested all microbeads within 24 hours. This study suggests that ingesting low concentrations of 8μm microplastics do not impair the feeding or growth of amphipods along the exposure period. We hope that negative results such as these may further assist in assessing the impact posed by microplastics to marine organisms.

The presence of 137Cesium (137Cs) in the environment after nuclear accidents at Chernobyl and more recently Fukushima Daiichi raises many health issues for the surrounding populations chronically exposed through the food chain. To mimic different exposure situations, we set up a male rat model of exposure by chronic ingestion of a 137Cs concentration likely to be ingested daily by residents of contaminated areas (6500 Bq.l−1) and tested contaminations lasting 9 months for adult, neonatal and fetal rats. We tested plasma and serum biochemistry to identify disturbances in general indicators (lipids, proteins, carbohydrates and electrolytes) and in biomarkers of thyroid, heart, brain, bone, kidney, liver and testis functions. Analysis of the general indicators showed increased levels of cholesterol (+26%), HDL cholesterol (+31%), phospholipids B (+15%) and phosphorus (+100%) in the postnatal group only. Thyroid, heart, brain, bone and kidney functions showed no blood changes in any model. The liver function evaluation showed changes in total bilirubin (+67%) and alkaline phosphatase (–11%) levels, but only for the rats exposed to 137Cs intake in adulthood. Large changes in 17β-estradiol (–69%) and corticosterone (+36%) levels affected steroidogenesis, but only in the adult model. This study showed that response profiles differed according to age at exposure: lipid metabolism was most radiosensitive in the postnatal model, and steroid hormone metabolism was most radiosensitive in rats exposed in adulthood. There was no evidence of deleterious effects suggesting a potential impact on fertility or procreation.

A miniature dachshund male with severe azotemia of unknown cause was referred. Serum biochemistry revealed severe azotemia and hypercalcemia, but serum intact parathormone and parathormone-related protein were normal. Although the owner reported that the dog had never ingested any drugs or supplements, it was revealed that the owner's son used antipsoriatic ointment, maxacalcitol, which contained an active vitamin D3 analogue, daily and the dog often ate the son's dander and licked his skin, especially after he applied the maxacalcitol ointment. After the dog was insulated from the maxacalcitol ointment and the son as much as possible, the hypercalcemia and azotemia improved gradually and had mostly resolved at 3 mo. The dog has been generally free of clinical signs without any treatment for over 2 yr.

To assess the dosimetry of Ra-226 in a two-year chronic ingestion study in laboratory maintained fathead minnow fed environmentally relevant levels of the isotope known to occur in gut contents of fish from a uranium mining area.Fish were established on reconstituted commercial fish food containing 10 mBq-10 Bq Ra-226.g(- 1) dry food. The fish were sampled at 1, 6, 18 and 24 months and the Ra-226 levels in the whole fish were directly determined using measurement performed using inorganic mass spectrometry. Pilot experiments using higher doses were also done during development of a liquid scintillation detection system which support some data.The data show that after 1 month the levels of accumulation in the fish were below detection. At 6 months there was an activity dependent accumulation which was relatively higher in the low activity groups. By 18 and 24 months the radium was very low in all groups - well below 6 month levels suggesting considerable loss of radium from the fish. These data were confirmed in a small and shorter study using higher dietary activities. The highest dose calculated for any measurement point was 16 μGy.h(- 1) in the 6-month-old fish fed the diet containing 10 Bq.g(- 1).We conclude that environmentally relevant levels of Ra-226 have a maximum impact at early time-points when the fish are still growing. After that they appear to depurate accumulated radium. In terms of environmental impact, the maximum accumulation peaks at the age where fish could be spawning but is extremely low leading to μGy.year(- 1) doses even after exposure to the high activity diets.

Insect pests have caused economic losses valued at billions of dollars in agricultural production. Anagasta kuehniella (Zeller), the Mediterranean flour moth, is of major economic importance as a flour and grain feeder and is often a severe pest in flourmills. This study provides a suitable route for the direct preparation of thiosulfonates 2 and 3 from thiols, under mild conditions, with good yields; these thiosulfonates were tested for their regulatory effect on insect growth. The chronic ingestion of thiosulfonates resulted in a significant reduction in larval survival and weight. In addition, the tryptic activity of larvae was sensitive to these thiosulfonates. Results suggest that thiosulfonates 2 and 3 have a potential antimetabolic effect when ingested by A. kuehniella. The use of AgNO(3)/BF(3)·OEt(2) and Al(H(2)PO(4))(3)/HNO(3) provides a suitable route for the direct preparation of thiosulfonates from thiols under mild conditions with good yields. These thiosulfonates were toxic for A. kuehniella larvae, suggesting their potential as biotechnological tools.

