RESUMEN

Ochratoxin A (OTA) is a mycotoxin produced by species of Penicillium and Aspergillus, and is found in many commodities including cereal grains, nuts, and coffee. OTA is a renal carcinogen and nephrotoxin at high concentrations, targeting the proximal tubules. This study uses transcriptomics and the previously reported apical data (Bondy et al., 2021) to infer mode-of-action of OTA toxicity in male and female rats exposed to low doses of OTA in utero and throughout development. Our findings support a male-specific activation of the innate and adaptive immune responses in F1 pups to OTA exposure. This was not found in the female F1 pups, and may be due to female-specific increased p38 activity and VDR signaling. Differentially expressed genes related to karyomegaly, MAPK activity, and immune activation appears to develop from in utero exposure to OTA whereas those related to decreased kidney and liver function, and changes to reproductive pathways occur in both rat generations. Together, these transcriptional results confirm that dietary exposure to OTA causes renal toxicity as well as alterations to hepatic and reproductive pathways in rats. In utero exposure of rats to OTA results in sex-specific alterations in immune response pathways, VDR signaling, and p38 activity.

Asunto(s)

Exposición Dietética , Ocratoxinas , Animales , Femenino , Genómica , Riñón/metabolismo , Masculino , Ocratoxinas/metabolismo , Ocratoxinas/toxicidad , Ratas , Ratas Endogámicas F344

RESUMEN

Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium molds. Grain-based foods account for most human dietary exposures to OTA. OTA is a teratogen, but its reproductive and developmental effects are poorly understood. A one-generation reproductive toxicity study was conducted with groups of 16 male and 16 female Fischer rats exposed to 0, 0.026, 0.064, 0.16, 0.4 or 1.0 mg OTA/kg in diet. Dams exposed to 1.0 mg OTA/kg diet had statistically significant F1 pup losses between implantation and postnatal day (PND 4). Delays in preputial separation (PPS) and vaginal opening (VO) were indicative of delayed puberty in F1 rats. Mild renal lesions in nursing pups indicated that exposure prior to weaning impacted the kidneys. The developing kidney was more susceptible to OTA than the adult kidney. Significant increases in multi-oocyte follicles (MOFs) and proportional changes in resting and growing follicles were observed in F1 female ovaries. Plasma testosterone was reduced in F0 males, and there were negative effects on sperm quality in F0 and F1 male rats. The results confirm that continuous dietary exposure to OTA causes post-implantation fetotoxicity in dams, and renal and reproductive toxicity in their male and female offspring.

Asunto(s)

Blastocisto/efectos de los fármacos , Infertilidad Femenina/inducido químicamente , Infertilidad Masculina/inducido químicamente , Enfermedades Renales/inducido químicamente , Ocratoxinas/toxicidad , Motilidad Espermática/efectos de los fármacos , Animales , Animales Lactantes , Bloqueadores de los Canales de Calcio/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ocratoxinas/administración & dosificación , Folículo Ovárico/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Endogámicas F344

RESUMEN

Hexabromocyclododecane (HBCD) is a brominated flame retardant which was recommended by a UN expert body under the Stockholm Convention to be eliminated from the global marketplace in 2011; however, due to its ability to persist in the environment, undergo long-range transport and bioaccumulate, it remains a concern for human health. The commercial mix of HBCD (T-HBCD) consists of α-HBCD, ß-HBCD and γ-HBCD. Although the γ-HBCD (79%) isomer is the predominant isomer of T-HBCD, the most bioaccumulative isomer detected in mammals is the α-HBCD isomer. This study was undertaken to investigate three rat strains treated with commercial grade (technical) HBCD or HBCD enriched with the α isomer (A-HBCD) and to examine strain- and sex-related differences in response to exposure. Female Sprague Dawley (SD), Wistar (WI) and Fischer F344 (FI) rats were exposed for 28 days to either T-HBCD or A-HBCD in feed, at doses of 0, 250, 1250 and 5000 mg/kg diet. The FI rodent strain was found to be the most sensitive to effects of HBCD based on the greatest number of significantly affected endpoints which indicated that T-HBCD primarily affected liver and thyroid, resulting in multiple health effects. Consequently, male FI were included in the study and exposed to T- and A-HBCD. Histopathological data supports previously reported effects of HBCD on the thyroid and endocrine system although the effects in FI rats are significantly elevated compared to other strains. As with T-HBCD, liver and thyroid were found to be target organs of A-HBCD. Sex differences, specifically in tissue concentration levels, immune response parameters and in number and severity of thyroid and liver lesions, following exposure to either T- or A-HBCD were apparent, with treatment eliciting a greater response in males. Residue analysis revealed that α-HBCD is more bioaccumulative than γ-HBCD in all rodent strains, with levels of HBCD in animals treated with A-HBCD several fold higher for all tissues tested (7-11 fold at the highest dose). Thus, residue data supports the selective uptake (implies there are differences in bioavailability and/or bioaccumulation; is this the case or do certain isomers simply have a longer half-life) of specific isomers, with α-HBCD > γ-HBCD. Taken together, our study highlights the importance of selecting the most appropriate strain and of including both sexes in studies to ensure that sex-related differences in response to test chemical is taken into consideration. Moreover, ours is the first study to show the effects of a sub-acute exposure to a diet containing only HBCD enriched for the α isomer, which better represents the isomer ratios present in the biota due to bioaccumulation.

