Effects of Low- and High-Dose Valproic Acid and Lamotrigine on the Heart in Female Rats.

Epilepsy is a chronic neurological disease that affects more than 50 million people worldwide. Antiepileptic drugs (AEDs) are the mainstay of treatment for most patients with epilepsy. However, AEDs have been reported to be associated with adverse cardiac effects. In this study, it was aimed to investigate the possible cardiac effects of low-dose (LD) and high-dose (HD) treatment of valproic acid (VPA) and lamotrigine (LTG), which are commonly used AEDs, in rats without epilepsy. Rats were randomly grouped as control, LD-VPA, HD-VPA, LD-LTG, and HD-LTG. The cardiac effects of AEDs were evaluated using immunohistological, biochemical, and hemodynamic parameters. A dose-dependent increase in the intensity of caspase-3 staining was detected in the VPA and LTG groups. The intensity of connexin-43 and troponin-T staining in the VPA groups and desmin staining in the LTG groups was significantly reduced. Biochemically, HD-VPA and HD-LTG administrations caused a significant increase in MDA level in myocardial tissue. In addition, as a result of hemodynamic evaluations, cardiac functions were found to be affected and blood pressure increased in HD-LTG group. The results of present study support that VPA and LTG treatment can increase cardiac risk markers.

Protective effect of starch-stabilized selenium nanoparticles against melamine-induced hepato-renal toxicity in male albino rats.

Melamine and its analogues are illegally added to raise the apparent protein content in foods. The elevated concentrations of these compounds cause adverse effects in humans and animals. In this contribution, the protective effects of the synthesized starch-stabilized selenium nanoparticles (Se-NPs@starch) on melamine-induced hepato-renal toxicity have been systematically investigated. The Se-NPs@starch were characterized by X-ray photoelectron spectroscopy (XPS) analysis, energy dispersive spectroscopy (EDS) mapping analysis, TEM, and FT-IR. Starch plays a crucial role in the stabilization and dispersion of Se NPs, as noticed from the TEM and EDS investigations. Furthermore, the atomic ratio of Se distribution over the starch surface is approximately 1.67%. The current study was conducted on four groups of adult male rats, and the oral daily treatments for 28 days were as follows: group I served as control, group II received Se-NPs@starch, group III was exposed to melamine, while group IV was treated with melamine and Se-NPs@starch. The results reveal a significant alteration in the histoarchitecture of both hepatic and renal tissues induced by melamine. Furthermore, elevated liver and kidney function markers, high malondialdehyde, and increased expression levels of apoptosis-related genes besides a reduction in GSH and expression levels of antioxidant genes were observed in the melamine-exposed group. Interestingly, the administration of the Se-NPs@starch resulted in remarkable protection of rats against melamine-induced toxicity through increasing the antioxidant capacity and inhibiting oxidative damage. Collectively, this study provides affordable starch-stabilized Se-NPs with potent biological activity, making them auspicious candidates for prospective biomedical applications.

Wild garlic extract reduces lipid peroxidation in terbuthylazine-treated human erythrocytes.

Background: Among other negative effects, herbicides induce oxidative stress, leading to lipid peroxidation and protein oxidation. Therefore, there is a growing need to identify natural compounds with sufficient antioxidant capacity and mitigate the negative effects of herbicides without side effects.Objective: Our study aimed to examine the protective effect of the phenolic extract of wild garlic (WG) leaves on terbuthylazine-treated erythrocytes.Material and methods: In human erythrocytes treated with the herbicide terbuthylazine (4.5 mg/L) alone and a combination of terbuthylazine and WG extract, we measured malondialdehyde (MDA) and haemoglobin (Hb) concentrations and the antioxidant activities of CuZn superoxide dismutase (SOD1; EC 1.15.1.1) and catalase (CAT; EC 1.11.1.6) in vitro.Results: In comparison with terbuthylazine, WG extract reduced the concentrations of MDA and Hb from 59.69 to 43.45 nmol/gHb (27%, p < 0.001) and 165.08 to 128.64 g/L (22%, p < 0.05), respectively. Catalase activity was induced for samples treated with both WG extract and terbuthylazine compared with terbuthylazine alone (p < 0.05).Conclusions: The results demonstrated that WG may reduce the toxicity of terbuthylazine, and the erythrocyte membrane may be the primary site of phenolic action. Therefore, the lipid peroxidation intensity could be a biomarker of oxidative damage caused by terbuthylazine and the protective effect of WG.

