Xenoestrogens are chemical pollutants that can disrupt the endocrine system of animals by binding to and activating the estrogen receptor(s). They include both natural and synthetic steroid estrogens, together with a variety of estrogen mimicking chemicals such as 4-nonylphenol, bisphenol A and various pesticides. In vertebrates, estrogens play a fundamental role in reproduction, in somatic cell function, the regulation of calcium and water homeostasis. Exposure to xenoestrogens may therefore have unscheduled effects on these systems that can potentially compromise species survival. With the ever-increasing number of xenoestrogens identified and detected in the environment, together with the fact that they are seldom detected alone, there is a need to develop specific and sensitive biomarkers to detect estrogenic activity of chemicals in the environment when present alone and in mixtures. In this study, the effect of selected xenoestrogens was assessed using an in-vitro yeast estrogen screen (YES) both individually and in mixtures and in-vivo in a native fish species, the Murray rainbowfish (Melanotaenia fluviatilis).

<p>   </p> <p>Copper (Cu) dyshomeostasis in the brain, especially Cu overload, has been associated with neurodegenerative disorders such as Alzheimer’s disease (AD). Brain Cu levels are partly regulated by the choroid plexus (CP), a tissue that forms a barrier between the blood and cerebrospinal fluid (CSF) and is rich in Cu-transporting proteins. Literature data have shown that ADP-ribosylation factor 1 (ARF1) plays a role in regulating cellular Cu homeostasis; yet its presence and function in the blood-CSF barrier was unknown. The main purpose of the project was to prove the presence of ARF1 in the CP and explore its possible function with regards to Cu regulation. Since the CP is known to accumulate toxic metal lead (Pb) from human and animal studies, the project also aimed to test whether Pb exposure caused CSF Cu dyshomeostasis through disrupting ARF1-mediated Cu regulatory mechanism. Using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), our data clearly demonstrated that ARF1 was highly enriched in the choroidal epithelial Z310 cells and expressed in CP tissues. Acute Pb exposure in mice (one ip. dose at 27 mg Pb/kg followed by tissue dissection 24 hrs later) significantly increased ARF1 expression in the CP as compared to saline-injected controls, suggesting a high responsiveness of the protein to Pb exposure. In the subsequent chronic study, mice were exposed to Pb via drinking water at 200ppm (low-dose) or 800ppm (high-dose) at libitum for 4 weeks (control group had sodium in drinking water). Atomic absorption spectrometry (AAS) analyses verified a dose-dependent Pb accumulation in the CP. Importantly, Cu concentrations in the CSF displayed a Pb dose-dependent increase as compared to controls. IHC data further revealed an altered ARF1 expression in the choroidal epithelia in chronic Pb exposed animals. Further knocking down ARF1 expression in choroidal epithelial Z310 cells using in vitro Arf1-targeting siRNA transfection approach revealed a decreased Cu level in cells, suggesting a critical role of ARF1 in cellular Cu regulation. In choroidal epithelial cells exposed to Pb in culture medium, a down-regulated ARF1 expression partly reversed Pb-induced Cu overload. Taken together, this study provides first-hand evidence to support the presence of ARF1 in the blood-CSF barrier. Further, our data demonstrate that Pb exposure causes Cu overload in the CSF, which is likely mediated by an altered expression of ARF1 in the blood-CSF barrier.</p>