Asunto(s)

Hidrocarburos Bromados/toxicidad , Pruebas de Toxicidad , Administración Oral , Animales , Contaminantes Ambientales/toxicidad , Femenino , Retardadores de Llama/toxicidad , Masculino , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Ratas Wistar

RESUMEN

A 90-day gavage study was conducted with 0.0, 0.02, 0.075, 0.25, 1.0 and 4.0 mg/kg bw/day dose groups of 3-methylfuran to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects including changes in gross anatomy, histopathology, clinical biochemistry and hematology. There were significant changes in the serum clinical biochemistry markers related to liver injury where males were more affected than the females for most parameters analysed. The serum liver injury marker γ-glutamyltransferase, alanine and aspartate aminotransferases were significantly increased in males in the 4.0 mg/kg dose group. Alkaline phosphatase was increased in females and males. There were increases in both gross and histological lesions in the liver of both sexes in addition to statistical differences in female liver weights at the 4.0 mg/kg bw/day dose. Significant increases in spleen weights were found in both genders. This was accompanied by a dose-dependent atrophy of both B- and T-cell regions in which the males were more affected. There were no significant changes in male kidney weights but there was microscopically decreased protein in the proximal tubules and crowding of their nuclei in the 4.0 mg/kg bw/day dose group. There were also significant changes in the kidney serum biomarkers including various electrolytes, blood urea nitrogen, creatinine and uric acid. A small, but significant increase in female kidney weights was observed and which increase was accompanied by changes in electrolytes, kidney specific markers and a dose-dependent increase in mineralization. In both genders, amylase decreased whereas lipase increased but these were not accompanied by any histological changes in the pancreas. Histopathological changes in the liver were observed consistently in male and female rats in the 0.25 mg/kg dose group and higher. Hence, a lowest observed adverse effect level (LOAEL) of 0.25 mg/kg bw/d and a no observed adverse effect level (NOAEL) of 0.075 mg/kg bw/day are proposed for 3-methylfuran-induced hepatic lesions in this study. Benchmark dose modelling based on a BMR of 10% change in lesion incidence, generated BMDLs10 of 0.08 mg/kg bw/day in male rats and 0.05-0.17 mg/kg bw/day in female rats for increased incidence of liver lesions.

Asunto(s)

Contaminantes Atmosféricos/toxicidad , Furanos/toxicidad , Pruebas de Toxicidad Subcrónica/métodos , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Furanos/administración & dosificación , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Bazo/efectos de los fármacos , Bazo/patología

RESUMEN

Deoxynivalenol (DON) is a secondary metabolite associated with Fusarium species pathogenic to important food crops. A two-year feeding study reported that DON was non-carcinogenic in B6C3F1 mice. The present study was conducted to further characterize the chronic effects of DON by exposing cancer-prone transgenic p53 heterozygous (p53+/-) male mice and p53 homozygous (p53+/+) male mice to 0, 1, 5, or 10 mg DON/kg in diet for 26 weeks. Gross and microscopic organ-specific neoplastic and non-neoplastic changes and expression profiles of key hepatic and renal genes were assessed. Few toxicologic differences between p53+/+ and p53+/- mice were observed, and no tumours were observed due to DON. The results indicated that DON was non-carcinogenic and that reduced expression of the p53 gene did not play a key role in responses to DON toxicity. The lack of inflammatory and proliferative lesions in mice may be attributed to the anorectic effects of DON, which resulted in dose-dependent reductions in body weight in p53+/+ and p53+/- mice. Hepatic and renal gene expression analyses confirmed that chronic exposure to DON was noninflammatory. The effects of 26-week DON exposure on p53+/+ and p53+/-mice were consistent with those previously seen in B6C3F1 mice exposed to DON for two years.

Asunto(s)

Peso Corporal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Inflamación/patología , Tricotecenos/toxicidad , Proteína p53 Supresora de Tumor/fisiología , Animales , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Heterocigoto , Homocigoto , Inmunoglobulinas/genética , Inmunoglobulinas/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Riñón/metabolismo , Riñón/patología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Noqueados , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

Brominated diphenyl ethers (BDEs) are used as flame retardants in consumer products. Rodent studies indicate that the liver, thyroid, and nervous system of developing animals are targets of BDEs. To explore the relationship between exposure and health in developing animals, BDE accumulation in adult and juvenile rats was examined in conjunction with changes in liver weight and serum thyroxine (T4). Adult (F0) rats received the commercial BDE mixture DE-71 by gavage at doses of 0.5, 5, and 25 mg kg(-1) body weight (bw)/day for 21 weeks. F0 rats were mated and exposure continued throughout breeding, pregnancy, lactation, and postweaning until the pups (F1 generation) reached postnatal day (PND) 42. Milk was collected from lactating dams. Adipose and liver samples were collected from F0 and F1 males and females for BDE congener analysis. Congener prevalence in rat tissues mimicked congener prevalence in wildlife and humans. Tissue concentrations of all congeners except BDE-153 were lower than would be expected based on dose proportionality, confirming that BDE-153 has a high capacity for bioaccumulation. BDEs were transferred from maternal tissues to milk during lactation. Milk congener profiles differed from maternal tissue profiles indicating that degree of bromination and maternal sequestration influenced BDE transfer to milk. Female F1 rats accumulated more BDEs than F1 males, indicating that female rats were less able to metabolize and/or excrete BDEs. Significant effects on liver weight and serum T4 levels were observed in adults and juveniles in the middle and high dose groups, corresponding to BDE levels in the µg g(-1) range. Although it remains to be determined how human liver and thyroid are affected by exposure to much lower BDE levels, the present study confirmed that gender and reproductive status influence BDE accumulation in tissues and BDE transfer to the neonate via milk.

