Toxicological and Environmental Chemistry最新文献

The marine toxin, okadaic acid (OA) is produced by dinoflagellates of the genera Prorocentrum and Dinophysis and is the causative agent of the syndrome known as diarrheic shellfish poisoning (DSP). In addition, OA acts as both a tumor promoter, attributed to OA-induced inhibition of protein phosphatases as well as an inducer of apoptosis. To better understand the potentially divergent toxicological profile of OA, the concentration dependent cytotoxicity and alterations in gene expression on the human liver tumor cell line HepG2 upon OA exposure were determined using RNA microarrays, DNA fragmentation, and cell proliferation assays as well as determinations of cell detachment and cell death in different concentrations of OA. mRNA expression was quantified for approximately 15,000 genes. Cell attachment and proliferation were both negatively correlated with OA concentration. Detached cells displayed necrotic DNA signatures but apoptosis also was broadly observed. Data suggest that OA has a concentration dependent effect on cell cycle, which might explain the divergent effects that at low concentration OA stimulates genes involved in the cell cycle and at high concentrations it stimulates apoptosis.

Autism is defined by a behavioral set of stereotypic and repetitious behavioral patterns in combination with social and communication deficits. There is emerging evidence supporting the hypothesis that autism may result from a combination of genetic susceptibility and exposure to environmental toxins at critical moments in development. Mercury (Hg) is recognized as a ubiquitous environmental neurotoxin and there is mounting evidence linking it to neurodevelopmental disorders, including autism. Of course, the evidence is not derived from experimental trials with humans but rather from methods focusing on biomarkers of Hg damage, measurements of Hg exposure, epidemiological data, and animal studies. For ethical reasons, controlled Hg exposure in humans will never be conducted. Therefore, to properly evaluate the Hg-autism etiological hypothesis, it is essential to first establish the biological plausibility of the hypothesis. This review examines the plausibility of Hg as the primary etiological agent driving the cellular mechanisms by which Hg-induced neurotoxicity may result in the physiological attributes of autism. Key areas of focus include: (1) route and cellular mechanisms of Hg exposure in autism; (2) current research and examples of possible genetic variables that are linked to both Hg sensitivity and autism; (3) the role Hg may play as an environmental toxin fueling the oxidative stress found in autism; (4) role of mitochondrial dysfunction; and (5) possible role of Hg in abnormal neuroexcitory and excitotoxity that may play a role in the immune dysregulation found in autism. Future research directions that would assist in addressing the gaps in our knowledge are proposed.

The purpose of this blinded study was to evaluate potential environmental toxicity in a cohort of neurotypical children (n = 28) living in a suburban area of north-central Texas in the United States (US) with a comparable age- and gender-matched cohort of neurotypical children (n = 28) living in a suburban area of southeastern France using urinary porphyrin testing: uroporphyrin (uP), heptacarboxyporphyrin (7cxP), hexacarboxyporphyrin (6cxP), pentacarboxyporphyrin (5cxP), precoproporphyrin (prcP), and coproporphyrin (cP). Results showed significantly elevated 6cxP, prcP (an atypical, mercury-specific porphyrin), and cP levels, and increasing trends in 5cxP levels, among neurotypical children in the USA compared to children in France. Data suggest that in US neurotypical children, there is a significantly increased body-burden of mercury (Hg) compared to the body-burden of Hg in the matched neurotypical children in France. The presence of lead contributing to the higher levels of cP also needs to be considered. Further, other factors including genetics can not be completely ruled out.

Dichloroacetate (DCA) and trichloroacetate (TCA) were previously found to induce various levels of oxidative stress in the hepatic tissues of mice after subacute and subchronic exposure. The cells are known to have several protective mechansims against production of oxidative stress by different xenobiotics. To assess the roles of the antioxidant enzymes and glutathione (GSH) in DCA- and TCA-induced oxidative stress, groups of B6C3F1 mice were administered either DCA or TCA at doses of 7.7, 77, 154 and 410 mg/kg/day, by gavage for 4 weeks (4-W) and 13 weeks (13-W), and superoxide dismutase (SOD) catalase (CAT) and glutathione peroxidase (GSH-Px) activities, as well as GSH were determined in the hepatic tissues. DCA at doses ranging between 7.7-410, and 7.7-77 mg/kg/day, given for 4-W and 13-W, respectively, resulted in either suppression or no change in SOD, CAT and GSH-Px activities, but doses of 154-410 mg DCA/kg/day administered for 13-W were found to result in significant induction of the three enzyme activities. TCA administration on the other hand, resulted in increases in SOD and CAT activities, and suppression of GSH-Px activity in both periods. Except for the DCA doses of 77-154 mg/kg/day administered for 13-W that resulted in significant reduction in GSH levels, all other DCA, as well as TCA treatments produced no changes in GSH. Since these enzymes are involved in the detoxification of the reactive oxygen species (ROS), superoxide anion (SA) and H(2)O(2), it is concluded that SA is the main contributor to DCA-induced oxidative stress while both ROS contribute to that of TCA. The increases in the enzyme activities associated with 154-410 mg DCA/kg/day in the 13-W period suggest their role as protective mechanisms contributing to the survival of cells modified in response to those treatments.