Translational research is an emerging discipline that aims to fill the gap through the whole pipeline from bench to bedside. This review highlights the importance and urgency of incorporating translational research into the study of pharmacokinetic herb drug interactions (PHDI), based on an intensive discussion on the controversial and inconsistent reports from preclinical to clinical, in vitro to in vivo, and across different studies concerning PHDI. Current controversial and dispersed reports confer poor translational capacity of experimental research data to guiding the clinical practices. We propose that the herbal complexities in their chemical compositions, biphasic and tissue-specific effects of enzymes, and the present incomplete understanding of the disposition properties of herbal medicines themselves; and the enzymatic complexities in the species differences, individual genotype and phenotype, differential regulation during healthy and pathological conditions, substrate dependent modulations, and their interplay with transporters, collectively constitute the major translational blocks in PHDI from experimental research to daily clinical practice. In clinical considerations, this review indicates that PHDI are far from clear based on the isolated preclinical findings, and that the intestine is a much more susceptible site than liver when subjected to herbal regulations, and that enzymatic induction could be more predominant than inhibition upon chronic ingestion of herbal medicines. Hopefully, this review would be helpful for better understanding the nature of hurdles in PHDI research, and for igniting the future translational research initiatives.

The aim of our study was to define the biokinetics of 90Sr after chronic contamination by ingestion using a juvenile and adult murine model. Animals ingested 90Sr by drinking water containing 20 kBq l -1 of 90Sr. For the juvenile model, parents received 90Sr before mating and their offspring were killed between birth and 20 weeks of ingestion. For the adult model, 90Sr ingestion started at 9 weeks of age and they were killed after different ingestion periods up to 20 weeks. The body weight, food and water consumption of the animals were monitored on a weekly basis. Before killing and sampling of organs, animals were put in metabolic cages. 90Sr in organs and excreta was determined by liquid scintillation \textgreekb counting. Highest 90Sr contents were found in bones and were generally higher in females than in males, and 90Sr retention varied according to the skeletal sites. An accumulation of 90Sr in the bones was observed over time for both models, with a plateau level at adult age for the juvenile model. The highest rate of 90Sr accumulation in bones was observed in early life of offspring, i.e. before the age of 6 weeks. With the exception of the digestive tract, 90Sr was below the detection limit in all other organs sampled. Overall, our results confirm that 90Sr mainly accumulates in bones. Furthermore, our results indicate that there are gender- and age-dependent differences in the distribution of 90Sr after low-dose chronic ingestion in the mouse model. These results provide the basis for future studies on possible non-cancerous effects during chronic, long-term exposure to 90Sr through ingestion in a mouse model, especially on the immune and hematopoietic systems. © 2011 Springer-Verlag.

Urinary bladder tumours in cattle are caused by chronic ingestion of bracken fern and BPV-1/2 infection. The objective of the present study was to assess if BPV-2 was present in urinary bladder lesions from cattle with chronic enzootic haematuria (CEH) from the Azores archipelago (Portugal), in order to gain further information regarding the epidemiologic distribution of this virus. Samples were analysed using PCR specific primers for BPV-2 DNA and an immunohistochemistry for BPV E5 oncoprotein detection. We found a 28% incidence rate of BPV-2 DNA in different types of tumours and cystitis cases (13 out of 46 samples). Tested positive samples for PCR were also positive for the viral E5 oncoprotein; protein immunolabeling was mainly detected within the cytoplasm of urothelial cells, displaying a juxtanuclear distribution. This is the first report of BPV-2 detection in urinary bladder tumours associated with CEH in cattle from the Azores archipelago.

Cyclooxygenase (COX)-2, an inducible enzyme involved in prostaglandin biosynthesis, has attracted considerable attention recently, due to its role in human cancer biology. Several studies have correlated an increase in the expression of COX-2 with a poor clinical outcome, while epidemiological studies demonstrate a reduced risk of cancer mortality in persons with longterm, chronic ingestion of non-steroidal anti-inflammatory drugs (NSAIDs). Originally, these observations were made in patients with colorectal cancer, and subsequent studies suggest a protective role of NSAIDs in other human cancers as well. With the development of COX-2 specific inhibitors, numerous laboratory and clinical studies are underway to help understand the role of COX-2 in cancer and the potential use of COX-2 selective inhibitors for cancer treatment or prevention. This review focuses on the physiological function of COX, and the clinical rationale for evaluating COX-2 selective inhibitors for use in oncology.

Chronic ingestion of diets containing 34% or 54% fat have been reported [Peptides 19 (1998) 1407] to decrease the inhibitory effect on food intake of doses of cholecystokinin-8 (CCK-8) less than 1 microg/kg i.p. We attempted to replicate this phenomenon in three experiments by comparing the effect of high-fat and low-fat diets on the threshold dose of CCK-8 for inhibition and on the dose-response function for doses of CCK-8 that ranged from 0.125 to 2.0 microg/kg. The first experiment tested rats five times per week. Rats on a 34% fat diet had a higher threshold (1.0 microg/kg) than rats on a 5% fat diet (0.25 microg/kg). The dose-response functions, however, were not significantly different. This result replicated the earlier report [Peptides 19 (1998) 1407]. The second experiment tested rats maintained on the same diets every other day as in the original report. It failed, however, to replicate the results of the first experiment or the earlier report because the threshold doses and the dose-response functions of CCK-8 were not significantly different between rats on 34% and 5% fat diets. The third experiment compared the potency of CCK-8 in rats on a 60% fat diet with the potency in rats on a 5% fat diet. CCK-8 was significantly more potent in the rats on the 60% fat diet because the threshold dose of these rats was lower (0.125 microg/kg) than in rats on the 5% fat diet (0.25 microg/kg), and the dose-response function in rats on the 60% fat diet was significantly more potent than in rats on the 5% fat diet. Thus, we observed two effects of the chronic ingestion of high-fat diets on the inhibitory potency of CCK-8: (1). A 34% fat diet increased the threshold dose of CCK-8 without changing the dose-response function in one of two experiments. (2). A 60% fat diet increased the potency of CCK-8 because it decreased the threshold dose and increased the dose-response function significantly.

