^17th Global Toxicology and Risk Assessment Conference October 22-24, 2018 Budapest, Hungary

Yongwei Luo has completed his PhD at the Department of Pharmacy, Fudan University, China in 2018. He is now working as a Study Director in National Evaluation Centre for the Toxicology of Fertility Regulating Drug, Shanghai, China, which has acquired the GLP certificate of CDA (China Drug Administration). He has been showing great expertise in the area of preclinical toxicity evaluation of new drugs for nearly 10 years and has published a number of articles in reputed international journals

Miscarriage is a common obstetric disease, occurring in 15% to 40% women of reproductive age. Various traditional Chinese medicines treating miscarriage have been widely used throughout the pregnancy race, which were defined as one category of the complementary and alternative medicines by the National Center for Complementary and Alternative Medicine. Thereby, the long term toxicology of these medicines and their impacts on liver is more and more concerned by clinical physicians and infertility couples. Zishen Yutai pill (ZYP) is one of the most commonly used Chinese medicines for miscarriage. The objective of this 39 weeks study was to investigate the potential long-term toxicity and hepatotoxicity of ZYP administered to beagle dogs at dose levels of 1.5, 3.0 and 6.0 g/kg bw/day by oral gavage and to determine reversibility of any findings after the four weeks recovery period. Physiological saline was used as control respectively. Clinical observation, mortality, body weight, blood pressure and electrocardiogram, clinical pathology, organ weights, histopathology, hormones and traditional and potential hepatotoxicity biomarkers were detected and recorded. There were no mortality or toxic clinical symptoms and abnormalities in both sexes of beagle dogs except for the expected exaggerated pharmacological effects typically associated with female reproductive organs, which typically induced on endometrial thickening, dilated lactiferous ducts in mammary gland and vigorous-growth of oocytes in ovary. No obvious ZYP-related hepatotoxicity was observed after 13 and 39 weeks of ZYP treatment. Based on these results, the no-observed-adverse-effect-level (NOAEL) of ZYP in dogs is higher than 6.0 g/kg when administered orally for 39 consecutive weeks. Therefore, this study has suggested that no drug related toxicity was induced by ZYP administered up to 6.0 g/kg bw/day to beagle dogs for nine months. Since this dose is approximately 24 times as much as the clinical dose, it indicates a good safety margin of this product

Zuyue Sun is the Research Director of National Evaluation Centre for the Toxicology of Fertility Regulating Drug; a laboratory has acquired the GLP certificate of CFDA (China Food and Drug Administration). He has published more than 312 theses in China and abroad reputed journals, and 258 study projects being carried out in his laboratory.

Objective: The objective of this study was to determine the toxicokinetic profile of curdione in pregnant SD rats as well as the transference of curdione into the fetus through the placental barrier system using LC-MS/MS.\r\n\r\nMethods: A sensitive analytical method for determining the plasma concentration of curdione was developed and applied in the determination of curdione in pregnant SD rats as a simulated model. Thirteen pregnant SD rats were treated with 7, 21 and 63 mg/kg curdione once daily from GD6 to GD15. Blood samples were collected at different time points on GD6 and GD15. Maternal plasma, placental plasma, placenta tissue, amniotic fluid and fetal tissue were collected for concentration analysis after all the animals were sacrificed following one repeated dose.\r\n\r\nResults: The results indicated that Cmax, AUC (0-t) and AUC (0-∞) increased in a dose-dependent manner both on GD6 and GD15. At 7 mg/kg group, the total serum clearance value on GD15 was reduced to approximately 16.4% of that on GD6, and the volume of distribution was also significantly decreased (p<0.05). Curdione could be detected in the maternal plasma, placental plasma, placenta tissue, amniotic fluid and fetal tissue, and its concentration in the fetal tissue reached saturation at 21 mg/kg. \r\n\r\nConclusion: It presents with the risk of toxic accumulation in the concomitant toxicokinetics of reproductive toxicity studies in SD rats and it may affect the fetus via transference through the placental barrier system. \r\n\r\nImage\r\n\r\n \r\n

Paula Moyano received her Juris Doctor degree from the Complutense University of Madrid in 2013. She has completed his/her Master’s degree in Pedagogical Sciences. She specialized in Neurotoxicology and Legal Sciences and received his/her PhD in Toxicology and Legal Medicine in 2016.

Cadmium is a toxic compound reported to produce cognitive dysfunctions, though the mechanisms involved are unknown. Previously, it has been reported that cadmium induces a greater cell death in primary cholinergic neurons from the basal forebrain. It also induces cell death in SN56 cholinergic neurons from the basal forebrain partially through increase of amyloid-beta (Aβ) protein levels, among other mechanism. It was observed that the silencing or blockage of muscarinic 1 receptor (M1R) altered acetylcholinesterase (AChE) splice variants gene expression and Aβ protein formation. Furthermore, AChE-S variants were associated with the same actions modulated by M1R. Accordingly, we hypothesized that cadmium induced Aβ production in basal forebrain cholinergic neurons is mediated by M1R blockage, which triggers this effect through alteration of the expression of AChE variants. To prove this hypothesis, we evaluated that in SN56 cholinergic neurons from basal forebrain region, whether M1R silencing mediated Aβ production observed after cadmium exposure through alteration of the expression of AChE variants. Our results proved that cadmium induce Aβ production and this effect was mediated by M1R through AChE altered expression. Thus, our results help to explain the mechanism by which cadmium induces Aβ production in basal forebrain cholinergic neurons and may explain cognitive dysfunctions observed in cadmium toxicity.

Javier Del Pino received his PharmD degree at the University Complutense University of Madrid in 2004. He has two Masters in Sciences 2009 and 2010. He specialized in neurotoxicology and neurodevelopmental toxicology and received his PhD in Toxicology in 2009. In 2010 he worked in Institute of Health Carlos III in the National Center of Environmental Health. From 2010 to 2012 he was Associated Researcher at University of Massachusetts (UMASS) working in Sandra Petersen´s Lab in a National Institute of Health (NIH) project on developmental effects of TCDD endocrine disruptor on sexual differentiation. In 2016 he got a position as Associated Professor of Toxicology at the Complutense University of Madrid

Chlordimeform, as well as other formamidine pesticides, induce permanent sex- and region-dependent effects on development of monoaminergic neurotransmitter systems. These effects could be related to monoamine oxidase (MAO) inhibition. However, chlordimeform is a very weak MAO inhibitor, which suggests that other mechanism should be involved. In this regard, formamidines, in general, and chlordimeform, in particular, alter the serum levels of steroid hormones, which regulate the expression of enzymes that mediate the synthesis and metabolism of monoaminergic neurotransmitters. Therefore, an alteration of these hormones in the brain could mediate the effects observed. In order to confirm that the formamidines produce disruption of sex hormones in the brain, we evaluated, in hippocampus of male and female rats, the effect on the levels of testosterone and estradiol at 11 days of age, after maternal exposure to chlordimeform (5 mg/kg body weight). Chlordimeform induced a significant decrease in testosterone levels and a significant increase in estradiol levels in hippocampus of rats at 11 days of age. We observed sex interaction with treatment in the content of T and E2. The present findings indicate that after maternal exposure to chlordimeform, a sex hormones disruption, in hippocampus, is induced