Asunto(s)

Tejido Adiposo/metabolismo , Éteres Difenilos Halogenados/metabolismo , Hígado/metabolismo , Leche/metabolismo , Animales , Femenino , Retardadores de Llama/metabolismo , Éteres Difenilos Halogenados/toxicidad , Masculino , Bifenilos Polibrominados/metabolismo , Embarazo , Complicaciones del Embarazo , Ratas , Ratas Sprague-Dawley , Glándula Tiroides/metabolismo

RESUMEN

Rodent studies have shown that furan is a hepatocarcinogen. Previous studies conducted with high doses showed tumors at nearly 100% incidence at all doses. In this paper, a ninety-day gavage experiment conducted with lower doses (0.0, 0.03, 0.12, 0.5, 2.0, and 8.0 mg/kg bw) to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects including gross changes and histopathology, clinical biochemistry, hematology, and immunotoxicology is reported. As indicated by changes in serum biomarkers, increased liver weights and gross and histological lesions, the liver is the major target organ affected by furan. There were no changes in body weights, food consumption, or histology in other organs. Some of the serum electrolyte markers, including phosphorus, were altered. There was a significant increase in serum thyroxine and triidothyronine in males. This increase was not accompanied by histological thyroid changes. Immunophenotypic analysis showed that thymic lymphocyte maturation was altered in male rats. Although altered clinical biochemistry and hematological parameters were observed at a dose of > 0.5 mg/kg bw, mild histological lesions in the liver were observed at > 0.12 mg/kg bw. Based on this finding, a furan dose of 0.03 mg/kg bw was proposed as the no-observed adverse effect level for hepatic toxicity.

Asunto(s)

Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Furanos/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Análisis de Varianza , Animales , Biomarcadores/sangre , Plaquetas/metabolismo , Peso Corporal/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Dieta , Femenino , Furanos/administración & dosificación , Histocitoquímica , Incidencia , Hígado/patología , Pruebas de Función Hepática , Masculino , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Linfocitos T/metabolismo

RESUMEN

BACKGROUND: Highly active antiretroviral therapy (HAART) with protease inhibitors (PI) is successful in suppressing viral replication, but may lead to a range of metabolic abnormalities associated with cardiovascular disease (CVD). OBJECTIVES: The first objective of the study was to compare baseline demographic and clinical characteristics between PI users and non-PI users referred to a specialized metabolic clinic during 1999-2003. The second objective was to assess the associations of prescription drugs and fish oil with dyslipidaemia and to determine whether or not patients achieved treatment targets during 6 months of treatment. METHODS: A retrospective analysis was performed using two sets of charts based on standardized forms with entries for personal data, drug treatment and clinical history. Anonymous linkage with the British Columbia HIV/AIDS Drug Treatment Program and the hospital laboratory was performed to gather information about HAART prescriptions and blood work. RESULTS: In total, 237 patients were included in the study. There were few differences in any demographic or clinical factors between PI users and non-PI users. Compared with controls not taking lipid-lowering drugs or fish oil (n=48), statins appeared to be the only agent that was significantly associated with a reduced total cholesterol concentration (-15.6%; P=0.009). Fibrate treatment was associated with the largest reduction of triglyceride concentration (-37.4%; P=0.012), closely followed by fish oil (n=18;-32%; P=0.027). Six-month treatment success rates ranged between 17 and 43% of patients for total cholesterol (<5.2 mmol/L) and between 15 and 44% of patients for triglycerides (<2.3 mmol/L). CONCLUSIONS: Despite the apparent lowering of blood lipids with drug and fish oil treatments, a majority of patients in these treatment groups (56.5-83.3%) still had elevated concentrations after 6 months.

Asunto(s)

Terapia Antirretroviral Altamente Activa/efectos adversos , Enfermedades Cardiovasculares/metabolismo , Dislipidemias/complicaciones , Aceites de Pescado/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Proteasas/efectos adversos , Adulto , Enfermedades Cardiovasculares/inducido químicamente , Femenino , Infecciones por VIH/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Carga Viral