International audience; Deoxynivalenol (DON), nivalenol (NIV) and zearalenone (ZEA) are mycotoxins commonly produced by Fusarium species. The purpose of the present study was to investigate the effects of DON alone and in combination with NIV and ZEA on several parameters including weight gain and histological aspects of pigs submitted to chronic intoxication. Twenty, 5-week-old piglets received for 28 days one of the following diets: a control diet, a diet mono- contaminated with DON (1.5 mg/kg), a diet multi-contaminated with DON (2 mg/kg) + NIV (1.3 mg/kg) + ZEA (1.5 mg/kg) or a diet contaminated with DON (3 mg/kg) + NIV (1.3 mg/kg) + ZEA (1.5 mg/kg). Animals fed the multi-contaminated diets presented a significant decrease in weight gain over the total period. The chronic ingestion of the contaminated diets induced a significant increase on histological changes on the intestine, liver and lymphoid organs. In addition, a significant increase on lymphocyte apoptosis was observed in lymph nodes and spleen in the animals receiving the contaminated diets. These data provide a better understanding of the possible effects of Fusarium toxins, alone or in combinations on the morphology of the intestine and lymphoid organs, which would contribute to the risk assessment of these toxins.

Chronic hypervitaminosis A can occur in many species after excessive dietary intake of Vitamin A (retinol). The most common presentation of chronic hypervitaminosis A is a polyarthropathy with hyperostosis and ankylosis of various joints. This case report describes a probable case of naturally occurring hypervitaminosis A-induced polyarthropathy in a rabbit after chronic ingestion of a diet made up almost exclusively of carrots. Carrots do not contain retinol, but are rich in provitamin A (or beta-carotene). Rabbits are unique in that they can convert 100% of dietary beta-carotene into retinol. A syndrome of naturally occurring hypervitaminosis A-induced polyarthropathy has not been described in a rabbit before.

Enterostatin (Ent), the activation pentapeptide from procolipase, inhibits the intake of dietary fat. The selectivity of the response to fat suggests that the rat must recognize a permissive signal related to dietary fat for the Ent biological response. To investigate the nature of this signal, we studied the effects of Ent in rats that were adapted to either a high-fat (HF) or high-carbohydrate/low-fat (HC) diet and then naively exposed to either HF or HC diets. Ent (1 nmol) was injected into the lateral ventricle of overnight-fasted rats, and food intake was measured. Rats adapted to HF diet and tested with HC diet responded to Ent, but rats adapted to HC diet and tested with HF did not respond to Ent. The groups were maintained on their new test diets for up to 21 days and tested again for their response to Ent at 3, 7, 14, and 21 days. Ent response did not appear in HC-adapted rats switched to HF diet before 21 days. Conversely, the HF-adapted rats, which responded to Ent when tested with HC diet for the first time, did not respond at any subsequent testing time. The data suggest that chronic ingestion of dietary fat is required for Ent action and that chronic consumption of fat initiates a postingestion metabolic, endocrine, or neurochemical change that is required for the biological response to Ent.

The pertinent literature concerning the experimental induction of analgesic nephropathy is reviewed. Based on the accumulated data from animal experiments that induced a pathologic lesion resembling chronic analgesic nephropathy, of the limited number of analgesics tested, aspirin seems to be the most nephrotoxic of the commonly available analgesics. When aspirin is combined with other analgesics, the limited data available suggest at least an additive nephrotoxic effect, if not a synergism. The histologic presentation of acute intoxication is substantially different from that following chronic ingestion. With improvements in pathologic analysis of experimental results, future studies may well provide more insight as to the significance, relative contribution, and risk of combination analgesic products in inducing experimental analgesic nephrotoxicity.

