The Speciation of Metals in Mammals Influences Their Toxicokinetics and Toxicodynamics and Therefore Human Health Risk Assessment

Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal toxicokinetics and toxicodynamics in mammals, and therefore the adverse effects of metals, is reviewed to illustrate how the physicochemical characteristics of metals and their handling in the body (toxicokinetics) can influence toxicity (toxicodynamics). Generalizing from mercury, arsenic, lead, aluminum, chromium, and manganese, it is clear that metal speciation influences mammalian toxicity. Methods used in aquatic toxicology to predict the interaction among metal speciation, uptake, and toxicity are evaluated. A classification system is presented to show that the chemical nature of the metal can predict metal ion toxicokinetics and toxicodynamics. Essential metals, such as iron, are considered. These metals produce low oral toxicity under most exposure conditions but become toxic when biological processes that utilize or transport them are overwhelmed, or bypassed. Risk assessments for essential and nonessential metals should consider toxicokinetic and toxicodynamic factors in setting exposure standards. Because speciation can influence a metal\u27s fate and toxicity, different exposure standards should be established for different metal species. Many examples are provided which consider metal essentiality and toxicity and that illustrate how consideration of metal speciation can improve the risk assessment process. More examples are available at a website established as a repository for summaries of the literature on how the speciation of metals affects their toxicokinetics

Mempelajari Sifat Fisika Sol Karet Cetak Dengan Filler Cangkang Telur Ayam

Tujuan penelitian adalah untuk menpelajari sifat fisika sol karet cetak dengan filler cangkang telur ayam. Sifat fisika yang dipelajari meliputi kekerasan, tegangan putus, ketahanan sobek dan ketahanan kikis. Penelitian dilakukan dengan 4 tahap yaitu pembuatan filler cangkang telur ayam, pembuatan sol karet cetak, pengujian sifat fisika dan penilaian secara visual. Perlakuan terdiri dari penggunaan cangkang telur ayam menggantikan filer karbon hitam meliputi perlakuan tanpa penggunaan cangkang telur ayam (A1), penggunaan filler cangkang telur ayam 15 Phr (B1), penggunaan filer cangkang telur ayam 30 Phr (C1) dan penggunaan filler cangkang telur ayam 45 Phr (D1). Hasil penelitian menunjukkan bahwa cangkang telur ayam dapat digunakan sebagai filler pada pembuatan sol karet cetak. Penggunaan filler cangkang telur ayam yang semakin meningkat menghasilkan sol karet cetak dengan kekerasan yang cenderung semakin menurun, tegangan putus yang semakin menurun, ketahanan sobek yang semakin menurun dan ketahanan kikis yang semakin meningkat. Secara fisual sol karet cetak yang dihasilkan dari filler cangkang telur ayam menghasilkan sol karet cetak yang baik (tidak cacat berupa sobek, lubang, lepuh, retak dan goresan)

Altered Gut Microbiome in a Mouse Model of Gulf War Illness Causes Neuroinflammation and Intestinal Injury via Leaky Gut and TLR4 Activation

Many of the symptoms of Gulf War Illness (GWI) that include neurological abnormalities, neuroinflammation, chronic fatigue and gastrointestinal disturbances have been traced to Gulf War chemical exposure. Though the association and subsequent evidences are strong, the mechanisms that connect exposure to intestinal and neurological abnormalities remain unclear. Using an established rodent model of Gulf War Illness, we show that chemical exposure caused significant dysbiosis in the gut that included increased abundance of phylum Firmicutes and Tenericutes, and decreased abundance of Bacteroidetes. Several gram negative bacterial genera were enriched in the GWI-model that included Allobaculum sp. Altered microbiome caused significant decrease in tight junction protein Occludin with a concomitant increase in Claudin-2, a signature of a leaky gut. Resultant leaching of gut caused portal endotoxemia that led to upregulation of toll like receptor 4 (TLR4) activation in the small intestine and the brain. TLR4 knock out mice and mice that had gut decontamination showed significant decrease in tyrosine nitration and inflammatory mediators IL1β and MCP-1 in both the small intestine and frontal cortex. These events signified that gut dysbiosis with simultaneous leaky gut and systemic endotoxemia-induced TLR4 activation contributes to GW chemical-induced neuroinflammation and gastrointestinal disturbances

The acute effects of AICAR on purine nucleotide metabolism and postischemic cardiac function.

The purine precursor AICAR (5-amino-4-imidazolecarboxamide) has been advocated as a substrate for myocardial adenine nucleotide repletion during postischemic reperfusion. The purpose of this study was to investigate the acute effects of this agent on adenine nucleotides, inosine monophosphate, and postischemic ventricular function in an isolated rat heart preparation. The hearts were perfused at constant flow, either continuously for 90 minutes or for a 30 minute period followed by 10 minutes of global normothermic (37 degrees C) ischemia. The ischemic hearts were then reperfused for 15, 30, and 60 minutes. Both groups were treated with AICAR in a concentration of 100 mumol/L throughout the perfusion protocols. In the nonischemic time control group there was no effect on the levels of adenosine nucleotides or developed pressure over 90 minutes of perfusion. In contrast, AICAR treatment increased tissue inosine monophosphate content four-fold and sevenfold at 60 and 90 minutes, respectively (p less than 0.05), but had no effect on tissue adenosine monophosphate levels. During ischemia, there was a 50% decrease in adenosine triphosphate content in the AICAR-treated hearts and a thirteen-fold increase in adenosine monophosphate levels (p less than 0.05). After 60 minutes of reperfusion, adenosine triphosphate and monophosphate levels in the AICAR-treated hearts recovered to only 52% and 59% of preischemic values, respectively. These findings were similar to those observed in the untreated ischemic hearts. In contrast, tissue inosine monophosphate content in the AICAR-treated hearts during reperfusion remained significantly elevated and was fivefold greater than the reperfusion values in the untreated group. Concurrently, AICAR failed to enhance the recovery of postischemic left ventricular developed pressure. These results suggest that inhibition of the conversion of inosine monophosphate to adenosine monophosphate limits the usefulness of the agent in evaluating the temporal relationships between postischemic adenosine triphosphate repletion and recovery of myocardial function in the acute setting

Functional and metabolic evidence of enhanced myocardial tolerance to ischemia and reperfusion with adenosine.