RESUMEN

The objectives of this paper are to: assess the impact of exposure to current levels of environmental contaminants in the Canadian Arctic on human health; identify the data and knowledge gaps that need to be filled by future human health research and monitoring; examine how these issues have changed since our first assessment [Van Oostdam, J., Gilman, A., Dewailly, E., Usher, P., Wheatley, B., Kuhnlein, H. et al., 1999. Human health implications of environmental contaminants in Arctic Canada: a review. Sci Total Environ 230, 1-82]. The primary exposure pathway for contaminants for various organochlorines (OCs) and toxic metals is through the traditional northern diet. Exposures tend to be higher in the eastern than the western Canadian Arctic. In recent dietary surveys among five Inuit regions, mean intakes by 20- to 40-year-old adults in Baffin, Kivalliq and Inuvialuit communities exceeded the provisional tolerable daily intakes (pTDIs) for the OCs, chlordane and toxaphene. The most recent findings in NWT and Nunavut indicate that almost half of the blood samples from Inuit mothers exceeded the level of concern value of 5 microg/L for PCBs, but none exceeded the action level of 100 microg/L. For Dene/Métis and Caucasians of the Northwest Territories exposure to OCs are mostly below this level of concern. Based on the exceedances of the pTDI and of various blood guidelines, mercury and to a lesser extent lead (from the use of lead shot in hunting game) are also concerns among Arctic peoples. The developing foetus is likely to be more sensitive to the effects of OCs and metals than adults, and is the age groups of greatest risk in the Arctic. Studies of infant development in Nunavik have linked deficits in immune function, an increase in childhood respiratory infections and birth weight to prenatal exposure to OCs. Balancing the risks and benefits of a diet of country foods is very difficult. The nutritional benefits of country food and its contribution to the total diet are substantial. Country food contributes significantly more protein, iron and zinc to the diets of consumers than southern/market foods. The increase in obesity, diabetes and cardiovascular disease has been linked to a shift away from a country food diet and a less active lifestyle. These foods are an integral component of good health among Aboriginal peoples. The social, cultural, spiritual, nutritional and economic benefits of these foods must be considered in concert with the risks of exposure to environmental contaminants through their exposure. Consequently, the contamination of country food raises problems which go far beyond the usual confines of public health and cannot be resolved simply by risk-based health advisories or food substitutions alone. All decisions should involve the community and consider many aspects of socio-cultural stability to arrive at a decision that will be the most protective and least detrimental to the communities.

Asunto(s)

Indio Americano o Nativo de Alaska , Exposición a Riesgos Ambientales , Contaminantes Ambientales/toxicidad , Contaminación de Alimentos , Animales , Regiones Árticas , Biomarcadores , Canadá , Monitoreo del Ambiente , Contaminantes Ambientales/análisis , Cadena Alimentaria , Humanos , Metales Pesados/análisis , Compuestos Orgánicos/análisis , Radioisótopos/análisis , Medición de Riesgo , Selenio/análisis

RESUMEN

Tributyltin (TBT) is a biocide that contaminates foods, especially shellfish. TBT is an endocrine disrupter in several marine species and is neurotoxic and immunotoxic in mammals. We have examined the effects of exposure to low doses of tributyltin chloride (TBTC) from day 8 of gestation until adulthood. Pregnant rats were gavaged daily with 0, 0.025, 0.25 or 2.5 mg TBTC/kg body weight from day 8 of gestation until weaning. Stomach contents of suckling pups contained undetectable levels of TBT and dibutyltin (DBT) levels were detectable only in the highest TBTC dose used, indicating negligible lactational transfer to pups. Post weaning, pups were gavaged daily with the same dose of TBTC administered to their mothers and sacrificed on post-natal days (PND) 30 (males and females), 60 (females) and 90 (males). TBTC had no effects on dams' body weights, food consumption, litter size, sex ratio or survival of pups to weaning. However, all doses of TBTC significantly affected parameters of the growth profile of the pups (mean body weights, average slope, curvature) and the ratio of weekly food consumption to weekly body weight gain indicated enhanced food conversion to body mass in females but a decreased conversion in males. Liver, spleen and thymus weights were also affected by TBTC. In male pups dosed at 2.5 mg/kg/day, reduced serum thyroxine levels were evident, indicating that the thyroid is a target for TBTC toxicity. No histopathological lesions were seen in the liver but elevated serum alanine aminotransferase, gamma-glutamyl transferase and amylase indicated hepatotoxicity. Significant decreases in liver weights in female pups exposed to 0.025 mg/kg/day TBTC were observed at PND 60. Decreases in spleen and thymus weights also pointed towards toxic effects of TBTC on the immune system. The 0.025 mg/kg/day TBTC should have been a no affect dose and yet this dose caused significant effects on growth profiles, decreased liver weights and elevated serum GGT levels in females.

Asunto(s)

Reproducción/efectos de los fármacos , Compuestos de Trialquiltina/toxicidad , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Contaminación de Alimentos , Intubación Gastrointestinal , Tamaño de la Camada/efectos de los fármacos , Masculino , Embarazo , Ratas , Ratas Sprague-Dawley , Compuestos de Trialquiltina/administración & dosificación

RESUMEN

The immunotoxic effects of tributyltin chloride (TBTC) were examined in the offspring of Sprague-Dawley rats exposed in utero from day 8 of gestation, through lactation and post-weaning until pups reached the age of 30 days (male and female), 60 days (female) and 90 days (male). Daily oral (gavage) doses of 0.025, 0.25 and 2.5 mg/kg body weight/day were administered in olive oil 7 days/week. Immunologic endpoints were investigated at the termination of each study. Statistically significant results (P<0.05) included the following: At 30 days, the mean percent and absolute natural killer (NK) cell numbers were increased in male and female rats treated with the high TBTC dose. At 60 days, female rats had increased mean serum IgM levels at the low and high TBTC doses, increased mean percentage CD4(+)8(+) (immature) T lymphocytes at the middle and high doses, a non-linear dose-response increase in NK cell activity at the 50:1 and 100:1 effector:target cell ratios (pairwise comparisons significant at the low dose compared with control), and increased mean numbers of L. monocytogenes colony-forming bacteria on Day 2 post-infection (significant for trend) and Day 3 post infection (pairwise comparisons significant only in the middle dose). The 90-day male rats had decreased mean serum IgA levels at the middle dose group; increased IgM levels at the high dose group, increased IgG levels at the middle and high doses; decreased IgG2(a) in the high dose compared to the control; a dose-related increase in the mean percentage NK cell numbers (pairwise comparisons significant at the high dose compared with the control) and increased mean NK cell activity (pairwise comparisons significant at all dose groups compared with the control). The delayed-type hypersensitivity response to oxazolone was increased in the low and middle doses and decreased in the high dose. Thymus atrophy was observed in the high TBTC dose across all ages. Thus, in utero and post-natal treatment of F1 rats with low levels of TBTC affected some aspects of humoral and cell mediated immunity as well as the number and function of cells which are involved in the host's immunosurveillance mechanisms against tumours and viral infections.