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / O expectorante MelagriÃo à um fitoterÃpico composto de seis plantas medicinais com conhecida aÃÃo no trato respiratÃrio: Mikania glomerata, Cephaelis ipecacuanha, Aconitum napellus, Polygala senega, Myroxylon balsamum e Nasturtium officinale. O objetivo desse estudo foi avaliar a seguranÃa, o potencial genotÃxico do MelagriÃo em voluntÃrios sadios e sua eficÃcia terapÃutica em pacientes com diagnÃstico clÃnico de bronquite aguda. Este estudo contemplou dois protocolos clÃnicos: no protocolo A foi avaliado a Toxicologia ClÃnica e seguranÃa do MelagriÃo que consistiu de um estudo duplo-cego, controlado por placebo, randomizado e paralelo, com 46 voluntÃrios, adultos, que foram aleatoriamente distribuÃdos em dois grupos: MelagriÃo e Placebo ambos constituÃdos por 28 e 18 voluntÃrios, respectivamente. Os voluntÃrios foram tratados durante 28 dias ininterruptos com 120 mL de MelagriÃo ou Placebo dividido em 4 doses diÃrias. AvaliaÃÃes clÃnica e laboratorial foram realizadas no prÃ-estudo, durante o perÃodo de tratamento, bem como apÃs o encerramento do estudo. A genotoxicidade do MelagriÃoÂ, por sua vez, foi investigada mediante o emprego do teste do cometa. A idade mÃdia dos voluntÃrios foi de 19,37  17,36 anos para o grupo MelagriÃo e de 24,70  23,50, para o grupo Placebo. As funÃÃes hematolÃgica, hepÃtica, renal e metabÃlica foram analisadas, antes, durante (7o, 14o e 28o dia) e 7 dias apÃs o estudo atravÃs dos exames laboratoriais, os quais nÃo evidenciaram sinais de toxicidade. Cefaleia, vÃmito, dor abdominal, tosse seca, sonolÃncia, diarrÃia, flatulÃncia, pirose e insÃnia foram os eventos adversos atribuÃdos aos dois grupos. Pelo teste do cometa, nÃo foram observados danos (p>0,05) nos linfÃcitos perifÃricos dos voluntÃrios tratados com o MelagriÃoÂ. Os estudos de toxicologia clÃnica e genotoxicidade nÃo evidenciaram nenhuma toxicidade nos voluntÃrios tratados por 28 dias ininterruptos com o MelagriÃoÂ. Jà o protocolo B consistiu de um estudo duplo-cego, randomizado e paralelo, com 86 pacientes. Os quais foram aleatoriamente distribuÃdos em dois grupos: MelagriÃo ou Bromexina constituÃdos por 43 voluntÃrios em cada grupo. Os voluntÃrios foram tratados durante 7 dias consecutivos, utilizando posologia de acordo com grupo e idade. AvaliaÃÃes clÃnica foram realizadas no prÃ-estudo e no sÃtimo dia, e laboratorial somente no prÃ-estudo. A idade mÃdia dos voluntÃrios foi de 19,37  17,36 anos para o grupo MelagriÃo e de 24,70  23,50, para o grupo Bromexina. Resultados do Protocolo B mostram equivalÃncia entre as formulaÃÃes testadas, nÃo sendo evidenciadas diferenÃas clÃnicas e estatÃsticas dentro dos parÃmetros avaliados, sendo, portanto o fitomedicamento MelagriÃo eficaz no tratamento da bronquite aguda. VÃmito, dor abdominal e febre foram os eventos adversos atribuÃdos aos dois grupos. O MelagriÃo demonstrou seguranÃa na dose terapÃutica, carÃter genotÃxico negativo e eficaz na melhora dos sinais e sintomas da bronquite aguda. / The expectorant MelagriÃo is a phytotherapic medicine composed of six medicinal plants with known action in the respiratory tract: Mikania glomerata, Cephaelis ipecacuanha, Aconitum napellus, Polygala senega, Myroxylon balsamum and Nasturtium officinale. The aim of this study was to evaluate the safety, the genotoxic potential of MelagriÃo in healthy volunteers and its efficacy in patients with clinical diagnosis of acute bronchitis. This study contemplated two clinical protocols. Protocol A evaluated the Clinical Toxicology and safety of MelagriÃo and consisted of a double-blind, placebo-controlled, randomized, parallel, with 46 adults subjects, randomly divided into two groups: Placebo and MelagriÃoÂ, each consisting of 28 and 18 volunteers, respectively. The subjects were treated for 28 uninterrupted days with 120 mL of MelagriÃo or Placebo, divided into four daily doses. Clinical and laboratory evaluations were performed in the pre-study, during the treatment period and after the end of the study. The genotoxicity of MelagriÃoÂ, was investigated through the comet assay. The mean age of the subjects was 19.37  17.36 years for the MelagriÃo group and 24.70  23.50 for the placebo group. The hematological, hepatic, renal and metabolic functions were analyzed before, during (7th, 14th and 28th day) and 7 days after the study through laboratory findings, which did not evidence signs of toxicity. Headache, vomiting, abdominal pain, dry cough, drowsiness, diarrhea, flatulence, heartburn and insomnia were the found adverse events attributed to both groups. No damage was observed (p >0.05) in peripheral lymphocytes of the subjects treated with MelagriÃo by the comet assay. The clinical toxicology and genotoxicity studies showed no toxicity in the volunteers treated with MelagriÃo for 28 uninterrupted days. Protocol B consisted of a double-blind, randomized and parallel study with 86 patients, randomly divided into two groups: MelagriÃo (n = 43) or bromhexine (n = 43). They were all treated for 7 consecutive days using the recommended dosage according to the treatment group and age. Clinical and laboratory evaluations were performed in the pre-study and only clinical evaluation was performed on the seventh day. The mean age of the subjects was 19.37  17.36 years for the MelagriÃo group and 24.70  23.50 for bromhexine group. Results of Protocol B show equivalence between the formulations tested, not being evident clinical and statistical differences within the parameters evaluated, and therefore the phytomedication MelagriÃo effective in treating acute bronchitis. Abdominal pain and fever were the found adverse events attributed to both groups. The MelagriÃo demonstrated safety in therapeutic dose, genotoxic negative character and effective in improving the signs and symptoms of acute bronchitis.