An immunology-based in vivo screening regime was used to assess the potential pathogenicity of biotechnology-related microbes. Strains of Bacillus cereus (Bc), Bacillus subtilis (Bs), Bacillus thuringiensis (Bt), and Bt commercial products (CPs) were tested. Balb/c mice were endotracheally instilled with purified spores, diluted CP, or vegetative cells (VC) (live or dead). Exposed mice were evaluated for changes in behavioral and physical symptoms, bacterial clearance, pulmonary granulocytes, and pulmonary and circulatory pyrogenic cytokines (interleukins (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α), as well as acute phase biomarkers (fibrinogen and serum amyloid A). Except for some differences in clearance rates, no marked effects were observed in mice exposed to any spore at 10(6) or 10(7) colony forming units (cfu). In contrast, live Bc or Bt VCs (10(5) or 10(6) cfu) produced shock-like symptoms (lethargy, hunched appearance, ruffled fur, and respiratory distress), and 11-200-fold elevations in pyrogenic cytokines at 2-h post-exposure. In the study, 4-h effects included increased lethargy, ocular discharge, and 1.5-4-fold rise in circulatory acute phase markers, but no indications of recovery. Bs VC did not produce any changes in symptoms or biomarkers. After 2 or 4 h of exposure to dead VC, increases of only plasma IL-1? and TNF-α (4.6- and 12.4-fold, respectively) were observed. These findings demonstrate that purified spores produced no marked effects in mice compared to that of metabolically active bacteria. This early screening regime was successful in distinguishing the pathogenicity of the different Bacillus species, and might be useful for assessing the relative hazard potential of other biotechnology-related candidate strains.

Sensory neurons originating in nodose and jugular ganglia that innervate airway epithelium (airway neurons) play a role in inflammation observed following exposure to inhaled environmental irritants such as ozone (O(3)). Airway neurons can mediate airway inflammation through release of the neuropeptide substance P (SP). While susceptibility to airway irritants is increased in early life, the developmental dynamics of afferent airway neurons are not well characterized. The hypothesis of this study was that airway neuron number might increase with increasing age, and that an acute, early postnatal O(3) exposure might increase both the number of sensory airway neurons as well as the number SP-containing airway neurons. Studies using Fischer 344 rat pups were conducted to determine if age or acute O(3) exposure might alter airway neuron number. Airway neurons in nodose and jugular ganglia were retrogradely labeled, removed, dissociated, and counted by means of a novel technique employing flow cytometry. In Study 1, neuron counts were conducted on postnatal days (PD) 6, 10, 15, 21, and 28. Numbers of total and airway neurons increased significantly between PD6 and PD10, then generally stabilized. In Study 2, animals were exposed to O(3) (2 ppm) or filtered air (FA) on PD5 and neurons were counted on PD10, 15, 21, and 28. O(3) exposed animals displayed significantly less total neurons on PD21 than FA controls. This study shows that age-related changes in neuron number occur, and that an acute, early postnatal O(3) exposure significantly alters sensory neuron development.

Components of the innate immune system such as macrophages and dendritic cells are instrumental in determining the fate of immune responses and are, also, among the most sensitive targets of early life environmental alterations including developmental immunotoxicity (DIT). DIT can impede innate immune cell maturation, disrupt tissue microenvironment, alter immune responses to infectious challenges, and disrupt regulatory responses. Dysregulation of inflammation, such as that observed with DIT, has been linked with an increased risk of chronic inflammatory diseases in both children and adults. In this review, we discuss the relationship between early-life risk factors for innate immune modulation and promotion of dysregulated inflammation associated with chronic inflammatory disease. The health risks from DIT-associated inflammation may extend beyond primary immune dysfunction to include an elevated risk of several later-life, inflammatory-mediated diseases that target a wide range of physiological systems and organs. For this reason, determination of innate immune status should be an integral part of drug and chemical safety evaluation.