The ameliorative effect of nanoselenium on histopathological and biochemical alterations induced by melamine toxicity on the brain of adult male albino rats.

Melamine is a chemical substance used as a food adulterant because of its high nitrogen content; it is known to induce neurotoxicity, thereby adversely affecting the central nervous system. The biocompatibility, bioavailability, lower toxicity, and the large surface area of nanosized selenium relative to its other forms indicate that selenium nanoparticles (SeNPs) have a potential ameliorative effect against melamine-induced neurotoxicity. In this study, we tested this hypothesis using 40 adult male albino rats that were randomly assigned into four groups (n = 10 per group): group I rats served as the untreated negative controls and were fed with standard diet and distilled water; group II rats were orally treated with melamine (300 mg/kg body weight/d); group III rats orally received melamine (300 mg/kg body weight/d) and SeNPs (2 mg/kg body weight/d); and group IV rats received SeNPs only (2 mg/kg body weight/d) for 28 days. Blood and brain samples were collected from all rats and processed for biochemical, histopathological, and immunohistochemical investigations. SeNPs were encapsulated in starch as a natural stabilizer and a size-controlling agent (SeNP@starch). The prepared SeNPs were characterized using different techniques. Inductively coupled plasma-optical emission spectrometry (ICP-OES) indicated that the percentage of selenium loaded in starch was 1.888 %. Powder x-ray diffractometer (XRD) was used to investigate the crystalline structure of the Se-NP@starch, to be tubular and composed of amorphous starch as well as metallic selenium. Thermogravimetric analysis confirmed the thermal stability of the product and determined the interactions among the different components. Transmission electron microscope demonstrated the spherical shape of SeNPs and their dispersion into starch surface as well as evaluating their size in nanoscale (range 20-140 nm). Our results revealed that the melamine- exposed rats had significantly elevated in malondialdehyde levels, significantly reduced in total antioxidant capacity, down-regulated expression of the antioxidant related genes Nrf2 (nuclear factor erythroid 2-related factor 2) and GPx (glutathione peroxidase), as well as up-regulated expression of the apoptosis-related gene Bax (B-cell lymphoma 2-associated X protein), with down regulation of Bcl-2 (B-cell lymphoma 2). Histopathological examination exhibited several alterations in the cerebrum, cerebellum, and hippocampus of the treated rats compared with the controls. Neuronal degeneration, vacuolation of the neuropils, and pericellular and perivascular spaces were observed. In addition, the pyramidal and granular cell layers of the hippocampus and cerebellum, respectively, were found to have significantly reduced thickness. Furthermore, a significant decrease in the percentage area of the glial fibrillary acidic protein and a significant increase in the percentage area of caspase-3 were noted. On the other hand, co-treatment with SeNPs partially ameliorated these alterations. A significant reduction in malondialdehyde levels; a non- significant elevation in total antioxidant capacity; up-regulation, upregulation of Nrf2, GPx, and Bcl-2 and downregulation of Bax were recorded. Neuronal degeneration, vacuolation of neuropils, and pericellular spaces were reduced. The pyramidal and granular cell layers restored their normal thickness. The percentage area of the glial fibrillary acidic protein significantly increased, whereas that of caspase-3 significantly decreased. In conclusion, SeNPs have an ameliorative effect against melamine-induced neurotoxicity in albino rats.

Prevention of melamine-induced hepatorenal impairment by an ethanolic extract of Moringa oleifera: Changes in KIM-1, TIMP-1, oxidative stress, apoptosis, and inflammation-related genes.

