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1.
Toxicol Sci ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609516

RESUMO

Particulate matter (PM) causes adverse developmental outcomes following prenatal exposure, but the underlying biological mechanisms remain uncertain. Here we elucidate the effects of diesel exhaust ultrafine particle (UFP) exposure during pregnancy on placental and fetal development. Time-mated C57Bl/6n mice were gestationally exposed to UFPs at a low dose (LD, 100 µg/m3) or high dose (HD, 500 µg/m3) for 6 hours daily. Phenotypic effects on fetuses and placental morphology at gestational day (GD) of 18.5 were evaluated, and RNA sequencing was characterized for transcriptomic changes in placental tissue from male and female offspring. A significant decrease in average placental weights and crown to rump lengths was observed in female offspring in the LD exposure group. Gestational UFP exposure altered placental morphology in a dose and sex-specific manner. Average female decidua areas were significantly greater in the LD and HD groups. Maternal lacunae mean areas were increased in the female LD group, whereas fetal blood vessel mean areas were significantly greater in the male LD and HD groups. RNA sequencing indicated several disturbed cellular functions related to lipid metabolism, which were most pronounced in the LD group and especially in female placental tissue. Our findings demonstrate the vulnerability of offspring exposed to UFPs during pregnancy, highlighting sex-specific effects and emphasizing the importance of mitigating PM exposure to prevent adverse health outcomes.

3.
Environ Health Prev Med ; 26(1): 72, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253165

RESUMO

BACKGROUND: Particulate matter (PM), a major component of ambient air pollution, accounts for a substantial burden of diseases and fatality worldwide. Maternal exposure to PM during pregnancy is particularly harmful to children's health since this is a phase of rapid human growth and development. METHOD: In this review, we synthesize the scientific evidence on adverse health outcomes in children following prenatal exposure to the smallest toxic components, fine (PM2.5) and ultrafine (PM0.1) PM. We highlight the established and emerging findings from epidemiologic studies and experimental models. RESULTS: Maternal exposure to fine and ultrafine PM directly and indirectly yields numerous adverse birth outcomes and impacts on children's respiratory systems, immune status, brain development, and cardiometabolic health. The biological mechanisms underlying adverse effects include direct placental translocation of ultrafine particles, placental and systemic maternal oxidative stress and inflammation elicited by both fine and ultrafine PM, epigenetic changes, and potential endocrine effects that influence long-term health. CONCLUSION: Policies to reduce maternal exposure and health consequences in children should be a high priority. PM2.5 levels are regulated, yet it is recognized that minority and low socioeconomic status groups experience disproportionate exposures. Moreover, PM0.1 levels are not routinely measured or currently regulated. Consequently, preventive strategies that inform neighborhood/regional planning and clinical/nutritional recommendations are needed to mitigate maternal exposure and ultimately protect children's health.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Exposição Materna/efeitos adversos , Material Particulado/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Poluição do Ar/prevenção & controle , Animais , Doenças Cardiovasculares/induzido quimicamente , Saúde da Criança , Pré-Escolar , Modelos Animais de Doenças , Doenças do Sistema Endócrino/induzido quimicamente , Epigenômica , Feminino , Humanos , Doenças do Sistema Imunitário/induzido quimicamente , Lactente , Recém-Nascido , Masculino , Doenças do Sistema Nervoso/induzido quimicamente , Estresse Oxidativo , Tamanho da Partícula , Placenta , Gravidez , Resultado da Gravidez/epidemiologia , Doenças Respiratórias/induzido quimicamente , Adulto Jovem
4.
Artigo em Inglês | MEDLINE | ID: mdl-34131287