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<p>Iodine is considered an essential nutrient as lack can cause severe metabolic and neurological issues in adults, with the added consequence of permanent developmental damage in children and infants. However, excessive iodine intake can result in similar symptoms, with a wide variance in adverse health outcomes. The safe range of iodine intake may be relatively low, with some studies suggesting the possibility of a high frequency of subclinical cases of iodine poisoning going unnoticed or misdiagnosed. </p> <p>In this study, the zebrafish model was tested as an integrative whole animal model to demonstrate behavioral, morphological, and genetic responses to overt and subclinical iodine poisoning in developing humans. Zebrafish embryos were treated with sodium iodide (NaI) immediately after fertilization. Survivability was monitored every 24 hours until 120 hours post fertilization (hpf). Concentrations with no statistical significance on survival, plus the smallest dose of significant lethality were then examined using behavioral analysis at 120 hpf to compare both overt and subclinical outcomes. Morphology measurements of body length, head length, head width, brain length, swim bladder volume, jaw length, and ventral dissension were also recorded at 120 hpf. Gene expression of <i>slc5a5</i>, <i>tpo</i>, and <i>tshba</i> at 72 hpf was also measured using quantitative PCR (qPCR). </p> <p>A significant decrease in survival rates were observed at 24 hpf for 25, 37.5, and 50 mM NaI treatments (p<0.0001). Morphological measurements taken at 120 hpf showed a significant increase in body length, head length, head width, jaw length, and swim bladder volume in the 10 mM NaI treatment group (p<0.0001) and a significant decrease in body length, head length, jaw length, and swim bladder volume in the 25 mM treatment group (p<0.0001). A ventral distension also developed near the location of the thyroid gland exclusively in the 25 mM group. </p> <p>Behavioral analysis showed significant increases in movement for both the 10 mM and 25 mM treatment groups during dark phases (p<0.0001). The 25 mM treatment group had an increase in movement during dark phases for standard well environments (p<0.0001), but this did not hold true for larger well environments, instead trending towards a non-significant decrease (p>0.05). The 10 mM group had a significant decrease during the first light phase in standard wells (p=0.002), with a significant increase in the second light phase for large wells (p=0.005). There were no significant changes in the expression of selected genes associated with the thyroid pathway (<i>slc5a5</i>, <i>tpo</i>, or <i>tshba</i>) across all treatment groups (p>0.05). </p><p><br></p> <p>Overall, the results suggest zebrafish larvae exhibit both overt and subclinical symptoms of excess iodine intake. Future studies are needed to determine internalization, biodistribution, clearance, and further characterization of adverse outcomes along the thyroid pathway for additional exploration into subclinical thyrotoxicosis due to excess iodine intake. Researchers should express caution with time points, as the Wolff-Chaikoff effect may influence exposure windows in zebrafish. </p>

<p>  </p> <p>The choroid plexus (CP) in brain ventricles secrete cerebrospinal fluid (CSF) that bathes the adjacent subventricular zone (SVZ); the latter is the largest neurogenic region in adult brain harboring neural stem/progenitor cells (NSPCs) and supplies newborn neurons to the olfactory bulb (OB) for normal olfaction. We discovered the presence of a CP-SVZ regulatory (CSR) axis in which the CP, by secreting small extracellular vesicles (sEVs), regulated adult neurogenesis in the SVZ and maintained olfaction. The proposed CSR axis was supported by 1) differential neurogenesis outcomes in the OB when animals treated with intracerebroventricular (ICV) infusion of sEVs collected from the CP of normal or manganese (Mn)-poisoned mice, 2) progressively diminished SVZ adult neurogenesis in mice following CP-targeted knockdown of SMPD3 to suppress CP sEV secretion, and 3) compromised olfactory performance in these CP-SMPD3-knockdown mice. Collectively, our findings demonstrate the biological and physiological presence of this sEV-dependent CSR axis in adult brains.</p>

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