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Reproductive toxicity, with its many targets and mechanisms, is a complex area of toxicology; thus, the screening and identification of reproductive toxicants is a main scientific challenge for the safety assessment of chemicals, including the European Regulation on Chemicals (REACH). Regulatory agencies recommend the implementation of the 3Rs principle (refinement, reduction, replacement) as well as of intelligent testing strategies, through the development of in vitro methods and the use of mechanistic information in the hazard identification and characterization steps of the risk assessment process. The EU Integrated Project ReProTect (6th Framework Programme) implemented an array of in vitro tests to study different building blocks of the mammalian reproductive cycle: methodological developments and results on male and female germ cells, prostate and placenta are presented.

Backgrounds and aims: Adrenal insufficiency (AI) has been reported in patients with stable cirrhosis. A lack of substrates has been suggested as a possible contributing pathogenic mechanism leading to glucocorticoid deficiency in these subjects. To better explore this hypothesis, we studied lipoproteins in cirrhotics with and without AI. Methods. A total of 81 cirrhotic patients and 30 normal volunteers were enrolled. The severity of liver disease was graded by Child-Pugh score. Total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), and apolipoprotein AI (Apo-AI) levels were evaluated. HDL subfractions were measured by gradient gel electrophoresis. Adrenal function was assessed by the Low-Dose Short Synacthen Test. Results. Cirrhotic patients showed a significant reduction of TC, HDL, LDL, TG, and Apo-AI levels compared with controls. HDL3 was significantly lower, while HDL2 was higher, in cirrhotics compared with the controls. AI was observed in 26 patients. TC, TG, HDL, and Apo-AI were significantly reduced in cirrhotics with AI compared with those with normal adrenal function. HDL2 and HDL3 did not differ between these two groups. Delta cortisol was related to TC (r = 0.30, p < 0.01), TG (r = 0.22, p = 0.05), and Apo-AI (r = 0.37, p < 0.001). Multivariate analysis revealed that Apo-AI and HDL were independently associated with AI. Conclusion. Our study shows that TC, TG, HDL, and Apo-AI are reduced in cirrhotics with AI. In particular, because both HDL and Apo-AI play a primary role in providing substrates for steroidogenesis to adrenal cells, this deficiency may contribute to the pathogenesis of AI in these patients.

A large body of evidence has demonstrated that LDL-C reduction by statins decrease cardiovascular risk. Statin treatment may also lead to non-lipid effects which may improve vascular protection, including an amelioration of endothelial function. On the other hand, despite a good tolerability demonstrated by several studies, statin treatment may lead to side effects, in particular when higher dosages are used. Alternative hypolipidemic treatments are nutraceuticals which are a food, or part of a food, that provides medical bene ts. Due to the low ef cacy associated to a high tolerability, patients with mild or moderate risk and/or statin-intolerant subjects are the best target of nutraceuticals. Despite a large clinical use, there is a paucity of controlled clinical studies of ef cacy and tolerability of this class of drugs. The purpose of the present study, with a double-blind, parallel group, randomized controlled design was to examine the ef cacy, safety, and tolerability of a nutraceutical product in hypercholesterolemic patients with a mild/ moderate risk previously intolerant to statins or refusing classical pharmaceutical treatments. We also analyzed the pulse wave velocity as expression of arterial stiffness and, indirectly, of endothelial function. Patients received daily either a nutraceutical-combined pill (NCP), containing red yeast rice 200 mg (corresponding to monakoline 3 mg) or placebo for six weeks. We observed a reduction of 10,4% and 12,2% of total cholesterol and LDL-cholesterol respectively. No signi cative variation was observed in the placebo group. Pulse wave velocity signi cantly decreased only in the NCP (-6,5%). Safety parameters did not change during the study and no patient reported myalgia. The mild hypolipidemic effect of red yeast rice is associated to an improvement of arterial function and high tolerability. Therefore we conclude that patients with low or moderate cardiovascular risk and/or statin-intolerant subjects may bene t of this treatment.

Alzheimer Disease is a degenerative disease characterized by progressive impairment of cognitive function. The main feature of AD the generation of an abnormal peptide, beta amyloid 42 (Ab42) from Amyloid Precursor Protein (APP). Ab42 is the main constituent of neurotangles and amyloid plaques, microscopic lesions found in AD patients brain. Ab42 triggers an inflammatory response that is responsible for most of the observed tissue damage. The diagnosis of AD is a complex task, mostly based on imaging techniques and clinical evaluation of the patient’s neurological and cognitive functions. The search for plasma biomarkers able to detect early mild cognitive impairment is one of the recent attempt the supply the clinician with new diagnostic tools. In this study we focused on a gas-chromatography mass-spectrometry (GC-MS) analysis coupled to chemometric automated metabolomic analysis of AD plasma samples compared with plasma of healthy subjects of comparable age and gender. Sera from twenty AD and twenty controls have been subjects to a procedure optimized to extract short chain organic acids, sugars and some fatty acids that can be detected by GC coupled to ion trap/MS detection. The method allowed the detection of over five thousands of individual ions that have been collected and measured by the XCMS software. After automated peak detection and alignment by XCMS, peaks have been normalized by a set of internal standards (C13 Leucine, C13 palmitic acid) and clustered into putative compounds by a homemade software. About 80 compounds were differentially expressed between AD and controls. After manual verification of the automated data, most of the compounds have been excluded since they represent column leakage or method artifacts, but some compounds represent true plasma constituents that are under investigation. Current findings will be presented after putative compound identification by the AMDIS/NIST software.

Lipids are used by the liver mainly for energy storage and membrane building, but they also contribute to cell signaling. Fatty liver is characterized by activation of metabolic and inflammatory pathways. In this work differences in lipidomic profiles of sphyngolipids (SL) and fatty acids (FA) have been evaluated in biopsies from 10 NAFLD patients, 22 (14 FL, 8 w/o FL) HCV patients and 13 healthy controls. FL is characterized by increased content of the main FA as myristic, palmitic, oleic, linoleic, saturated and monounsaturated FA in both model. FL of HCV is characterized by a more severe degree of cell damage and fibrosis associated with an increase of palmitoleic acid, long chain SL and desaturase (SCD) activity, measured as oleic/stearic ratio. FL of NAFLD shows a higher degree of metabolic disturbances as increased total cholesterol, triglycerides, HOMA, some long chain FA (C21:0, C22:2, C24:1) and n9 FA. A combination of 6 FA and 4 SL completely resolved the two model of FL (NAFLD, HCV) from non-FL by discriminant analysis. HCV vs healthy non-FL patients showed higher levels of long chain SL. In conclusion FL is characterized by accumulation of the most abundant FA, but only FL of HCV is characterized by increased long chain SL. The accumulation of SL, in particular ceramides, might be responsible of the more severe features of FL due to HCV infection.