RESUMO

BACKGROUND: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health effects in children. Valid exposure assessment methods with accurate spatial and temporal resolution across pregnancy is a critical need for advancing environmental health studies. OBJECTIVE: The objective of this study was to quantify maternal PAH exposure in pregnant women residing in McAllen, Texas where the prematurity rate and childhood asthma prevalence rates are high. A secondary objective was to compare PAH levels in silicone wristbands deployed as passive samplers with concentrations measured using standardized active air-sampling techniques. METHODS: Participants carried a backpack that contained air-sampling equipment (i.e., filter and XAD sorbent) and a silicone wristband (i.e., passive sampler) for three nonconsecutive 24-h periods. Filters, XAD tubes, and wristbands were analyzed for PAHs. RESULTS: The median level of exposure for the sum of 16 PAHs measured via active sampling over 24 h was 5.54 ng/m3 (filters) and 43.82 ng/m3 (XADs). The median level measured in wristbands (WB) was 586.82 ng/band. Concentrations of the PAH compounds varied across sampling matrix type. Phenanthrene and fluorene were consistently measured for all participants and in all matrix types. Eight additional volatile PAHs were measured in XADs and WBs; the median level of exposure for the sum of these eight PAHs was 342.98 ng/m3 (XADs) and 632.27 ng/band. The silicone wristbands (WB) and XAD sorbents bound 1-methynaphthalyne, 2-methylnaphthalene, biphenyl following similar patterns of detection. SIGNIFICANCE: Since prior studies indicate linkages between PAH exposure and adverse health outcomes in children at the PAH levels detected in our study, further investigation on the associated health effects is needed. Data reflect the ability of silicone wristbands to bind smaller molecular weight, semivolatile PAHs similar to XAD resin. Application of wristbands as passive samplers may be useful in studies evaluating semivolatile PAHs.

5.
Environ Int ; 148: 106378, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33508708

RESUMO

Low birth weight is an important risk factor for many co-morbidities both in early life as well as in adulthood. Numerous studies report associations between prenatal exposure to particulate matter (PM) air pollution and low birth weight. Previous systematic reviews and meta-analyses report varying effect sizes and significant heterogeneity between studies, but did not systematically evaluate the quality of individual studies or the overall body of evidence. We conducted a new systematic review to determine how prenatal exposure to PM2.5, PM10, and coarse PM (PM2.5-10) by trimester and across pregnancy affects infant birth weight. Using the Navigation Guide methodology, we developed and applied a systematic review protocol [CRD42017058805] that included a comprehensive search of the epidemiological literature, risk of bias (ROB) determination, meta-analysis, and evidence evaluation, all using pre-established criteria. In total, 53 studies met our inclusion criteria, which included evaluation of birth weight as a continuous variable. For PM2.5 and PM10, we restricted meta-analyses to studies determined overall as "low" or "probably low" ROB; none of the studies evaluating coarse PM were rated as "low" or "probably low" risk of bias, so all studies were used. For PM2.5, we observed that for every 10 µg/m3 increase in exposure to PM2.5 in the 2nd or 3rd trimester, respectively, there was an associated 5.69 g decrease (I2: 68%, 95% CI: -10.58, -0.79) or 10.67 g decrease in birth weight (I2: 84%, 95% CI: -20.91, -0.43). Over the entire pregnancy, for every 10 µg/m3 increase in PM2.5 exposure, there was an associated 27.55 g decrease in birth weight (I2: 94%, 95% CI: -48.45, -6.65). However, the quality of evidence for PM2.5 was rated as "low" due to imprecision and/or unexplained heterogeneity among different studies. For PM10, we observed that for every 10 µg/m3 increase in exposure in the 3rd trimester or the entire pregnancy, there was a 6.57 g decrease (I2: 0%, 95% CI: -10.66, -2.48) or 8.65 g decrease in birth weight (I2: 84%, 95% CI: -16.83, -0.48), respectively. The quality of evidence for PM10 was rated as "moderate," as heterogeneity was either absent or could be explained. The quality of evidence for coarse PM was rated as very low/low (for risk of bias and imprecision). Overall, while evidence for PM2.5 and course PM was inadequate primarily due to heterogeneity and risk of bias, respectively, our results support the existence of an inverse association between prenatal PM10 exposure and low birth weight.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Efeitos Tardios da Exposição Pré-Natal , Adulto , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Peso ao Nascer , Exposição Ambiental/análise , Feminino , Humanos , Lactente , Recém-Nascido , Exposição Materna/efeitos adversos , Material Particulado/análise , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia
6.
Environ Epigenet ; 6(1): dvaa011, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33214907