Asunto(s)

Activación de Linfocitos/efectos de los fármacos , Compuestos de Trialquiltina/toxicidad , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Contaminación de Alimentos , Inmunoglobulina M/sangre , Intubación Gastrointestinal , Listeria monocytogenes/inmunología , Masculino , Embarazo , Ratas , Ratas Sprague-Dawley , Organismos Libres de Patógenos Específicos , Bazo/citología , Bazo/efectos de los fármacos , Timo/efectos de los fármacos , Compuestos de Trialquiltina/administración & dosificación

RESUMEN

To provide an overview of the epidemiologic parameters of emerging adverse effects associated with antiretroviral therapy for human immunodeficiency virus (HIV) disease. All available antiretroviral agents are associated with significant adverse drug effects. Of particular interest are newly emerging suspected adverse drug effects which were not generally noted in pre-marketing trials nor captured under current standard clinical care practices. Suspected antiretroviral toxicities meeting these criteria include: HIV-associated lipodystrophy which can include peripheral lipoatrophy, lipohypertrophy and metabolic abnormalities; hyperlactatemia and lactic acidosis; and metabolic bone abnormalities such as decreased bone mineral density, osteoporosis and osteonecrosis. Results of prospective and observational studies reported to date suggest that these abnormalities, while aetiologically complex, are likely attributable to treatment factors and may be intricately interrelated. The medical management of these symptoms remains unsatisfactory given the unexplored efficacy of traditional approaches in the HIV positive population. While the pathogenic mechanism of these disorders remains obscure, a theory of tissue-specific mitochondrial toxicity has been proposed. With the continued introduction of novel therapies and standard treatment with combination therapy, new adverse events will continue to emerge among persons being treated for HIV disease. Beyond their immediate clinical implications, these events may contribute to changing patterns of antiretroviral utilisation including therapy initiation, adherence and cessation.

Asunto(s)

Terapia Antirretroviral Altamente Activa/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Acidosis Láctica/inducido químicamente , Enfermedades Óseas Metabólicas/inducido químicamente , ADN Mitocondrial/metabolismo , Infecciones por VIH/metabolismo , Humanos , Ácido Láctico/sangre , Lipodistrofia/inducido químicamente , Enfermedades Metabólicas/inducido químicamente

RESUMEN

The immunotoxicity of cis- and trans-nonachlor and chlordane were investigated in adult male and female Sprague-Dawley rats following a 28-day oral (gavage) treatment. Rats were randomly assigned to six experimental groups: cis-nonachlor, females; trans-nonachlor, females; technical chlordane females; cis-nonachlor, males; trans-nonachlor, males; technical chlordane, males. The immunologic endpoints included: quantification of the total serum immunoglobulin (Ig) levels and subclasses and flow cytometric analysis of peripheral blood leukocytes and T-lymphocyte subsets, evaluation of the lymphoproliferative activity of splenocytes in response to concanavalin A (Con A) and Salmonella typhimurium (STM) mitogens, and natural killer (NK) cell activity of splenocytes. Satellite experiments to examine the delayed-type hypersensitivity (DTH) response to oxazolone, and resistance to Listeria monocytogenes were set up for female rats treated with cis- or trans-nonachlor. Statistically significant (P<0.05) effects included: increased serum immunoglobulin M (IgM) levels in the chlordane-treated females at the 25 mg/kg dose (pairwise comparison); increased serum IgG(1) and IgG(2c) in the cis-nonachlor-treated males at the 2.5 and 25 mg/kg doses and increased serum IgG(2a) levels at all doses; increased serum IgG(2b) at the 25 mg/kg dose and decreased (dose-related) serum IgM levels in the cis-nonachlor-treated male rats; increased (linear trend) IgG(1) and IgG(2a) in the cis-nonachlor-treated females with effects on IgG(2a) significant at the 25 mg/kg dose compared with control; increased serum IgG(2a) in the trans-nonachlor-treated male and female rats at the 2.5 mg/kg dose; increased absolute numbers (linear trend) of peripheral white blood cells, B lymphocytes, natural killer (NK) cells, T-suppressor/cytotoxic lymphocytes, and the double positive (T-helper/inducer, T-suppressor/cytotoxic) cells in the trans-nonachlor-treated females; increased (non-linear trend) lymphoproliferative activity in the Con A-stimulated splenocytes and decreased (linear trend) activity in the S. typhimurium mitogen-stimulated splenocytes of the cis-nonachlor-treated females; reduced resistance to L. monocytogenes in the cis-nonachlor (day 3, P=0.034)- and trans-nonachlor (day 2, P=0.0001)-treated females, and reduced (linear trend) NK cell activity in the cis-nonachlor-treated males. The present data indicated that the chlordane compounds tested in this study had significant effects on a number of immunologic endpoints. In comparison to technical chlordane, cis- and trans-nonachlors were more immunotoxic. Therefore, an evaluation of the risk these chlorinated compounds may pose to human health should consider the potential effects different chlordane compounds may have on the immune system.