BACKGROUND/AIMS: Melamine (ML) is a common food adulterant and contaminant. Moringa oleifera is a well-known medicinal plant with many beneficial biological properties. This study investigated the possible prophylactic and therapeutic activity of an ethanolic extract of M. oleifera (MEE) against ML-induced hepatorenal damage. METHOD: Fifty male Sprague Dawley rats were orally administered distilled water, MEE (800 mg/kg bw), ML (700 mg/kg bw), MEE/ML (prophylactically) or MEE+ML (therapeutically). Hepatic aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphate (ALP) in serum were measured. Serum total bilirubin, direct bilirubin, indirect bilirubin, protein, albumin, and globulin contents were also assayed, and urea and creatinine levels were determined. Moreover, antioxidant enzyme activity of glutathione peroxidase (GPx) and catalase (CAT) in serum levels were quantified. Complementary histological and histochemical evaluation of renal and hepatic tissues was conducted, and expression of oxidative stress (GPx and CAT) and apoptosis-related genes, p53 and Bcl-2, in hepatic tissue were assessed. In parallel, transcriptional expression of inflammation and renal injury-related genes, including kidney injury molecule 1 (KIM-1), metallopeptidase inhibitor 1 (TIMP1), and tumor necrosis factor alpha (TNF-α) in the kidney tissue were determined. RESULTS: ML caused significant increases in serum levels of ALT, AST, ALP, total bilirubin, direct bilirubin, indirect bilirubin, urea, and creatinine. Further, ML treated rats showed significant reductions in serum levels of protein, albumin, globulin, GPx, and CAT. Distinct histopathological damage and disturbances in glycogen and DNA content in hepatic and renal tissues of ML treated rats were observed. KIM-1, TIMP-1, and TNF-α gene expression was significantly upregulated in kidney tissue. Also, GPx, CAT, and Bcl-2 genes were significantly downregulated, and p53 was significantly upregulated in liver tissue after ML treatment. MEE significantly counteracted the ML-induced hepatorenal damage primarily for co-exposed rats. CONCLUSION: MEE could be an effective therapeutic supplement for treatment of ML-induced hepato-renal damage, probably via modulating oxidative stress, apoptosis, and inflammation.

Detecting effects of herbicide runoff: The use of Cassiopea maremetens as a biomonitor to hexazinone.

Herbicides are an integral part of global agricultural activity but can be advected into local drainages that can discharge to coastal marine systems. Herbicide runoff can impact coastal marine organisms, including those associated with coral reefs and coastal mangrove forests. In this study, the symbiotic sedentary jellyfish Cassiopea maremetens were exposed to analytical grade hexazinone to determine their sensitivity and potential for recovery after exposure to a press herbicide event of 14 days followed by a recovery period of matching duration. Bell surface area, photosynthetic yield (i.e. effective quantum yield, EQY), statolith count and zooxanthellae density were analyzed. Most metrics demonstrated significant decreases when exposed to higher concentrations of hexazinone, while EQY was significantly decreased at exposure concentrations from 31 µg/L hexazinone and above. In contrast, zooxanthellae density (cells/mm2) increased in the highest concentrations compared to control animals. At the end of the exposure period the EC50 for bell surface area, EQY, and statolith count were 176 µg/L, 81.96 µg/L, and 304.3 µg/L, respectively. Jellyfish were able to recover to similar start values for all measured metrics at the end of the 14-day recovery period, with EQY showing recovery by Day 7 of the recovery period. This study demonstrated that statolith counts as an estimate of age were not affected by herbicides. We conclude that the depressed metrics from herbicide related impacts of C. maremetens are effective indicators of a relatively recent herbicide perturbation in that the recovery timeframe for these jellyfish is relatively short.

Melamine and curcumin enriched diets modulate the haemato-immune response, growth performance, oxidative stress, disease resistance, and cytokine production in oreochromis niloticus.