RESUMO

It is now clear that parental histories of drug use, toxicant exposure, and social stress all have a significant influence on the health and development of the next generation. However, the ability of epigenetic parental life memories to interact with subsequent gestational exposures and cumulatively modify the developmental trajectory of the offspring remains an unexplored perspective in toxicology. Studies from our laboratory have identified male-specific postnatal growth restriction in a mouse model of chronic, preconception paternal alcohol exposure. The goal of the current study was to determine if paternal alcohol use, before conception, could modify the susceptibility of the offspring to a completely separate exposure encountered by the mother during pregnancy. In independent experiments, we previously identified altered developmental programming and increased markers of severe asthma induced by gestational exposure to particulate air pollution. In this study, male mice were exposed to either the control or alcohol preconception treatments, then mated to naive females, which we subsequently exposed to an ultrafine mixture of particulate matter via inhalation. Individually, neither preconception paternal drinking nor gestational exposures to particulate air pollution impacted the postnatal growth of female offspring. However, when both exposures were combined, females displayed a 30% reduction in weight gain. Unexpectedly, this exposure paradigm resulted in a dramatic postnatal increase in litter loss due to maternal cannibalism, which prevented additional measures of offspring health. These preliminary studies provide evidence of a complex interplay between preconception life history and intrauterine environmental factors in the control of postnatal growth.

7.
Mol Carcinog ; 58(11): 2017-2025, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31373075

RESUMO

Exploration of animal models leads to discoveries that can reveal candidate biomarkers for translation to human populations. Herein, a model of hepatocarcinogenesis and protection was used in which rats treated with aflatoxin (AFB1 ) daily for 28 days (200 µg/kg BW) developed tumors compared with rats completely protected from tumors by concurrent administration of the chemoprotective agent, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im). Differential expression of miRNAs in tumors (AFB1 ) and nontumor (AFB1 + CDDO-Im) bearing livers and their levels in sera over the life-course of the animals was determined. miRNA transcriptome analysis identified 17 miRNAs significantly upregulated at greater than five-fold in the tumors. The ten most dysregulated miRNAs judged by fold-change and biological significance were selected for further study, including liver-specific miR-122-5p. Validation of sequencing results by real-time PCR confirmed the upregulation of the majority of these miRNAs in tumors, including miR-182, as well as miR-224-5p as the most dysregulated of these miRNAs (over 400-fold). The longitudinal analysis of levels of miR-182 in sera demonstrated significant and persistent increases (5.13-fold; 95% CI: 4.59-5.70). The increase in miR-182 was detected months before any clinical symptoms were present in the animals. By the terminal time point of the study, in addition to elevated levels of serum miR-182, serum miR-122-5p was also found to be increased (>1.5-fold) in animals that developed hepatocarcinomas. Thus, using the data from an unbiased discovery approach of the tissue findings, serum miR-182 was found to track across the complex, multistage process of hepatocarcinogenesis opening an opportunity for translation to human populations.


Assuntos
Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/sangue , MicroRNAs/sangue , Aflatoxinas/toxicidade , Animais , Biomarcadores Tumorais/sangue , Carcinogênese , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Ratos
8.
Appl Clay Sci ; 168: 196-202, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31435120

RESUMO

People and animals can be unintentionally exposed to complex mixtures of hazardous chemicals that can threaten the safety of food and water supplies following natural and man-made disasters and emergencies. Our research has focused on the development of broad-acting adsorbents that will tightly bind environmental contaminants in the gastrointestinal tract and decrease their bioavailability to humans and animals during these events. In this study, benzo[a]pyrene (BaP) and aldicarb were used as representative chemicals due to their high toxicity and extensive distribution in the environment. Both chemicals have been commonly detected in water and sediments in the US, and their distribution and concentrations can be enhanced during disasters. To address this problem, we have amended and functionalized montmorillonite clays with the nutrients, L-carnitine and choline to enhance their attraction for lipophilic toxins, such as BaP and aldicarb. Based on equilibrium isothermal analyses, we have demonstrated a significantly increased binding capacity (Qmax) and affinity (Kd) for BaP and aldicarb compared to the parent clay. Adsorption isotherms also showed that talc bound strongly to BaP with the highest Qmax, which was twice that of activated carbon. Additionally, cultures of adult hydra with a metabolism activation package were used as an in vivo toxicity indicator to confirm the ability of test adsorbents to protect against toxicity at low inclusion levels. We anticipate that the optimal adsorbents developed can be delivered in food and flavored water, or administered by sachet or capsule during emergencies and disasters to decrease human and animals exposures to environmental toxins.