Chronic intake of alcohol increases the risk of gastrointestinal and hepatic carcinogenesis. The present study was focused to investigate the incidence and mechanism of pathogenesis of hepatocellular carcinoma (HCC) during chronic ingestion of alcohol without any additional hepatic injury.Ethanol was administered to Institute for Cancer Research male mice through drinking water for 70 weeks at concentrations of 5 % (first week), 10 % (next 8 weeks), and 15 % thereafter. The animals were killed at 60 and 70 weeks, the livers were examined for hepatic tumors, and evaluated for foci of cellular alteration (FCA). Immunohistochemical staining was performed in the liver sections for cytochrome P4502E1 (CYP2E1), 4-hydroxy-nonenal (4-HNE), and proto-oncogene, c-Myc.At the 60th week, 40 % of the mice in the ethanol group had visible white nodules (5-10 mm) in the liver, but not in the control mice. At the 70th week, several larger nodules (5-22 mm) were present in the livers of 50 % mice in the ethanol group. In the control group, one mouse developed a single nodule. All nodules were histologically trabecular HCC composed of eosinophilic and vacuolated cells. In the livers of both control and ethanol group, several foci with cellular alteration were present, which were significantly higher in ethanol group. Staining for CYP2E1, 4-HNE and c-Myc depicted marked upregulation of all these molecules in the FCA.Our data demonstrated that upregulation of CYP2E1 and subsequent production of reactive oxygen species along with the persistent expression of c-Myc play a significant role in the pathogenesis of HCC during chronic ingestion of ethanol.

International audience; Reports have described apparent biological effects of Cs-137 (the most persistent dispersed radionuclide) irradiation in people living in Chernobyl-contaminated territory. The sensitive analytical technology described here should now help assess the relation of this contamination to the observed effects. A rat model chronically exposed to Cs-137 through drinking water was developed to identify biomarkers of radiation-induced metabolic disorders, and the biological impact was evaluated by a metabolomic approach that allowed us to detect several hundred metabolites in biofluids and assess their association with disease states. After collection of plasma and urine from contaminated and non-contaminated rats at the end of the 9-months contamination period, analysis with a LC-MS system detected 742 features in urine and 1309 in plasma. Biostatistical discriminant analysis extracted a subset of 26 metabolite signals (2 urinary, 4 plasma non-polar, and 19 plasma polar metabolites) that in combination were able to predict from 68 up to 94% of the contaminated rats, depending on the prediction method used, with a misclassification rate as low as 5.3%. The difference in this metabolic score between the contaminated and non-contaminated rats was highly significant (P = 0.019 after ANOVA cross-validation). In conclusion, our proof-of-principle study demonstrated for the first time the usefulness of a metabolomic approach for addressing biological effects of chronic low-dose contamination. We can conclude that a metabolomic signature discriminated Cs-137-contaminated from control animals in our model. Further validation is nevertheless required together with full annotation of the metabolic indicators.

International audience; Kidney disease is a frequent consequence of heavy metal exposure and renal anemia occurs secondarily to the progression of kidney deterioration into chronic disease. In contrast, little is known about effects on kidney of chronic exposure to low levels of depleted uranium (DU). Study was performed with rats exposed to DU at 40 mg/l by chronic ingestion during 9 months. In the present work, a approximately 20% reduction in red blood cell (RBC) count was observed after DU exposure. Hence, three hypotheses were tested to determinate origin of RBC loss: (1) reduced erythropoiesis, (2) increased RBC degradation, and/or (3) kidney dysfunction. Erythropoiesis was not reduced after exposure to DU as revealed by erythroid progenitors, blood Flt3 ligand and erythropoietin (EPO) blood and kidney levels. Concerning messenger RNA (mRNA) and protein levels of spleen iron recycling markers from RBC degradation (DMT1 [divalent metal transporter 1], iron regulated protein 1, HO1, HO2 [heme oxygenase 1 and 2], cluster of differentiation 36), increase in HO2 and DMT1 mRNA level was induced after chronic exposure to DU. Kidneys of DU-contaminated rats had more frequently high grade tubulo-interstitial and glomerular lesions, accumulated iron more frequently and presented more apoptotic cells. In addition, chronic exposure to DU induced increased gene expression of ceruloplasmin (x12), of DMT1 (x2.5), and decreased mRNA levels of erythropoietin receptor (x0.2). Increased mRNA level of DMT1 was associated to decreased protein level (x0.25). To conclude, a chronic ingestion of DU leads mainly to kidney deterioration that is probably responsible for RBC count decrease in rats. Spleen erythropoiesis and molecules involved in erythrocyte degradation were also modified by chronic DU exposure.

PURPOSE. To investigate how supplementation of the monkey's diet with high doses of lutein (L), zeaxanthin (Z), or a combination of the two affects the plasma levels and ocular tissue deposition of these carotenoids and their metabolites over time and to determine whether these high doses can cause ocular toxicity. METHODS. Eighteen female rhesus monkeys were divided into groups of control (n = 3 control), L-treated (n = 5, 9.34 mg lutein/kg and 0.66 mg zeaxanthin/kg), Z-treated (n = 5, 10 mg zeaxanthin/kg), and L/Z-treated (n = 5, lutein and zeaxanthin, each 0.5 mg/kg). After 12 months of daily supplementation, one control animal, two L-treated animals, two Z-treated animals, and all the L/Z-treated animals were killed. The rest of the monkeys were killed after an additional six months without supplementation. Plasma and ocular tissue carotenoid analyses, fundus photography, and retina histopathology were performed on the animals. RESULTS. Supplementation of monkeys with L and/or Z increased the mean plasma and ocular tissue concentrations of these carotenoids and their metabolites. The mean levels of L and Z in the retinas of the L- and Z-treated animals after 1 year increased significantly over baseline. High dose supplementation of monkeys with L or Z did not cause ocular toxicity and had no effect on biomarkers associated with kidney toxicity. CONCLUSIONS. The mean levels of L and Z in plasma and ocular tissues of the rhesus monkeys increase with supplementation and in most cases correlate with the levels of their metabolites. Supplementation of monkeys with L or Z at high doses, or their combination does not cause ocular toxicity.