Currently, feed adulteration and contamination with melamine (MEL) are considered one of the serious issues in the aquatic industry. With the limited studies of MEL exposure alone in fish, its adverse impacts on fish cannot be evaluated well. Accordingly, this study aimed to investigate the effects of MEL containing diets on the immune response, disease resistance to Aeromonas hydrophila, growth performance, chemical composition, immune-related genes expression, and histopathology of both spleen and head kidneys. Also, the efficacy of curcumin (CUR) dietary supplementation to alleviate MEL negative impacts were evaluated. A total of 180 apparently healthy Oreochromis niloticus (O. niloticus) were divided into four groups with three replicates fed the basal diet only, basal diet fortified with 200 mg/kg CUR, basal diet containing 1 % MEL, or a basal diet containing CUR + MEL. The results displayed that MEL significantly reduced growth performance indices and body crude lipid contents. Anemic, leukopenic, lymphocytopenic, heterocytopenic, esonipenic, hypoproteinemic and hypoalbuminic conditions were apparent. Moreover, depleted immune and antioxidant indicators including lysozyme activity, nitric oxide, immunoglobulin M, complement 3, glutathione peroxidase, and superoxide dismutase enzyme activity were recorded. Also, MEL reduced the disease resistance of O. niloticus to bacterial infection. Furthermore, MEL induced downregulation of mRNA levels of interleukin 1ß and tumor necrosis factor α in the spleen together with obvious pathological perturbations in both spleen and head kidneys. The CUR addition resulted in a significant enhancement in most indices. These results may conclude that MEL could alter both innate and adaptive immune responses via the negative transcriptional effect on immune-related genes together with the oxidative damage of the immune organs. Furthermore, CUR dietary supplements could be advantageous for mitigating MEL negative impacts, thus offering a favorable aquafeed additive for O. niloticus.

Palliative effects of Moringa olifera ethanolic extract on hemato-immunologic impacts of melamine in rats.

Melamine (MEL) is a widespread food contaminant and adulterant. Moringa olifera is a widely known medicinal plant with various pharmacological properties. Herein, this study aimed to investigate, for the first time, the probable protective or therapeutic role of M. olifera ethanolic extract (MOE) against MEL induced hemato-immune toxic hazards. Fifty Sprague Dawely male rats were orally treated with distilled water, MOE (800 mg/kg bw), MEL (700 mg/kg bw), MOE/MEl or MOE + MEl. Erythrogram and leukogram profiling were evaluated to assess hematological status. Innate immune functions were evaluated via measuring lysozyme levels, nitric oxide concentration, and bactericidal activity of phagocytes. Serum immunoglobulin levels were estimated as indicators of humoral immunity. Histologic and immunohistochemical evaluations of splenic tissues were also performed. The results indicated that MEL caused a significant decline in RBC, Hb, PCV, total WBC, neutrophil, lymphocyte, phagocytes bactericidal activity, lysozyme activity, nitric oxide, total IgM and IgG levels. Also, MEL induced various pathologic lesions in the spleen with strong expression of CD4 and CD8 positive cells. MOE significantly counteracted the former anaemic, leucopenic, innate and humoral depressant effects of MEL particularly at co-exposure. In conclusion, these findings revealed that MOE could be candidate therapy against MEL hemato-immunotoxic impacts.

Reproductive toxicity of melamine against male mice and the related mechanism.