Asunto(s)

Células Productoras de Anticuerpos/efectos de los fármacos , Clordano/toxicidad , Hidrocarburos Clorados/toxicidad , Insecticidas/toxicidad , Activación de Linfocitos/efectos de los fármacos , Administración Oral , Animales , Células Productoras de Anticuerpos/inmunología , Proteínas Bacterianas , Clordano/administración & dosificación , Relación Dosis-Respuesta Inmunológica , Femenino , Citometría de Flujo , Hidrocarburos Clorados/administración & dosificación , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Insecticidas/administración & dosificación , Listeria monocytogenes/inmunología , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Organismos Libres de Patógenos Específicos , Estereoisomerismo

RESUMEN

BACKGROUND: After ischemia, glycolysis and dysfunction are greater, while coupling of glucose oxidation to glycolysis is lower in hypertrophied hearts than in nonhypertrophied hearts. OBJECTIVE: To test the hypothesis that accelerated glycolysis, reduced coupling of glucose oxidation to glycolysis and increased postischemic dysfunction in hypertrophied hearts compared with nonhypertrophied hearts occur in the absence of differences in coronary flow. MATERIALS AND METHODS: Function, glycolysis and glucose oxidation were measured in isolated working control and hypertrophied rat hearts studied for 30 min before, and for 40 min after no flow global ischemia for 20 min under conditions in which coronary flow was comparable between the two groups. The hearts were perfused with 1.2 mmol/L palmitate, 5.5 mmol/L [5-3H/U-14C]-glucose, 0.5 mmol/L lactate, 100 mU/L insulin at a preload of 11.5 mmHg, and an afterload of 60 mmHg in control hearts or 80 mmHg in hypertrophied hearts. RESULTS: Despite comparable rates of coronary flow, functional recovery was lower in hypertrophied hearts than in control hearts. The rates of glycolysis were accelerated in hypertrophied hearts, while glucose oxidation did not significantly differ between the two groups. As a result, the coupling of glucose oxidation to glycolysis was lower in hypertrophied hearts than in control hearts. CONCLUSIONS: Increased postischemic dysfunction, accelerated glycolysis and reduced coupling of glucose oxidation to glycolysis in hypertrophied hearts compared with control hearts cannot be accounted for by differences in coronary flow. These data provide support for the concept that alterations in glucose metabolism contribute to the exaggerated postischemic dysfunction of hypertrophied hearts.

Asunto(s)

Circulación Coronaria/fisiología , Glucosa/metabolismo , Glucólisis/fisiología , Hipertrofia Ventricular Izquierda/fisiopatología , Isquemia Miocárdica/fisiopatología , Daño por Reperfusión/patología , Animales , Modelos Animales de Enfermedad , Hipertrofia Ventricular Izquierda/terapia , Masculino , Probabilidad , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Valores de Referencia

RESUMEN

Tissues were obtained from three separate experiments in order to quantify the tissue distribution of organochlorine chemicals that are thought to be potential reproductive toxicants in males: 1) Sprague Dawley rats received 1 microCi of 14C-Aldrin or 14C-Dieldrin (20.6 microCi/micromole) i.p. once a week for three weeks. One week and four weeks after the last injection, tissues were harvested and stored at -80 degrees C. Tissue 14C levels were quantified by scintillation spectrometry. 2) Cis- or trans-nonachlor (0, 0.25, 2.5, 25 mg/kg body weight) were administered daily in corn oil to male rats by gavage for 28 days. Tissues were harvested and frozen at -80 degrees C on the 29th day. Organochlorine residues were extracted and quantified by gas chromatography with electron capture detection. 3) Technical grade toxaphene (0, 0.1, 0.4 or 0.8 mg/kg body weight) was ingested daily by female cynomolgus monkeys of reproductive age for 18 months prior to being mated with control males. Dosing continued during pregnancy and lactation. Their infants received toxaphene via breast milk, and upon weaning, they ingested the same dose as their mothers for 48 to 49 weeks until, at 77 to 80 weeks of age, tissues were harvested and stored at -80 degrees C. Organochlorine residues were extracted and quantified as previously stated. In all three experiments, organochlorine residues in the testis were lower than in most of the other reproductive tract and nonreproductive tract tissues we examined. For example, testicular aldrin and dieldrin levels were <5% the epididymal content; testicular cis- and trans-nonachlor were <25% the epididymal content and, testicular toxaphene levels were <15% of the epididymal content. The reasons for the low degree of accumulation by the testis in comparison with other tissues are unknown. However, the lower testicular content may afford germ cells some protection from the potentially toxic effects of these chemicals.