Eucalyptus leaf-eating marsupials such as the brushtail possum (Trichosurus vulpecula) ingest large amounts of terpenes, especially 1,8-cineole (cineole)--the major component of many eucalyptus oils. Brushtail possums were acclimated to a non-Eucalyptus diet with increasing concentrations of cineole (0.5-4.0% wet weight) added over 18 d. We measured food and cineole consumption and urinary metabolites of cineole. Food intake decreased with cineole content, indicating that it was constrained by the maximum tolerable intake of cineole that was 3.8 +/- 0.2 g kg(-1) or 5.2 +/- 0.3 g kg(-0.75) (mean +/- SE, N = 6). The pattern of metabolites was similar at all cineole intakes (56% hydroxycineolic acids, 27% cineolic acids, 13% hydroxycineoles, and 4% dihydroxycineoles). In another experiment, possums maintained on artificial diet were abruptly presented with 4% cineole for 5 d. Food intake fell by 45 +/- 6% (mean +/- SE, N = 6) and mean cineole intake was 2.9 +/- 0.3 g kg(-1). There was evidence of induction of secondary oxidative pathways, as hydroxycineoles were the major metabolites (48% total) on the first day, but rapidly dropped to 15% on subsequent days as the acid metabolites increased. These findings indicate that ingestion of cineole is not constrained by selective saturation of individual enzymes involved in its multiple pathways of oxidation, but rather the total detoxification capacity appears to limit feeding on a cineole diet.

The aim of this study was to determine the tissue distribution of 17 PCDD/Fs following the chronic ingestion of contaminated milk in rats and to assess the "target tissue/milk" BioConcentration Factors (BCFs) of these molecules. Contaminated milk, collected in a polluted area, has been incorporated into the diet of male rats at a low dose (31 pg I-TEQ/day/rat). For this exposure, the accumulation of PCDD/Fs in target tissues (liver and adipose tissue) was limited, the tissue concentrations stabilising between 90 and 120 days of daily intake to levels close to 3 pg/g of tissue (all tissues and molecules combined). The tissue distribution seemed to be governed by the congeners properties and by the tissue characteristics. An increase in the chlorination degree of dioxins caused a decrease in their incorporation in the adipose tissue, and consequently of the BCF values. Moreover, the distribution of dioxins between hepatocytes and adipocytes differed: unlike the liver, the quantities of dioxins in the adipose tissue were significantly (P

Brain serotonin synthesis depends on the uptake of its precursor, tryptophan (Trp), and is correlated to the plasma ratio of Trp to large neutral amino acids (LNAA) which compete for the same transporter system in the brain. As the plasma Trp/LNAA ratio decreases when the dietary protein content exceeds 5%, we tested whether a diet containing 17% of a Trp-rich protein, namely alpha-lactalbumin (LAC), might increase the plasma Trp/LNAA ratio over a long period. Blood samples were obtained at different days (-1, 3, 6 and 9) from rats receiving either a LAC or casein (CAS) diet, and plasma amino acids and insulin concentrations were determined. The increase in plasma Trp concentration was much higher during the LAC diet (49 vs 26%; P0.001), while the plasma LNAA concentration remained fairly constant. Consequently, the plasma Trp/LNAA ratio increased by 40% during the LAC diet while it decreased by 15% during the CAS diet (P0.001). The above results were not related to plasma insulin concentration differences during these diets. These data suggest that a balanced diet containing a natural Trp rich-protein increases the plasma Trp/LNAA ratio over a long period, leading to a probable increase in brain serotonin activity.

The aim of this study was to assess regional haemodynamic changes in conscious Brattleboro rats during chronic ingestion of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Animals were instrumented with renal, mesenteric and hindquarters pulsed Doppler flow probes and an intra-arterial catheter, and haemodynamic measurements were made before, during and after 14 days' exposure to L-NAME (0.01 mg ml-1 in the drinking water). Within 6 h after addition of L-NAME to the drinking water, mean arterial blood pressure was increased (maximum, 33 +/- 6 mm Hg), and remained so until L-NAME was withdrawn, whereupon blood pressure returned to normal levels within 24 h. The hypertension was accompanied by a transient reduction in mesenteric blood flow, and a more persistent reduction in hindquarters blood flow. Mesenteric and, particularly, hindquarters vascular conductance showed a sustained reduction. However, during ingestion of L-NAME, renal blood flow was not diminished and, over the final 4 days of exposure to L-NAME there was no significant renal vasoconstriction. All regional haemodynamic effects of L-NAME were lost within 24 h of its withdrawal. Hence, as with shorter periods of exposure to the less potent NO synthase inhibitor, NG-monomethyl-L-arginine, the hypertension caused by L-NAME is dependent on its continued administration, and is associated with a particularly marked hindquarters vasoconstriction.