Melamine is a nitrogen-containing heterocyclic organic compound with a triazine skeleton, which has been widely applied in industrial and chemical fields. Previous toxicity studies of melamine mainly focused on renal toxicity and hepatic pathological changes, but its toxicity against the reproductive system has seldom been assessed. We investigated the effects of melamine on the reproductive system of male mice. Forty healthy male Kunming mice were randomly divided into a normal saline negative control group, a low-dose melamine group, a medium-dose melamine group and a high-dose melamine group (n = 10). The mice were administered for five consecutive days and killed on the 35th day after first administration. In melamine administration groups, seminiferous tubules had disordered, loose arrangement, and spermatogenic cells at all levels obviously decreased. The sperm count and motility decreased significantly, and the sperm deformity rate increased significantly. Melamine induced apoptosis of testicular spermatogenic cells. To further explore the mechanism, we detected metabolism-related enzymes sorbitol dehydrogenase (SDH) and lactate dehydrogenase (LDH) as well as oxidative stress indices superoxide dismutase (SOD) and malondialdehyde (MDA). The activities of SDH, LDH and SOD in melamine treatment groups decreased significantly, and the MDA level increased obviously. The expressions of apoptosis-related proteins Bcl-2, Bax and caspase-3 were detected by immunohistochemistry. The expression of Bcl-2 significantly increased, but those of Bax and caspase-3 significantly reduced (p < 0.05). In conclusion, melamine damaged the reproductive system of mice via the oxidative stress pathway and by inducing cell apoptosis.

Identification of Atuveciclib (BAY†1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer.

Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.

Melamine contamination in nutritional supplements--Is it an alarm bell for the general consumer, athletes, and 'Weekend Warriors'?

BACKGROUND: Nutritional supplements are used or experimented with by consumers, notably these are; competitive and recreational athletes of all ages, and 'weekend warriors'. As a consequence the supplement industry has grown to meet the increasing demand. A Global Industry Analysts Inc. report indicates that the herbal supplement market has not declined during the worldwide recession, but in fact exhibited steady growth over the period 2008 to 2009. It is anticipated that the market will reach US$93.15 billion by the year 2015. These supplements may contain adulterated substances that may potentially have harmful short - and long-term health consequences to the consumer. "Scrap Melamine" is such an example, which has been implicated in the kidney failure and death of several cats, dogs and pigs. In China in 2008, reports described very severe health effects in infants and young children. At the time over 294,000 infants were screened and diagnosed with urinary tract stones and sand-like calculi associated with melamine in milk products, of which 50,000 infants were hospitalised, and at least six associated deaths, recorded. The extent that melamine contamination occurs in nutritional supplements is not known. Therefore, the aim of this study was to determine whether commercially available nutritional and traditional supplement products contain melamine, even though they are not declared by the manufacturer on the product label. METHODS: A total of 138 nutritional supplements products were obtained from (i) direct purchases from shops, pharmacies and outlets, (ii) directly from consumers, and (iii) from suppliers, manufacturers and distributors. The products were laboratory analysed for melamine, using Tandem Liquid Chromatography Mass Spectrometry. RESULTS: Forty-seven % of all the products (n = 138) tested positive for melamine. Eight-two % of the South African produced products (n = 27) tested positive and 58 % of the products imported into South Africa (n = 50) tested positive. The median concentration estimate for melamine in the products tested were, 6.0 µg/g for the 138 supplements tested, 8.9 µg/g for South African produced products, and 6.9 µg/g for products imported into South Africa. CONCLUSION: The melamine (undeclared on product label) levels detected in the nutritional supplements products investigated were within the Tolerable Daily intake (TDI) limit guidelines of 200 µg/g as set by WHO and others. Melamine over exposure within the context of the nutritional supplements consumption in the products investigated should not be of concern to the consumer provided the recommended guidelines of daily product use are adhered to. Further investigation is warranted to determine, (i) the link of melamine as (part) substitute for the perceived total declared protein content on the product label, (ii) cyanuric and uric acid presence in the supplement products that could form chemical-complex formation with melamine and/or analogues that could cause adverse health effects.

Anti-nephrolithic potential of catechin in melamine-related urolithiasis via the inhibition of ROS, apoptosis, phospho-p38, and osteopontin in male Sprague-Dawley rats.

