Mahshid Hodjat

Growing knowledge of using embryonic stem cells as a novel tool in developmental risk assessment of environmental toxicants

Developmental toxicology is an important area of novel toxicology. In recent years, there have been big concerns toward the increasing exposure to pharmaceutical agents, food additives, pesticides, occupational toxicants, and environmental pollutants, as well as their possible association with all aspects of male or female-mediated transient or permanent defects in progeny. Therefore, it is of great importance to look for new predictive models to evaluate environmental toxicants before they can harm the human health and embryo development. In this regard, new cell-based in vitro screening models have been developed and validated in predictive toxicology to minimize assay costs and animal usage. Stem cell-based models have been increasingly applied for predicting the toxicity of chemicals. One of the most promising existing in vitro developmental toxicity tests is the validated embryonic stem cell test (EST) which employs marine or human embryonic stem cells to assess the potential of chemicals embryotoxicity. These cells are very suitable for embryotoxicity assessment as they have been demonstrated to specify cellular developmental processes during early embryogenesis and gene expression patterns of differentiation to functionally competent specialized cell types. The present paper aimed at criticizing the human and experimental evidence for developmental toxic effects of environmental toxicants based on ESCs models. Accordingly, pesticides, heavy metals, plasticizers, nanomaterials and some solvents have been considered as the main evaluated environmental toxicants inducing developmental toxicity. At the end, current challenges, pros and cons of using ESCs as an alternative validated in vitro model for specific developmental toxicity screening are discussed.

On the mechanism of genotoxicity of ethephon on embryonic fibroblast cells

Abstract Ethephon is one of the most widely used plant growth regulator in agriculture that its application has been increased in recent years. Many reports have raised concern over the safety of this organophosphorus compound. The aim of the current study was to assess the potential genotoxic effect of ethephon on murine embryonic fibroblast (MEF) cell line, using two genotoxicity endpoints: γH2AX expression and comet assay. γH2AX served as an early and sensitive biomarker of genotoxic damage. Oxidative stress biomarkers, including reactive oxygen species (ROS), lipid peroxidation (LPO) and total antioxidant capacity were also examined. The results showed a significant increase in cell proliferation, 24 h post-treatment with 10, 40,160 μg/ml ethephon, while at the higher concentrations cytotoxic effect was observed. The γH2AX expression and γH2AX foci count per cell were significantly increased at non-cytotoxic concentrations of ethephon, accompanied with increased DNA damage as illustrated by comet assay. LPO and ROS levels were elevated only at 160 μg/ml and higher doses. The results interestingly showed that low non-cytotoxic doses of ethephon promoted DNA damage inducing cell proliferation, raising the possibility of ethephon mutagenicity. The genotoxic effect of ethephon at low doses might not relate to oxidative damage and that increased in the level of ROS and LPO generation at higher doses could account for the cytotoxic effect of ethephon. Taken together, our study provides strong in vitro evidence on potential genotoxicity of ethephon at low doses. More precise studies are needed to clarify the mutagenic effect of chronic exposure to ethephon.

Bio-guided fractionation and isolation of active component from Tragopogon graminifolius based on its wound healing property

ETHNOPHARMACOLOGICAL RELEVANCE Tragopogon graminifolius (T. graminifolius) from Asteraceae family has been used as a remedy in Persian traditional medicine for the treatment of various disorders such as wound healing. AIM OF THE STUDY The purpose of this study is to investigate the compounds of T. graminifolius, which are responsible for its wound healing activity. MATERIALS AND METHODS The experiment was performed in three phases; each phase consisted of fractionation of extracts followed by scratch assay. The results of the scratch assay were expressed using scratch closure index (SCI), representing the contraction of scratch. RESULTS In phase I, Ethyl acetate fraction (E) showed the maximum SCI (61.7 ± 3.5) that was selected for more fractionation in the next phase. In phase II, 12 fractions were obtained and labeled as fractions E- A to L, respectively. Based on the SCI of fractions, EF (SCI=68.9 ± 0.6) was the most active fraction in phase II and selected for further fractionation in phase III. In phase III, 8 fractions were resulted by fractionation of EF and labeled as EF- 1-8. Fraction EF5 with the highest SCI (30.8 ± 3.0) was the most effective fraction and Luteolin was the main component. Luteolin significantly improved viability of fibroblast cells and increased cell population that was accompanied by decreased cell apoptosis. Luteolin-induced cell number increase in the S and G2M phases of the cell cycle, further confirms the proliferative effect of this compound. CONCLUSION The results showed that the total extract and fractions of T. graminifolius stimulate proliferation and migration of skin fibroblast cells and Luteolin is one of the active compounds responsible for these effects.

The role of minocycline in alleviating aluminum phosphide-induced cardiac hemodynamic and renal toxicity

Poisoning with aluminum phosphide (AlP) has been attributed to the high rate of mortality among many Asian countries. It affects several organs, mainly heart and kidney. Numerous literature demonstrated the valuable effect of minocycline in mitigating pathological symptoms of heart and kidney disease. The aim of the present study was to evaluate the probable protective effect of minocycline on cardiac hemodynamic parameters abnormalities and renal toxicity induced by AlP-poisoning in the rat model. AlP was administered by gavage at 12 mg/kg body weight followed by injection of minocycline for two interval times of 12 and 24 h, at 40, 80, 120 mg/kg body weight. Electrocardiographic (ECG) parameters were monitored, 30 min after AlP gavage for 6 h using an electronic cardiovascular monitoring device. Kidney tissue and serum were collected for the study of histology, mitochondrial complexes I, II, IV, lactate dehydrogenase (LDH) and myeloperoxidase (MPO) activity, ADP/ATP ratio, mitochondrial cytochrome c release, apoptosis, lactate, BUN, and Cr levels. The results demonstrated that AlP induces ECG abnormalities, and failure of heart rate and blood pressure, which improved significantly by minocycline. Minocycline treatment significantly improved complexes I, IV, MPO and LDH activities, and also reduced the ADP/ATP ratio, lactate level, release of cytochrome c, and apoptosis in the kidney following AlP-poisoning. Also, the histological results showed an improvement of kidney injury in minocycline treated groups. In conclusion, the findings of this study showed that minocycline could improve cardiac hemodynamic abnormalities and kidney injury following AlP-poisoning, suggesting minocycline might be a possible candidate for the treatment of AlP-poisoning.