9.
Proc Natl Acad Sci U S A ; 116(24): 11590-11595, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31138695

RESUMO

Exposure to fine particulate matter (PM) during pregnancy is associated with high risks of birth defects/fatality and adverse long-term postnatal health. However, limited mechanistic data are available to assess the detailed impacts of prenatal PM exposure. Here we evaluate fine PM exposure during pregnancy on prenatal/postnatal organogenesis in offspring and in predisposing metabolic syndrome for adult life. Between days 0 and 18 of gestation, two groups of adult female rats (n = 10 for each) were placed in a dual-exposure chamber device, one with clean ambient air (∼3 µg·m-3) and the other with ambient air in the presence of 100 to 200 µg·m-3 of ultrafine aerosols of ammonium sulfate. At birth (postnatal day 0, PND0), four males and four females were selected randomly from each litter to be nursed by dams, whereas tissues were collected from the remaining pups. At PND21, tissues were collected from two males and two females, whereas the remaining pups were fed either a high- or low-fat diet until PND105, when tissues were obtained for biochemical and physiological analyses. Maternal exposure to fine PM increased stillbirths; reduced gestation length and birth weight; increased concentrations of glucose and free fatty acids in plasma; enhanced lipid accumulation in the liver; and decreased endothelium-dependent relaxation of aorta. This lead to altered organogenesis and predisposed progeny to long-term metabolic defects in an age-, organ-, and sex-specific manner. Our results highlight the necessity to develop therapeutic strategies to remedy adverse health effects of maternal PM exposure on conceptus/postnatal growth and development.


Assuntos
Exposição Materna/efeitos adversos , Síndrome Metabólica/induzido quimicamente , Organogênese/efeitos dos fármacos , Material Particulado/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/patologia , Poluição do Ar/efeitos adversos , Animais , Peso ao Nascer/efeitos dos fármacos , Suscetibilidade a Doenças/sangue , Suscetibilidade a Doenças/metabolismo , Suscetibilidade a Doenças/patologia , Exposição Ambiental/efeitos adversos , Ácidos Graxos/sangue , Feminino , Glucose/metabolismo , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Organogênese/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley
10.
Proc Natl Acad Sci U S A ; 116(9): 3443-3448, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808738

RESUMO

Early life exposure to fine particulate matter (PM) in air is associated with infant respiratory disease and childhood asthma, but limited epidemiological data exist concerning the impacts of ultrafine particles (UFPs) on the etiology of childhood respiratory disease. Specifically, the role of UFPs in amplifying Th2- and/or Th17-driven inflammation (asthma promotion) or suppressing effector T cells (increased susceptibility to respiratory infection) remains unclear. Using a mouse model of in utero UFP exposure, we determined early immunological responses to house dust mite (HDM) allergen in offspring challenged from 0 to 4 wk of age. Two mice strains were exposed throughout gestation: C57BL/6 (sensitive to oxidative stress) and BALB/C (sensitive to allergen exposure). Offspring exposed to UFPs in utero exhibited reduced inflammatory response to HDM. Compared with filtered air (FA)-exposed/HDM-challenged mice, UFP-exposed offspring had lower white blood cell counts in bronchoalveolar lavage fluid and less pronounced peribronchiolar inflammation in both strains, albeit more apparent in C57BL/6 mice. In the C57BL/6 strain, offspring exposed in utero to FA and challenged with HDM exhibited a robust response in inflammatory cytokines IL-13 and Il-17. In contrast, this response was lost in offspring exposed in utero to UFPs. Circulating IL-10 was significantly up-regulated in C57BL/6 offspring exposed to UFPs, suggesting increased regulatory T cell expression and suppressed Th2/Th17 response. Our results reveal that in utero UFP exposure at a level close to the WHO recommended PM guideline suppresses an early immune response to HDM allergen, likely predisposing neonates to respiratory infection and altering long-term pulmonary health.