The addition of melamine to infant formula may cause urolithiasis in humans and animals. This study examined the effects of catechin, an antioxidant, on melamine-cyanuric acid mixture (MCM)-induced crystallization in vitro and in vivo. In an in vitro study, crystal formation induced by an MCM was evaluated in media under various pH conditions and with catechin co-treatment. In an in vivo study, rats were administered an MCM (400 mg/kg, 1:1, via oral feeding tube) for four weeks and co-treated with catechin, after which crystal formation was observed. Oxidative stress biomarkers and nephrotoxicity were measured. Apoptotic cells were examined using the TUNEL assay. Phospho-p38 and osteopontin were evaluated via immunohistochemistry and Western blotting. MCM-induced crystal formation was pH-dependent in conditioned media, and catechin reduced the overall number of crystals. In the in vivo study, catechin suppressed MCM-induced protein expression and apoptosis in rats. Catechin consistently reduced the MCM-mediated production of renal malondialdehyde (MDA) and urinary 8-isoprostane (8-IP) in MCM-treated rats. The activities of antioxidant enzymes such as superoxide dismutase (SOD) were enhanced by catechin. Catechin consistently and significantly reduced levels of renal crystals and nephrotoxicity. Our findings suggest that catechin exhibits anti-nephrolithic potential by chemically inhibiting the formation of crystals and by inhibiting reactive oxygen species, apoptosis, phospho-P38, and osteopontin signaling in rats.

Genotoxicity assessment of melamine in the in vivo Pig-a mutation assay and in a standard battery of assays.

The genotoxicity of melamine was evaluated with the combined Pig-a mutation/micronucleus assay, the bacterial reverse mutation assay, and the in vitro cytokinesis-block micronucleus assay (CBMN). Five groups of six- to eight-week-old male Sprague-Dawley (SD) rats were given three daily doses of vehicle control (100% pure sesame oil), melamine (500, 1000, and 2000 mg/kg) or positive control (N-ethyl-N-nitrosourea, ENU, 20 mg/kg) by oral gavage. Peripheral blood was sampled pre-dose (day -1) and at time points up to day 60. Pig-a mutant frequencies were determined in total red blood cells (RBCs) and reticulocytes (RETs) as RBC(CD59-) and RET(CD59-) frequencies, on days -1, 15, 29 and 60, and micronucleus frequencies were measured in RETs on day 4. No significant increases in RBC(CD59-) or RET(CD59-) frequencies were observed for the melamine-treated group at any of the time points studied, but the positive control, ENU, induced statistically significant increases compared with the vehicle control. Similar results were obtained in the micronucleus assay. Melamine did not induce statistically significant increases in %MN-RET. In the bacterial reverse mutation assay, melamine was tested from 62.5 to 1000 µg/plate in tester strains TA97a, TA98, TA100, TA102, and TA1535, with and without metabolic activation, and no evidence of toxicity or mutagenicity was observed at any dose tested. In the in vitro CBMN assay, in Chinese hamster ovary (CHO) cells, melamine was tested (75, 150, and 300 µg/mL) in the presence and absence of S9 mix, and no positive increases in the number of cells containing micronuclei were seen. These results suggest that melamine does not exhibit significant genotoxic potential. These data could be valuable for risk assessment purposes and also for further characterizing the new in vivoPig-a gene mutation assay.

The protective role of bee honey against the toxic effect of melamine in the male rat kidney.

This study aimed to test the protective role of natural bee honey against melamine toxicity in the kidney of male albino rats. The dietary supplementation of melamine at a dose of 20,000 ppm for 28 days induced renal dysfunction, as reflected by a significant increase in kidney function parameters (urea, creatinine, and uric acid) and an increase in potassium levels. In addition, a decrease in catalase and glutathione-S-transferase and an increase in lipid peroxide in the kidney tissue homogenate were also observed. Histological changes in the melamine-treated group revealed hyperplasia and damage in kidney cells and the accumulation of melamine crystals in kidney tissues. Honey treatment for 28 days in rats concurrently administered melamine at a dose of 2.5 g/kg body weight for 28 days improved the kidney function, increased antioxidant enzymes, and decreased lipid peroxide levels. The morphology of the kidney cells of the melamine-fed rats was also improved as a result of honey treatment. In conclusion, this study revealed that natural bee honey protects the kidney against the adverse effects induced by melamine toxicity in male albino rats.