The chronic ingestion of .5% butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) by pregnant mice and their offspring resulted in a variety of behavioral changes. Compared to controls, BHA-treated offspring showed increased exploration, decreased sleeping, decreased self-grooming, slower learning, and a decreased orientation reflex. BHT-treated offspring showed decreased sleeping, increased social and isolation-induced aggression, and a severe deficit in learning.

1 The relationship between the intake of methylmercury in fish and mercury in blood has been investigated in man. 2 The intakes of methylmercury were carefully controlled and lay in the range 40 - 230 μg/day, the Provisional Tolerable Weekly Intake is equivalent to about 30 μg/day. 3 The results indicate that a daily intake of 1 μg methylmercury would, at equilibrium, produce a blood mercury concentration of 0.8 μg/kg. 4 There is a good close-to-linear correlation between methylmercury intake and blood mercury concentrations within the wide range of intakes employed.

Rats were submitted to three different manipulations: chronic ingestion of sodium barbitone, which was added to the drinking water; chronic administration of barbitone and subsequent withdrawal of the drug; and drinking water only. Both groups of experimental animals showed deficient acquisition in both shuttle-box avoidance and passive-avoidance response when compared to the control animals. Nevertheless, no impairment was observed in passive avoidance when the period of withdrawal was 15 days. Neither was impairment observed when the animals were tested in a T-maze or in another appetitive task. These results cannot be explained by differences in weight or fluid consumption.

4-Halopyrazoles acutely administered decreased the alcohol dehydrogenase activity of livers of treated mice but exerted little or no effect on the activity of aldehyde dehydrogenase. Ethanol administered to mice pretreated in this manner with 4-bromopyrazole disappeared slowly from blood as expected and gave no accumulation of acetaldehyde. In contrast, 4-bromopyrazole and 4-iodopyrazole, administered chronically via the drinking fluid, diminished the aldehyde dehydrogenase activity of livers of imbibing mice and elevated somewhat the alcohol dehydrogenase activity. In agreement with the blockade of aldehyde dehydrogenase observed in vivo , ethanol given to mice continually ingesting 4-bromopyrazole or 4-iodopyrazole resulted in the accumulation of acetaldehyde in blood. Moreover, chronic ingestion of 4-bromopyrazole caused a decrease in the natural ethanol preference of C57BL mice, a finding consistent with aldehyde dehydrogenase inhibition and the production of acetaldehyde from the interaction of 4-bromopyrazole and ethanol.

No. 2 fuel oil was fed to mallard (Anas platyrhynchos) ducklings in concentrations of 0.5 and 5.0% of the diet from hatching to 18 wk of age to assess the effects of chronic oil ingestion during early development. Five growth parameters (body weight, wing length, ninth primary length, tarsal length, and bill length) were depressed in birds receiving a diet containing 5% fuel oil. There was no oil-related mortality. The 5% fuel oil diet impaired avoidance behavior of 9-d-old mallard ducklings compared with controls or ducklings fed 0.5% oil. Open-field activity was greatly increased in 16-wk-old ducklings fed 5.0% oil. Liver hypertrophy and splenic atrophy were gross evidences of pathological effects in birds on the 5.0% oil diet. More subtle effects included biochemical lesions that resulted in the elevation of plasma alanine aminotransferase and ornithine carbamoyltransferase activity.

The concentrations of pyridoxal 5′-phosphate in the brains of DBA/2J mice during the withdrawal period following chronic ethanol ingestion were measured fluorimetrically. The brain of the ethanol-withdrawn mouse contains 22.4 ± 3.1% more pyridoxal 5′-phosphate than the brain of a control mouse. The enhanced susceptibility to epileptic seizures during the withdrawal phase may in part be due to the increased cerebral content of this coenzyme.

1. 1. Blood samples were collected from mallard ducks after 6, 12, and 18 weeks of dietary exposure to mash containing 0.015%, 0.150%, and 1.500% crude oil. 2. 2. Plasma corticosterone concentrations in ducks fed mash containing 0.150% or 1.500% Alaskan Prudhoe Bay crude oil were uniformly depressed when compared to values in untreated control birds. 3. 3. Plasma thyroxine concentration was not altered in ducks chronically exposed to crude oil. 4. 4. The observed alteration in corticosterone concentration could reduce tolerance to temperature and dietary fluctuations in the environment.