Asunto(s)

Insecticidas/farmacocinética , Testículo/metabolismo , Administración Oral , Aldrín/administración & dosificación , Aldrín/farmacocinética , Animales , Animales Recién Nacidos , Dieldrín/administración & dosificación , Dieldrín/farmacocinética , Relación Dosis-Respuesta a Droga , Epidídimo/efectos de los fármacos , Epidídimo/metabolismo , Femenino , Hidrocarburos Clorados/farmacocinética , Inyecciones Intraperitoneales , Insecticidas/administración & dosificación , Lactancia/efectos de los fármacos , Macaca fascicularis , Masculino , Exposición Materna , Embarazo , Ratas , Ratas Sprague-Dawley , Reproducción/efectos de los fármacos , Testículo/efectos de los fármacos , Distribución Tisular , Toxafeno/farmacocinética

RESUMEN

cis-Nonachlor and trans-nonachlor are bioaccumulating components of the pesticide chlordane, which can be detected in various environmental biota and in humans. Existing studies have focused on the potential adverse health effects of the parent chlordane mixture. Comparable toxicity data are nonexistent for individual chlordane constituents such as trans-nonachlor, cis-nonachlor, or oxychlordane, which are among the most common chlordane-related environmental contaminants and tissue residues. In this study, rats were administered cis-nonachlor, trans-nonachlor, or technical chlordane by gavage for 28 days at doses of 0.25 to 25 mg/kg body weight. Residue analyses indicated that trans-nonachlor accumulation in adipose was greater than cis-nonachlor when rats were administered each chemical under identical conditions of dose and exposure. For all test chemicals, the major metabolite oxychlordane accumulated in adipose tissue. Adipose tissue residue levels of all test chemicals and the major metabolite were higher in female rats. The liver was a target organ in male and female rats, indicated by increased liver weight and histopathological changes consistent with microsomal enzyme induction. Hepatic changes were most pronounced in rats treated with trans-nonachlor. Elevated kidney weights and depressed organic ion transport were observed in males treated with trans-nonachlor and chlordane. Although in general, changes in target organs and clinical chemistry endpoints were similar for all 3 test chemicals, the approximate toxicity ranking from most to least toxic was trans-nonachlor > technical chlordane > cis-nonachlor.

Asunto(s)

Clordano/toxicidad , Hidrocarburos Clorados/toxicidad , Insecticidas/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Riñón/efectos de los fármacos , Riñón/patología , Riñón/fisiología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/patología

RESUMEN

Fumonisins B1 and B2 (FB1 and FB2) are fungal secondary metabolites produced by members of the genus Fusarium. Although FB1 is usually detected in greater quantities, FB2 frequently co-occurs in contaminated feeds and foods and contributes to the total toxin load. In the present study, the comparative toxicity of FB1 and FB2 was examined in male Sprague-Dawley rats administered toxin (0.75 mg/kg body weight) or vehicle control intraperitoneally (ip) for 2, 4 or 6 consecutive days. Clinical changes, including elevated serum cholesterol, alanine aminotransferase (ALT), creatinine and protein, were slightly more pronounced in FB1-treated rats. The most consistent hematological change was an increase in vacuolated bone marrow cells, which was more pronounced in FB1-treated rats. Histopathological changes were similar in FB1- and FB2-treated rats and included single cell necrosis in kidneys and liver, cytoplasmic vacuolation in adrenal cortex and lymphocytolysis in thymus. In the liver mRNA expression for the cyclin kinase inhibitor p21 gene was significantly increased in FB1- and FB2-treated rats, compared to controls. Expression of mRNA for the cyclin D1 gene was significantly depressed in FB2-treated rats. Hepatic cyclin E mRNA was elevated in response to FB1 and FB2 compared to controls. In FB2-treated animals this corresponded with decreased liver p27 mRNA expression. Hepatic proliferating cell nuclear antigen (PCNA) transcription was elevated in FB1- but not FB2- treated rats. Changes in liver microsomal protein levels of p27, cyclin E and PCNA were similar to changes in gene expression. In contrast, cyclin D1 protein levels were elevated in rats treated with FB1 and, to a lesser extent, FB2. The data indicate that FB1 and FB2 can alter the expression of genes associated with the cell cycle, and indicate a need for a further understanding of the mechanistic basis of FB1 and FB2 toxicity.

Asunto(s)

Ácidos Carboxílicos/toxicidad , Ciclo Celular/efectos de los fármacos , Fumonisinas , Micotoxinas/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Ácidos Carboxílicos/administración & dosificación , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/fisiología , Ingestión de Alimentos/efectos de los fármacos , Inyecciones Intraperitoneales , Riñón/patología , Hígado/metabolismo , Hígado/patología , Masculino , Micotoxinas/administración & dosificación , Tamaño de los Órganos/efectos de los fármacos , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley

RESUMEN

We determined the effect of insulin on the fate of glucose and contractile function in isolated working hypertrophied hearts from rats with an aortic constriction (n = 27) and control hearts from sham-operated rats (n = 27). Insulin increased glycolysis and glycogen in control and hypertrophied hearts. The change in glycogen was brought about by increased glycogen synthesis and decreased glycogenolysis in both groups. However, the magnitude of change in glycolysis, glycogen synthesis, and glycogenolysis caused by insulin was lower in hypertrophied hearts than in control hearts. Insulin also increased glucose oxidation and contractile function in control hearts but not in hypertrophied hearts. Protein content of glucose transporters, protein kinase B, and phosphatidylinositol 3-kinase was not different between the two groups. Thus hypertrophied hearts are less responsive to the metabolic and functional effects of insulin. The reduced responsiveness involves multiple aspects of glucose metabolism, including glycolysis, glucose oxidation, and glycogen metabolism. The absence of changes in content of key regulatory molecules indicates that other sites, pathways, or factors regulating glucose utilization are responsible for these findings.