Cadmium (Cd(+2)), a known carcinogen mimics the effects of estrogen in the uterus and mammary gland suggesting its possible involvement in the development and progression of breast cancer. This lab showed through analysis of a small set of archival human diagnostic specimens that the third isoform of the classic Cd(+2) binding protein metallothionein (MT-3), is not expressed in normal breast tissue, but is expressed in some breast cancers and that expression tends to correlate with a poor disease outcome. The goals of the present study were to verify that overexpression of MT-3 in a large set of archival human diagnostic specimens tends to correlate with poor disease outcome and define the mechanism of MT-3 gene regulation in the normal breast epithelial cell. The results showed that MT-3 was expressed in approximately 90% of all breast cancers and was absent in normal breast epithelium. The lack of MT-3 staining in some cancers correlated with a favorable patient outcome. High frequency of MT-3 staining was also found for in situ breast cancer suggesting that MT-3 might be an early biomarker for breast cancer. The study also demonstrated that the MCF-10A cell line, an immortalized, non-tumorigenic model of human breast epithelial cells, displayed no basal expression of MT-3, nor was it induced by Cd(+2). Treatment of the MCF-10A cells with the demethylation agent, 5-Aza-2'-deoxycytidine, or the histone deacetylase inhibitor, MS-275, restored MT-3 mRNA expression. It was also shown that the MT-3 metal regulatory elements are potentially active binders of protein factors following treatment with these inhibitors suggesting that MT-3 expression may be subject to epigenetic regulation.

The abilities of various doses of 3,3',4,4',5-pentachlorobiphenyl (PCB126) to induce changes in antioxidant enzyme activities and glutathione levels in the brain tissues of rats were examined in rats after subchronic exposure. Groups of rats were administered 10,30, 100, 300, 550 or 1000 ng PCB 126/kg/day, p.o., for 13 weeks and the activities of supeoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as (GSH) levels were determined in the brain tissue homogenates. Treatment resulted in significant and dose-dependent increases in the activities of the three tested enzymes. While maximal increase GSH-Px activity was achieved with a dose of 100-175 mg/kg/day, CAT and SOD activities continued to increase in response to maximal dose used for this study. GSH levels on the other hand, were suppressed significantly in a dose-dependent fashion. Data suggest that previously observed increase in oxidative stress production by PCB-126 in the brain tissues of rats is associated with dose-dependent rise in antioxidant enzyme activities and GSH depletion. However, the increases in the antioxidant enzyme activities can not provide full protection against oxidative damage induced by the same doses. In addition, GSH depletion plays a critical role in the previously observed oxidative stress in response to this compound.

Thimerosal (ethylmercurithiosalicylic acid), an ethylmercury (EtHg)-releasing compound (49.55% mercury (Hg)), was used in a range of medical products for more than 70 years. Of particular recent concern, routine administering of Thimerosal-containing biologics/childhood vaccines have become significant sources of Hg exposure for some fetuses/infants. This study was undertaken to investigate cellular damage among in vitro human neuronal (SH-SY-5Y neuroblastoma and 1321N1 astrocytoma) and fetal (nontransformed) model systems using cell vitality assays and microscope-based digital image capture techniques to assess potential damage induced by Thimerosal and other metal compounds (aluminum (Al) sulfate, lead (Pb)(II) acetate, methylmercury (MeHg) hydroxide, and mercury (Hg)(II) chloride) where the cation was reported to exert adverse effects on developing cells. Thimerosal-associated cellular damage was also evaluated for similarity to pathophysiological findings observed in patients diagnosed with autistic disorders (ADs). Thimerosal-induced cellular damage as evidenced by concentration- and time-dependent mitochondrial damage, reduced oxidative-reduction activity, cellular degeneration, and cell death in the in vitro human neuronal and fetal model systems studied. Thimerosal at low nanomolar (nM) concentrations induced significant cellular toxicity in human neuronal and fetal cells. Thimerosal-induced cytoxicity is similar to that observed in AD pathophysiologic studies. Thimerosal was found to be significantly more toxic than the other metal compounds examined. Future studies need to be conducted to evaluate additional mechanisms underlying Thimerosal-induced cellular damage and assess potential co-exposures to other compounds that may increase or decrease Thimerosal-mediated toxicity.