Four groups of female Sprague-Dawley rats received a nutritionally adequate liquid diet formulated for rats. Two groups, one ethanol diet and one control diet swam 6 days/wk for 6 weeks and were designated swim ethanol (SWM-E) and swim control (SWM-C) respectively. Their swimming time increased from 15 min/day on the first day to 2 hrs/day during the final week. One sedentary group received an ethanol diet (SED-E) while another sedentary group received a control diet (SED-C). In the ethanol diet 35% of the calories as ethanol isoenergetically replaced dextrin. The group mean body weights were not different at the end of 6 weeks. The left ventricles of both swimming groups showed similar gains in weight, 13% for the ethanol and 15% for the control. Mitochondrial respiration in the ethanol groups showed a significant depression across substrates and across both populations of mitochondria (subsarcolemmal and intermyofibrillar). The swimming-ethanol interaction in the SWM-E group caused an atrophy of the gastrocnemius-plantaris muscle as evidenced by the 13% loss in weight of the muscle. We conclude that chronic ingestion of ethanol will suppress mitochondrial respiration in sedentary and swimming exercised rats, but will not suppress cardiac hypertrophy in the swimming exercised rats. Muscles that are not chronically overloaded by swimming, such as the gastrocnemius-plantaris muscles will undergo atrophy during the swimming protocol of 6 weeks.

The effects of a single oral dose or chronic ingestion of ethanol on in vivo and in vitro metabolism of enflurane were studied in Fischer 344 rats. At various intervals after ethanol treatment, enflurane was administered ip and 1 h after enflurane administration fluoride and ethanol levels were measured in plasma and hepatic microsomes were prepared. The concentration of ethanol in plasma (+/- SE) was 0.138 +/- 0.035% at 9 h after the single dose of ethanol and decreased almost to control levels by 17 h. The hepatic microsomal defluorination of enflurane was enhanced 3.5-fold and 6.3-fold at 9 and 25 h after the ethanol dose and returned to the control level by 33 h. In vivo defluorination was inhibited almost completely at 8 h after the ethanol dose, increased to 3.4 times the control level at 24 h, and decreased to the control level by 32 h. At 1 h after the end of chronic ethanol treatment, the concentration of ethanol in plasma was 0.254 +/- 0.018%, and it decreased to the control level by 9 h. Hepatic microsomal enflurane defluorinating activity was increased 10.5-fold at 1 h after the end of chronic treatment and decreased to the control level by 13 h. Immediately following chronic treatment, enflurane defluorination in vivo was almost totally inhibited. It increased to 9.3 times the control level at 4 h after chronic treatment was stopped and then decreased to nearly the control level at 12 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute exposure of an animal to ethanol has a biphasic effect on activity; at low doses incurring stimulation of locomotor activity whilst at higher doses eliciting a depression in activity level. The present study reports the effect of short-term (10 days) exposure to ethanol on running wheel activity in female Wistar rats. Ethanol treatment (3 g/100 ml in drinking water) increased significantly the rate of accumulation of total distance run but not the daily rate of running when compared to control animals. This increase was attributable to an increased rate of running stimulated by daily feeding and handling by the experimenter.

The feasibility of using a measure of palatability in a 2-bottle choice paradigm to determine detriments in fluid intake when unpalatable solutions containing drugs or chemicals were provided as a sole source of fluid was examined. Palatability measures obtained from testing various concentrations of quinine with water in a two-bottle choice paradigm were compared with intake of these same solutions when they were the sole fluid source for 20 consecutive days. Mice were observed to significantly avoid quinine solutions at concentrations as low as 0.0001 mg/ml in a choice situation while fluid intake was reduced in a forced drinking situation only at a concentration of 0.1 mg/ml. Palatability altered forced fluid intake only when quinine solutions comprised 20% or less of total intake in a choice situation. This approach was successfully employed to predict whether various concentrations of halogenated hydrocarbons could be administered in a repetitive forced drinking situation without reducting total fluid intake of mice.

Sprague‐Dawley rats were chronically exposed to particulate Mn 3 O 4 through two generations. At specific ages, observations were made of growth, tissue content, and distribution of Mn and Fe as affected by chronic exposure to Mn through an Fe‐sufficient diet and an Fe‐deficient diet. Chronic dietary Mn 3 O 4 resulted in dose‐related increases in Mn accumulation, and a concomitant Fe deficiency promoted Mn accumulation. In general, the addition of substantial amounts of Mn to either diet depressed tissue Fe levels.

Three experiments investigated the relationship between ethanol consumption and the percentage ethanol-derived kilocalories contained in liquid diets. Rats were chronically maintained on diets where different concentrations of ethanol (10%, 12%, 14%) were added to Metrecal so that 41%, 49% and 57% of all kilocalories consumed were derived from ethanol. The ethanol-Metrecal diet served as the sole source of calories. Results demonstrated that rats can be maintained fromextended time periods on diets where ethanol contributed approximately 50% of the daily kilocalories. Inspection of consummatory profiles revealed that an initial decrease occurred in volume of diet consumed when levels of ethanol were increased. This was followed by a gradual increase in the level of consumption until a new asymptotic level was established. Grams of ethanol/kg of body weight remained relatively constant over the range of ethanol concentrations employed. The results were discussed in respect to three factors controlling consummatory behavior-sensory stimuli, caloric intake and quantity of ethanol ingested.