Assuntos
Asma/imunologia , Hipersensibilidade/imunologia , Material Particulado/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Alérgenos/química , Alérgenos/toxicidade , Animais , Asma/induzido quimicamente , Asma/genética , Asma/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Feminino , Hipersensibilidade/genética , Hipersensibilidade/patologia , Imunossupressão , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Pyroglyphidae/química , Células Th17/imunologia , Células Th2/imunologia
11.
Mol Carcinog ; 56(11): 2382-2390, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28218475

RESUMO

Aflatoxin B1 (AFB1 ) is a potent human and animal hepatocarcinogen. To investigate the effects of aflatoxin on miRNA expression during the initiation phase of carcinogenesis, next-generation sequencing was used to analyze liver tissues from F344 rats exposed to 200 µg/kg per day AFB1 for 4 week. A panel of miRNAs was identified that was upregulated with AFB1 treatment compared to controls: rno-miR-434-3p, rno-miR-411-5p, rno-miR-221-3p, rno-miR-127-3p, rno-miR-205, rno-miR-429, rno-miR-34a-5p, rno-miR-181c-3p, rno-miR-200b-3p, and rno-miR-541-5p. Analysis of rat livers exposed to AFB1 plus the chemopreventive triterpenoid CDDO-Im revealed a striking abrogation of this upregulation. These changes were validated by real-time PCR. We also explored the temporal variation in expression of the candidate miRNAs during the 4-week dosing period. Most of the candidate miRNAs were upregulated at week 1 and increased for the duration of AFB1 dosing over the 4-week period. Treatment with CDDO-Im ameliorated these effects at all time points. All candidate miRNAs were detectable in serum from aflatoxin treated animals; however, there was no significant difference in expression for 7 of the 11 miRNAs examined. Exposure to AFB1 upregulated miR-122-5p (fivefold), 34a-5p (13-fold), and 181c-3p (170-fold) compared with controls. The findings from this study give insight into epigenetic changes induced by aflatoxin taking place during the initial step of carcinogenesis.


Assuntos
Aflatoxina B1/toxicidade , Anticarcinógenos/uso terapêutico , Carcinógenos/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/uso terapêutico , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/prevenção & controle , MicroRNAs/genética , Ácido Oleanólico/análogos & derivados , Aflatoxina B1/química , Animais , Aspergillus flavus/química , Carcinogênese/induzido quimicamente , Carcinogênese/efeitos dos fármacos , Carcinógenos/química , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , MicroRNAs/sangue , Ácido Oleanólico/uso terapêutico , Ratos Endogâmicos F344
12.
Cancer Prev Res (Phila) ; 7(7): 658-65, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24662598

RESUMO

In experimental animals and humans, aflatoxin B1 (AFB1) is a potent hepatic toxin and carcinogen. The synthetic oleanane triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a powerful activator of Keap1-Nrf2 signaling, protects against AFB1-induced toxicity and preneoplastic lesion formation (GST-P-positive foci). This study assessed and mechanistically characterized the chemoprotective efficacy of CDDO-Im against AFB1-induced hepatocellular carcinoma (HCC). A lifetime cancer bioassay was undertaken in F344 rats dosed with AFB1 (200 µg/kg rat/day) for four weeks and receiving either vehicle or CDDO-Im (three times weekly), one week before and throughout the exposure period. Weekly, 24-hour urine samples were collected for analysis of AFB1 metabolites. In a subset of rats, livers were analyzed for GST-P foci. The comparative response of a toxicogenomic RNA expression signature for AFB1 was examined. CDDO-Im completely protected (0/20) against AFB1-induced liver cancer compared with a 96% incidence (22/23) observed in the AFB1 group. With CDDO-Im treatment, integrated level of urinary AFB1-N(7)-guanine was significantly reduced (66%) and aflatoxin-N-acetylcysteine, a detoxication product, was consistently elevated (300%) after the first AFB1 dose. In AFB1-treated rats, the hepatic burden of GST-P-positive foci increased substantially (0%-13.8%) over the four weeks, but was largely absent with CDDO-Im intervention. The toxicogenomic RNA expression signature characteristic of AFB1 was absent in the AFB1 + CDDO-Im-treated rats. The remarkable efficacy of CDDO-Im as an anticarcinogen is established even in the face of a significant aflatoxin adduct burden. Consequently, the absence of cancer requires a concept of a threshold for DNA damage for cancer development.