Asunto(s)

Cardiomegalia/fisiopatología , Insulina/fisiología , Proteínas Serina-Treonina Quinasas , Animales , Cardiomegalia/metabolismo , Glucosa/metabolismo , Glucógeno/metabolismo , Glucólisis/efectos de los fármacos , Glucólisis/fisiología , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Immunoblotting , Técnicas In Vitro , Insulina/farmacología , Masculino , Proteínas de Transporte de Monosacáridos/metabolismo , Tamaño de los Órganos , Oxidación-Reducción , Perfusión , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Sprague-Dawley

RESUMEN

The availability of immunotoxicity data for fungal toxins varies considerably for different toxins. The following is a comprehensive review of the most recent literature on the immunotoxicity of aflatoxins, fumonisins, gliotoxin, ochratoxins, patulin, and trichothecenes. Aflatoxin is an immunomodulating agent that acts primarily on cell-mediated immunity and phagocytic cell function. In addition to further characterization of aflatoxin-induced immunotoxicity in various species, some recent studies have focused on ameliorating the effects of aflatoxin by supplementing or amending the diet. The immunomodulatory effects of ochratoxins have also been considered for many years. Notably, recent studies have examined immune function in the offspring of rats and mice exposed to ochratoxin pre- and perinatally. Fumonisin toxicity has been characterized relatively recently in comparison to aflatoxin and ochratoxin, and fumonisin-induced immunotoxicity is an area of active research. As these studies progress, they may also clarify the role of sphingolipid metabolism in immune function. The most recent study of patulin immunotoxicity in mice indicates that exposure to levels found in foods and feeds would not likely result in immunotoxicity. Exposure to gliotoxin would most likely be by infection with gliotoxin-producing fungi. Although the toxin is immunosuppressive in vitro, the link between immunosuppression and the presence of gliotoxin in infected tissues in vivo has yet to be made. The trichothecenes can both suppress and stimulate immune function. By comparison, more information is available on the molecular events associated with trichothecene-induced immunomodulation than for any other fungal toxins. The molecular basis of immune function modulation by fungal toxins remains a frontier for future research.

Asunto(s)

Contaminación de Alimentos , Inmunotoxinas/inmunología , Micotoxinas/inmunología , Fagocitosis/fisiología , Animales , Exposición a Riesgos Ambientales , Inmunidad Celular/efectos de los fármacos , Terapia de Inmunosupresión , Inmunotoxinas/efectos adversos , Inmunotoxinas/farmacología , Ratones , Micotoxinas/efectos adversos , Micotoxinas/farmacología , Conejos , Ratas , Esfingolípidos/metabolismo , Porcinos

RESUMEN

The sensitivity of elevated serum ornithine carbamyltransferase (OCT) as an index of hepatotoxicity in rats was assessed in different studies conducted over a number of years and originally designed to examine the toxicity or carcinogenicity of a variety of test chemicals and diets. Changes in serum OCT activities were compared with the more widely used clinical endpoints, alanine aminotranserase (ALT) and aspartate aminotransferase (AST). In the first study, rats received a single oral dose of the hepatotoxic and hepatocarcinogenic fungal toxin aflatoxin B(1) (AFB(1)). The increase in enzyme levels between control and AFB(1)-treated rats was greater for serum OCT than for ALT or AST. This response was similar to the changes in serum enzyme levels in studies where rats ingested a hepatotoxic and hepatocarcinogenic choline deficient (CD) diet. When rats were exposed to the hepatotoxic and nephrotoxic fungal toxin fumonisin B(1) (FB(1)) by intraperitoneal injection for 6 days, serum AST and ALT were significantly elevated above control levels while OCT was unaffected. The peroxisome proliferator ciprofibrate caused elevated ALT and AST but not OCT at week 52 of dietary exposure, after the development of liver nodules and tumours. Of the two liver-specific enzymes examined in all of the studies, ALT was more consistently predictive of hepatotoxicity than OCT.

Asunto(s)

Aflatoxina B1/toxicidad , Azaserina/toxicidad , Ácidos Carboxílicos/toxicidad , Ácido Clofíbrico/análogos & derivados , Fumonisinas , Hígado/enzimología , Ornitina Carbamoiltransferasa/efectos de los fármacos , Administración Oral , Aflatoxina B1/administración & dosificación , Alanina Transaminasa/sangre , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/toxicidad , Aspartato Aminotransferasas/sangre , Azaserina/administración & dosificación , Ácidos Carboxílicos/administración & dosificación , Deficiencia de Colina/enzimología , Ácido Clofíbrico/administración & dosificación , Ácido Clofíbrico/toxicidad , Relación Dosis-Respuesta a Droga , Ácidos Fíbricos , Inyecciones Intraperitoneales , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Masculino , Micotoxinas/administración & dosificación , Micotoxinas/toxicidad , Ornitina Carbamoiltransferasa/metabolismo , Proliferadores de Peroxisomas/administración & dosificación , Proliferadores de Peroxisomas/toxicidad , Valor Predictivo de las Pruebas , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Estudios Retrospectivos