Early pregnancy agricultural pesticide exposures and risk of gastroschisis among offspring in the San Joaquin Valley of California.

BACKGROUND: Prevalence of gastroschisis has inexplicably been increasing over the past few decades. Our intent was to explore whether early gestational exposures to pesticides were associated with risk of gastroschisis. METHODS: We used population-based data, accompanied by detailed information from maternal interviews as well as information on residential proximity to a large number of commercial pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley of California (). Cases were 156 infants/fetuses with gastroschisis and controls were 785 infants without birth defects. RESULTS: Among 22 chemical pesticide groups analyzed, none had an elevated odds ratio with an associated confidence interval that excluded 1.0, although exposure to the triazine group showed borderline significance. Among 36 specific pesticide chemicals analyzed, only exposure to petroleum distillates was associated with an elevated risk, odds ratio = 2.5 (1.1-5.6). In general, a substantially different inference was not derived when analyses were stratified by maternal age or when risk estimation included adjustment for race/ethnicity, body mass index, folic acid supplement use, and smoking. CONCLUSION: Our study rigorously adds to the scant literature on this topic. Our a priori expectation was that we would observe certain pesticide compounds to be particularly associated with young age owing to the disproportionate risk observed for young women to have offspring with gastroschisis. We did not observe an exposure profile unique to young women.

Toxicity of pesticides associated with potato production, including soil fumigants, to snapping turtle eggs (Chelydra serpentina).

Turtles frequently oviposit in soils associated with agriculture and, thus, may be exposed to pesticides or fertilizers. The toxicity of a pesticide regime that is used for potato production in Ontario on the survivorship of snapping turtle (Chelydra serpentina) eggs was evaluated. The following treatments were applied to clean soil: 1) a mixture of the pesticides chlorothalonil, S-metolachlor, metribuzin, and chlorpyrifos, and 2) the soil fumigant metam sodium. Turtle eggs were incubated in soil in outdoor plots in which these mixtures were applied at typical and higher field application rates, where the eggs were subject to ambient temperature and weather conditions. The pesticide mixture consisting of chlorothalonil, S-metolachlor, metribuzin, and chlorpyrifos did not affect survivorship, deformities, or body size at applications up to 10 times the typical field application rates. Hatching success ranged between 87% and 100% for these treatments. Metam sodium was applied at 0.1¯ times, 0.3¯ times, 1 times, and 3 times field application rates. Eggs exposed to any application of metam sodium had 100% mortality. At typical field application rates, the chemical regime associated with potato production does not appear to have any detrimental impacts on turtle egg development, except for the use of the soil fumigant metam sodium, which is highly toxic to turtle eggs at the lowest recommended application rate.

Screening of the toxic effects of a high melamine dose on the biochemical hematological and histopathological investigations in male rats.

Screening of the toxic effect of a high oral melamine dose (30,000 ppm supplemented in the diet) was performed for 28 days on male rats. The morphology, anatomy, complete blood count (CBC), serum electrolytes, kidney function, serum proteins, serum bilirubin, serum liver enzymes, catalase, glutathion-S-transferase, lipid peroxide, serum melamine concentration, total body weight, food intake, food efficiency ratio (FER), body weight gain percentage (BWG%), body weight gain, water consumption, and histopathological examinations of kidney, urinary bladder, testis, liver, heart, and spleen were investigated. The melamine-supplemented rats turned yellow and showed different degrees of hypertrophy and congestion, particularly the kidney and the ureter as a result of melamine toxicity. The CBC showed minimal changes in the melamine-supplemented groups. Na and Cl were decreased, whereas K, P, and Ca were increased. Serum creatinine, uric acid, and urea were elevated. Liver function enzymes were nonsignificantly affected. Catalase and glutathion-S-transferase were decreased, whereas lipid peroxide was increased in the kidney tissue homogenate. It was also noted that serum protein was decreased and serum bilirubin was increased. Histopathologically, most examined organs were severely injured specially the kidneys, liver, and testes.