Assuntos
Aflatoxina B1/toxicidade , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/prevenção & controle , Adutos de DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa S-Transferase pi/metabolismo , Imidazóis/uso terapêutico , Neoplasias Hepáticas Experimentais/prevenção & controle , Ácido Oleanólico/análogos & derivados , Aflatoxina B1/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/metabolismo , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Ácido Oleanólico/uso terapêutico , Análise de Sequência com Séries de Oligonucleotídeos , Venenos/toxicidade , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/prevenção & controle , Ratos , Ratos Endogâmicos F344
13.
Toxicol Sci ; 139(2): 293-300, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24675090

RESUMO

Mice are resistant to aflatoxin hepatotoxicity, primarily due to high expression of glutathione S-transferases (GSTs), and in particular the GSTA3 subunit. Nuclear factor erythroid 2 related factor 2 (Nrf2) signaling, which controls a broad-based cytoprotective response, was activated either genetically or pharmacologically in an attempt to rescue GSTA3 knockout mice from aflatoxin genotoxicity. Genetic activation of Nrf2 signaling was attained in a GSTA3: hepatocyte-specific Keap1 double knockout (DKO) mouse whereas pharmacologic activation of Nrf2 was achieved through pretreatment of mice with the triterpenoid 1-[2-cyano-3-,12-dioxoleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im) prior to aflatoxin B1 exposure. Following oral treatment with aflatoxin, urine was collected from mice for 24 h and hepatic and urinary aflatoxin metabolites then quantified using isotope dilution-mass spectrometry. Although Nrf2 was successfully activated genetically and pharmacologically, neither means affected the response of GSTA3 knockout mice to chemical insult with aflatoxin. Hepatic aflatoxin B1-N(7)-guanine levels were elevated 120-fold in GSTA3 knockout mice compared with wild-type and levels were not attenuated by the interventions. This lack of effect was mirrored in the urinary excretion of aflatoxin B1-N(7)-guanine. By contrast, urinary excretion of aflatoxin B1-N-acetylcysteine was >200-fold higher in wild-type mice compared with the single GSTA3 knockout or DKO mouse. The inability to rescue GSTA3 knockout mice from aflatoxin genotoxicity through the Nrf2 transcriptional program indicates that Gsta3 is unilaterally responsible for the detoxication of aflatoxin in mice.


Assuntos
Aflatoxina B1/toxicidade , Glutationa Transferase/genética , Hipertensão/tratamento farmacológico , Imidazóis/farmacologia , Mutagênicos/toxicidade , Fator 2 Relacionado a NF-E2 , Ácido Oleanólico/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Aflatoxina B1/farmacocinética , Aflatoxina B1/urina , Animais , Proteínas do Citoesqueleto/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Hipertensão/genética , Hipertensão/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutagênicos/farmacocinética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleanólico/farmacologia , Transdução de Sinais/genética
14.
Biomarkers ; 18(5): 391-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23697800

RESUMO

Aflatoxin B1 is a persistent public health issue in Ghana. Assessment of AFB1 intervention efficacy is currently dependent on long-term biomarkers. This study was designed to determine whether daily AFM1 biomarker levels could be utilized as an early detection method for intervention efficacy. Participants were treated with a refined calcium montmorillonite clay (UPSN) or a placebo (calcium carbonate) in a crossover study. Urine samples were assessed for AFM1 levels daily. UPSN treatment reduced AFM1 biomarkers by 55% compared to the placebo. This is the first study to show that daily urinary AFM1 levels can be used as a biomarker of internal aflatoxin B1 exposure in short-term intervention trials to determine efficacy.