An isolated, isovolumetrically contracting rat heart preparation, perfused at constant flow, was used to test the hypothesis that adenosine treatment (100 microM) throughout the experiment could enhance the repletion of adenosine triphosphate and the recovery of ventricular function following 10 minutes of global, normothermic (37 degrees C) ischemia. Left ventricular developed pressure was measured with an intraventricular balloon, and myocardial adenine nucleotides were measured from freeze-clamped tissues in a parallel series of experiments. The adenosine triphosphate level in the adenosine-treated hearts was not different from that of the untreated control hearts at the end of 30 minutes of equilibration but was significantly (p less than 0.05) higher at the end of 10 minutes of ischemia and at 15, 30, and 60 minutes of reperfusion. Left ventricular developed pressure in the adenosine-treated group at the end of 30 minutes of equilibration (92 +/- 3 mm Hg) was not significantly different from that of the control hearts (101 +/- 10 mm Hg). During the reperfusion period the control group returned to 75% +/- 7%, 73% +/- 6%, and 73% +/- 6% of the preischemic control function at 15, 30, and 60 minutes of reperfusion, respectively. The adenosine-treated group had significantly greater return of function to 86% +/- 3%, 96% +/- 3%, and 95% +/- 3% of the preischemic control at 15, 30, and 60 minutes of reperfusion, respectively. In a protocol to assess the effect of adenosine during ischemia, we found that adenosine (100 microM) increased the time to onset of ischemic contracture by 50% from 12 +/- 3 to 18 +/- 3 minutes and decreased the rate of net adenosine triphosphate degradation. Our data suggest that under these experimental conditions, adenosine enhances myocardial preservation by reducing the net degradation of adenosine triphosphate during ischemia and facilitating the repletion of adenosine triphosphate during reperfusion

Early Postnatal Manganese Exposure Reduces Rat Cortical and Striatal Biogenic Amine Activity in Adulthood.

Growing evidence from studies with children and animal models suggests that elevated levels of manganese during early development lead to lasting cognitive and fine motor deficits. This study was performed to assess presynaptic biogenic amine function in forebrain of adult Long-Evans rats exposed orally to 0, 25, or 50 mg Mn/kg/day over postnatal day 1-21 or continuously from birth to the end of the study (approximately postnatal day 500). Intracerebral microdialysis in awake rats quantified evoked outflow of biogenic amines in the right medial prefrontal cortex and left striatum. Results indicated that brain manganese levels in the early life exposed groups (postnatal day 24) largely returned to control levels by postnatal day 66, whereas levels in the lifelong exposed groups remained elevated 10%-20% compared with controls at the same ages. Manganese exposure restricted to the early postnatal period caused lasting reductions in cortical potassium-stimulated extracellular norepinephrine, dopamine, and serotonin, and reductions in striatal extracellular dopamine. Lifelong manganese exposure produced similar effects with the addition of significant decreases in cortical dopamine that were not evident in the early postnatal exposed groups. These results indicate that early postnatal manganese exposure produces persistent deficits in cortical and striatal biogenic amine function. Given that these same animals exhibited lasting impairments in attention and fine motor function, these findings suggest that reductions in catecholaminergic activity are a primary factor underlying the behavioral effects caused by manganese, and indicate that children exposed to elevated levels of manganese during early development are at the greatest risk for neuronal deficiencies that persist into adulthood

Early postnatal manganese exposure causes arousal dysregulation and lasting hypofunctioning of the prefrontal cortex catecholaminergic systems

Studies have reported associations between environmental manganese (Mn) exposure and impaired cognition, attention, impulse control, and fine motor function in children. Our recent rodent studies established that elevated Mn exposure causes these impairments. Here, rats were exposed orally to 0, 25, or 50 mg Mn/kg/day during early postnatal life (PND 1–21) or lifelong to determine whether early life Mn exposure causes heightened behavioral reactivity in the open field, lasting changes in the catecholaminergic systems in the medial prefrontal cortex (mPFC), altered dendritic spine density, and whether lifelong exposure exacerbates these effects. We also assessed astrocyte reactivity (glial fibrillary acidic protein, GFAP), and astrocyte complement C3 and S100A10 protein levels as markers of A1 proinflammatory or A2 anti-inflammatory reactive astrocytes. Postnatal Mn exposure caused heightened behavioral reactivity during the first 5 – 10 minute intervals of daily open field test sessions, consistent with impairments in arousal regulation. Mn exposure reduced the evoked release of norepinephrine (NE) and caused decreased protein levels of tyrosine hydroxylase (TH), dopamine (DA) and NE transporters, and DA D1 receptors, along with increased DA D2 receptors. Mn also caused a lasting increase in reactive astrocytes (GFAP) exhibiting increased A1 and A2 phenotypes, with a greater induction of the A1 proinflammatory phenotype. These results demonstrate that early life Mn exposure causes broad lasting hypofunctioning of the mPFC catecholaminergic systems, consistent with the impaired arousal regulation, attention, impulse control, and fine motor function reported in these animals, suggesting that mPFC catecholaminergic dysfunction may underlie similar impairments reported in Mn-exposed children