Diaryltriazine non-nucleoside reverse transcriptase inhibitors are potent candidates for pre-exposure prophylaxis in the prevention of sexual HIV transmission.

OBJECTIVES: Pre-exposure prophylaxis and topical microbicides are important strategies in the prevention of sexual HIV transmission, especially since partial protection has been shown in proof-of-concept studies. In search of new candidate drugs with an improved toxicity profile and with activity against common non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV, we have synthesized and investigated a library of 60 new diaryltriazine analogues. METHODS: From this library, 15 compounds were evaluated in depth using a broad armamentarium of in vitro assays that are part of a preclinical testing algorithm for microbicide development. Antiviral activity was assessed in a cell line, and in primary human cells, against both subtype B and subtype C HIV-1 and against viruses resistant to therapeutic NNRTIs and the candidate NNRTI microbicide dapivirine. Toxicity towards primary blood-derived cells, cell lines originating from the female reproductive tract and female genital microflora was also studied. RESULTS AND CONCLUSIONS: We identified several compounds with highly potent antiviral activity and toxicity profiles that are superior to that of dapivirine. In particular, compound UAMC01398 is an interesting new candidate that warrants further investigation because of its superior toxicity profile and potent activity against dapivirine-resistant viruses.

The reproductive toxicity of melamine in the absence and presence of cyanuric acid in male mice.

Melamine, a chemical compound, was used widely in the manufacture of amino resins and plastics. Cyanuric acid related structurally to melamine was used as a water stabilizer in swimming pools. The combination of melamine and cyanuric acid was thought to be responsible for renal impairment in mammals. In the present work, we investigated the reproductive toxicity of melamine in the absence and presence of cyanuric acid in male mice. Pathological damages in different degrees were observed in the testis of male mice treated with different doses of both melamine alone and combination of melamine and cyanuric acid in a dose-dependent manner. Based on the TUNEL assay, the mice treated with high dose of melamine (50 mg/kg/day) had a significant increase in apoptotic index of spermatogenic cells (p<0.05) compared with the control group. Sperm abnormality test indicated that melamine alone resulted in abnormal sperm morphology. The mice from co-administration groups of melamine and cyanuric acid were not eating, and were most likely in renal failure. The combined exposure to melamine and cyanuric acid was revealed to have certain toxic effects on testis of male mice at a relative low dose (each at 1 mg/kg/day). Also, in comparison to melamine treated groups, more severe apoptosis was observed in co-administration groups of melamine and cyanuric acid with both middle (each at 5 mg/kg/day) and high doses (each at 25 mg/kg/day). However, all mice administrated with combination of melamine and cyanuric acid (each at 206, 412, or 824 mg/kg/day) died before day 6 from which no data were obtained on sperm abnormality. These results from this study demonstrated that melamine had certain toxic effects on testes of male mice, especially when ingested in high concentration. These results might be useful in evaluating the toxicity of melamine on reproductive system of male animal, and they also would be a supplement to the existing toxic profile of melamine.

Nutritional chemoprevention of urinary tract tumors (UTT) induced by lithogenic agents: risk for UTT in children exposed to melamine-contaminated milk formulas.

Urinary tract tumors are tenth in frequency, and many environmental carcinogens are excreted by urine. Interplay between chronic inflammatory urolithiasis and urothelial carcinogenesis is not well understood. Experimental evidences show that dietary melamine induce these events even at low concentrations. This is important because thousands of children were exposed to melamine through intentionally contaminated milk formula worldwide. We propose that an increased risk for urinary tumors in adult life may occur and screenings for early urinary signs may be necessary. Therefore, urothelial biology, melamine carcinogenic potential, and related epidemiology are discussed, recommending a preventive dietary polyunsaturated fatty acid-based supplementation, since they modulate such interplay in rodents.