Assuntos
Aflatoxina M1/urina , Antídotos/administração & dosagem , Bentonita/administração & dosagem , Adsorção , Adulto , Aflatoxina B1/química , Aflatoxina B1/metabolismo , Idoso , Antídotos/química , Bentonita/química , Biomarcadores/urina , Estudos Cross-Over , Exposição Ambiental , Feminino , Contaminação de Alimentos , Alimentos Formulados , Humanos , Masculino , Pessoa de Meia-Idade , Paladar , Resultado do Tratamento , Adulto Jovem
15.
Sci Total Environ ; 408(23): 6027-31, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20870273

RESUMO

The incidence of hepatocellular carcinoma (HCC) is significantly elevated in a Hispanic community in Bexar County, Texas. Chronic exposure to dietary aflatoxins (AFs) is a major risk factor for HCC; increased risk has been linked to polycyclic aromatic hydrocarbon (PAH) co-exposure and hepatitis virus infection. The aims of this study were to assess AF and PAH exposures, investigate dietary factors that may contribute to increased AF exposure, and determine the prevalence of hepatitis virus infection in Bexar Co. Blood and urine samples were collected from 184 volunteers for biomarker analyses and hepatitis screening. Serum AFB(1)-lysine adduct, urinary AFM(1) and 1-hydroxypyrene (1-OHP) levels were measured using high-performance liquid chromatography. The average AFB(1)-lysine adduct level detected in 20.6% of serums was 3.84 ± 3.11 pg/mg albumin (range 1.01-16.57 pg/mg). AFM(1) was detected in 11.7% of urines, averaging 223.85 ± 250.56 pg/mg creatinine (range 1.89-935.49 pg/mg). AFM(1) detection was associated with increased consumption of corn tortillas (p=0.009), nuts (p=0.033) and rice (p=0.037). A significant difference was observed between mean 1-OHP values of non-smokers (0.07 ± 0.13) and smokers (0.80 ± 0.68) µmol/mol creatinine (p<0.01). A high hepatitis C virus positivity rate (7.1%) was observed. Findings suggest that the incidence and level of AF and PAH exposure were less than those observed in a high-risk population; however, participants consuming higher amounts of foods prone to AF contamination may be more vulnerable to exposure and interactions with other environmental/biological factors (i.e., HCV).


Assuntos
Aflatoxinas/toxicidade , Carcinoma Hepatocelular/epidemiologia , Poluentes Ambientais/toxicidade , Neoplasias Hepáticas/epidemiologia , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Adolescente , Adulto , Aflatoxina B1/sangue , Aflatoxina B1/urina , Aflatoxinas/metabolismo , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Biomarcadores/urina , Carcinoma Hepatocelular/metabolismo , Creatinina/metabolismo , Dieta , Exposição Ambiental/análise , Poluentes Ambientais/metabolismo , Feminino , Hepatite Viral Humana/epidemiologia , Humanos , Neoplasias Hepáticas/metabolismo , Lisina/sangue , Lisina/urina , Masculino , Pessoa de Meia-Idade , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Pirenos/metabolismo , Texas/epidemiologia , Adulto Jovem
16.
Am J Clin Nutr ; 92(1): 154-60, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20484447