Male rats arbitrarily selected for high and low motor activity (HA and LA-rats) were submitted to the chronic ingestion (30 days) of desipramine (DSP) in doses of about 1.5, 3 and 6 mg/kg/24 hr. Their motor activity was assessed in an animal activity monitor providing a measure of total horizontal movements and vertical movements and in a hole-board providing a measure of locomotion, head-dipping and grooming. There were significant differences between HA and LA-rats in their behavioral response to DSP treatment. At the doses used DSP did not affect horizontal and vertical movements and hole-board locomotion or exploration in HA-rats (Experiment 1). In LA-rats, however (Experiment 2), these motor activities were significantly stimulated by DSP. Such effect was dose dependent; 1.5 mg/kg/24 hr was ineffective while 6 mg/kg/24 hr produced a clear cut reversion of hypoactivity. It is speculated that DSP treatment increased resistance of LA-rats to the mild stress caused by testing.

The effects of the heat stable toxin produced by Bacillus thuringiensis var. thuringiensis Berliner (serotype 1) were studied upon Drosophila adult longevity. Chronic intoxication was obtained by incorporating the toxin to two nutritive media: a normal, complete medium and a deficient glucidique one. The toxin in the food results in a reduction of longevity, approximately proportional to the log of the concentration. The biological activity of the product may be measured either by the concentration which reduces mean life expectation to half its normal value, or by the percentages of mortality at various ages. Significant differences were observed between repetitions of the same experiment. This uncontrolled variability interferes with differences between males and females or with the shape of mortality frequency distributions. The biological effects of the toxin vary according to the nature of the food medium. But they do not seem to be influenced by the uncontrolled variability between experiments. From the study of whole data, it is supposed that the physiological alterations produced by the toxin are largely independent from those due to senescence.

Dextro-amphetamine at doses of 1 mg/kg/day was administered intragastrically to rats for one month. At 18 h after the final dose, a small (16%) increase of brain serotonin concentration was found as well as an increase (30%) of the synthesis and degradation of [3H] serotonin formed from intracisternally injected exogenous [3H]-l-tryptophan.

Experiments with rats have demonstrated the capacity of cysteine to reduce the modifications in brain cholinesterase levels caused by the chronic ingestion of alcohol. The suggestion is made that sulfhydryl may well possess the capacity to prevent the development of physical dependence on alcohol.

(1960). Chronic Ingestion by Dogs of Methyl Bromide-Fumigated Food. Archives of Environmental Health: An International Journal: Vol. 1, No. 4, pp. 316-323.

Oral administration of taurine (0.9%) in the drinking water resulted in impairment of acquisition and, to a lesser extent, retention of a step-down passive avoidance task in rats. No effect was found on spontaneous locomotor activity or habituation measured in photocell activity cages. There were also no differences observed in either the taurine-treated or control rats in their sensitivity to electric shock. These observations suggest that the administration of oral taurine may have adverse effects on inhibitory or memory functions.

Seizure-prone patients may be chronically treated with diphenylhydantoin, a mitogenic agent excreted in the urine. Chronic ingestion of diphenylhydantoin by 64 rats failed to demonstrate vesical epithelial tumor formation under conditions which demonstrate the tumorigenicity of other vesical carcinogens. Vesical neoplasms occurring in patients chronically ingesting diphenylhydantoin are probably co-incidental.

Chronic (72 days) administration of deoxycorticosterone acetate (DOCA), with or without saline as the sole drinking fluid, depleted atria of rats of their diuretic and natriuretic activities. Chronic ingestion of saline as the sole drinking fluid did not affect the diuretic, natriuretic, and kaliuretic activities of atria compared with those of rats receiving water to drink. Since systolic blood pressure of the DOCA-treated group did not differ significantly from that of the untreated control group, the decrease in potency of atrial extract from DOCA-treated rats most likely occurred in response to increases in extracellular and vascular volumes. The ability of DOCA to decrease diuretic and natriuretic activities of atria was dose dependent. The decreased activities of the atria of DOCA-treated rats could reflect an increased production and turnover of atrial natriuretic factor. Additional studies revealed an increased diuretic and natriuretic responsiveness of DOCA-treated recipients to atrial extract from untreated rats. Thus, the results of these studies suggest that chronic treatment with DOCA reduced the natriuretic and diuretic potencies of atrial extract and increased renal responsiveness to it.

Chronic ingestion of ethanol resulted in ultrastructural and mechanical changes in rat femurs. Scanning electron microscopy of the distal end of the femur revealed that the trabeculae of bones from ethanol-fed rats were thinner, more columnar, and more extensive than those from control rats. Three-point bending tests of the rat femurs showed that the maximum force or so-called “strength” required to break the bone was less in ethanol- than in control-fed animals. A significant inverse correlation was observed between the strength required to break the femur and the dose of ethanol calculated on a body weight basis. For the first time our study presents quantitative proof that a relationship exists between bone strength and the consumption of ethanol in rats. The study revealed that ethanol consumption resulted in a weaker femur compared to controls. We suggest that a common mechanism may be responsible for the decreased bone strength of ethanol-fed rats and the increased incidence of fractures in human alcoholics.