RESUMO

BACKGROUND: Promotion of the HIV epidemic by aflatoxin is postulated but not yet established. Sub-Saharan populations commonly consume food contaminated by mycotoxins, particularly aflatoxins (predominantly found in peanut, maize, rice, and cassava) and fumonisins, which occur primarily in maize. Aflatoxin promotes hepatocellular cancer, and fumonisin may promote esophageal cancer. OBJECTIVES: This analysis was undertaken to test the hypotheses that consumption of mycotoxin-prone staple foods is 1) related to the incidence of HIV infection in Africa and 2) related to "signature" cancer rates confirming exposure to aflatoxins and fumonisins. DESIGN: World Health Organization data for causes of death and the Food and Agriculture Organization per capita consumption data for commodities in sub-Saharan Africa were used. Per capita Gross Domestic Product and the percentage of Muslims (%Muslim) were the socioeconomic data sets exploited. Relations between causes of mortality, consumption of mycotoxin-prone foods, and socioeconomic variables were evaluated. Models for HIV transmission as a function of maize consumption and %Muslim were estimated. RESULTS: HIV and esophageal cancer deaths were significantly related to maize but were inversely related to %Muslim and rice consumption. HIV infections were minimized (74 compared with 435/100,000 people; odds ratio: 2.41; 95% CI: 1.73, 3.24; P < or = 0.0001) by the combination of low maize consumption and above-median % Muslim. Hepatocellular cancer deaths were positively related to rice but negatively related to maize consumption. CONCLUSIONS: HIV transmission frequency is positively associated with maize consumption in Africa. The relation between cancer and food suggests that fumonisin contamination rather than aflatoxin is the most likely factor in maize promoting HIV. Changes to the quality of maize may avoid up to 1,000,000 transmissions of HIV annually.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Neoplasias Esofágicas/epidemiologia , Doenças Transmitidas por Alimentos/complicações , Infecções por HIV/epidemiologia , Neoplasias Hepáticas/epidemiologia , Micotoxinas/toxicidade , África ao Sul do Saara/epidemiologia , Grupo com Ancestrais do Continente Africano , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/mortalidade , Causas de Morte , Meio Ambiente , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/mortalidade , Comportamento Alimentar , Fumonisinas/toxicidade , Infecções por HIV/induzido quimicamente , Infecções por HIV/mortalidade , Infecções por HIV/transmissão , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/mortalidade , Mortalidade , Oryza/toxicidade , Análise de Regressão , Zea mays/toxicidade
17.
Sci Total Environ ; 407(6): 1886-91, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19144392

RESUMO

It was postulated that a population in sub-Saharan Africa, known to be at high risk for aflatoxicosis due to frequent ingestion of aflatoxin (AF)-contaminated foods could also be exposed to polycyclic aromatic hydrocarbons (PAHs) from a variety of environmental sources. Previously, participants in this population were shown to be highly exposed to AFs, and this exposure was significantly reduced by intervention with NovaSil clay (NS). Objectives of this study were 1) to assess PAH exposure in participants from the AF study using urinary biomarker 1-hydroxypyrene (1-OHP); 2) examine the effect of NS clay and placebo (cellulose) treatment on 1-OHP levels; and 3) determine potential association(s) between AF and PAH exposures. A clinical trial was conducted in 177 Ghanaians who received either NS capsules as high dose or low dose, or placebo (cellulose) for a period of 3 months. At the start and end of the study, urine samples were analyzed for 1-OHP. Of the 279 total samples, 98.9% had detectable levels of 1-OHP. Median 1-OHP excretion in nonsmokers was 0.64 micromol/mol creatinine at baseline and 0.69 micromol/mol creatinine after 3 months. Samples collected at both time points did not show significant differences between placebo and NS-treated groups. There was no linear correlation between 1-OHP and AF-albumin adduct levels. Results show that this population is highly exposed to PAHs (and AFs), that NS and cellulose treatment had no statistically significant effect on 1-OHP levels, and that this urinary biomarker was not linearly related with AF exposure.


Assuntos
Exposição Ambiental/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Pirenos/análise , Adolescente , Adulto , Aflatoxinas/metabolismo , Aflatoxinas/envenenamento , Antídotos/uso terapêutico , Bentonita/uso terapêutico , Método Duplo-Cego , Exposição Ambiental/efeitos adversos , Feminino , Gana , Humanos , Masculino , Pessoa de Meia-Idade , Envenenamento/tratamento farmacológico , Envenenamento/prevenção & controle , Envenenamento/urina , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/envenenamento , Estatísticas não Paramétricas , Adulto Jovem
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