Bisphenol A: an emerging threat to female fertility.

Bisphenol-A (BPA) has been reported to be associated to female infertility. Indeed, BPA has been found to be more frequently detected in infertile women thus leading to hypothesize a possible effect of BPA on natural conception and spontaneous fecundity. In addition, in procedures of medically assisted reproduction BPA exposure has been found to be negatively associated with peak serum estradiol levels during gonadotropin stimulation, number of retrieved oocytes, number of normally fertilized oocytes and implantation. BPA deleterious effects are more critical during perinatal exposure, causing dysregulation of hypothalamic-pituitary-ovarian axis in pups and adults, with a precocious maturation of the axis through a damage of GnRH pulsatility, gonadotropin signaling and sex steroid hormone production. Further, BPA exposure during early lifestage may have a transgenerational effect predisposing the subsequent generations to the risk of developing BPA related disease. Experimental studies suggested that prenatal, perinatal and postnatal exposure to BPA can impair several steps of ovarian development, induce ovarian morphology rearrangement and impair ovarian function, particularly folliculogenesis, as well as can impair uterus morphology and function, in female adult animal and offspring. Finally, studies carried out in animal models have been reported the occurrence of endometriosis-like lesions after BPA exposure. Moreover, BPA exposure has been described to encourage the genesis of PCOS-like abnormalities through the impairment of the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis. The current manuscript summarizes the evidence regarding the association between BPA exposure and female infertility, reviewing both clinical and preclinical studies.

Occurrence and spatial-temporal distribution of atrazine and its metabolites in the aquatic environment of the Volturno River estuary, southern Italy.

The present study assesses the spatial distribution and temporal trends of the water dissolved phase (WDP), suspended particulate matter (SPM) and sediment partitioning of atrazine (ATR) and its metabolites in the Volturno River estuary. The load contribution of ATR and its metabolites in this river to the Central Mediterranean Sea was estimated. Samples were collected in 10 sampling sites during the four seasons. The total concentrations of ATR and DPs detected ranged from 18.1 to 105.5 ng L-1 in WDP, from 4.5 to 63.2 ng L-1 in SPM, and from 4.6 to 18.6 ng g-1 in sediment samples, indicating high levels of these pollutants. Structural equation model and the ratio study indicated that the relationship between sediment and WDP pollutants occurred through the SPM. The pollutants load at the Volturno River in its mouth was evaluated in about 30.4 kg year-1, showing that this river is an important source of these analytes through discharge into Central Mediterranean Sea. Principal component analysis indicated that ATR and its metabolites pollution moves from Volturno River mouth southward and increased in the rainy season. The desethylatrazine-to-atrazine ratio was higher than 0.5 for all samples analyzed, indicating an historical discharge and a long residence time of ATR in sediment about two decades after its ban, and classifying ATR as a nonpoint source contaminant. This study makes up the first record of ATR and its metabolites in superficial water of Southern Italy and provides helpful data as starting point for future studies.

Estimation of Polycyclic Aromatic Hydrocarbons Pollution in Mediterranean Sea from Volturno River, Southern Italy: Distribution, Risk Assessment and Loads.

This study reports the data on the contamination caused by polycyclic aromatic hydrocarbons (PAHs) drained from the Volturno River. The seasonal and spatial distribution of PAHs in water and sediment samples was assessed. The 16 PAHs were determined in the water dissolved phase (DP), suspended particulate matter (SPM), and sediments. A multidimensional statistical approach was used to identify three pollution composite indicators. Contaminant discharges of PAHs into the sea were calculated in about 3158.2 kg/year. Total concentrations of PAHs varied in ranges 434.8 to 872.1 ng g-1 and 256.7 to 1686.3 ng L-1 in sediment samples and in water (DP + SPM), respectively. The statistical results indicated that the PAHs mainly had a pyrolytic source. Considering the sediment quality guidelines (SQGs), the water environmental quality standards (USEPA EQS), and risk quotient (RQ), the Volturno River would be considered as an area in which the environmental integrity is possibly at risk.

Vitamin D reverts resistance to the mTOR inhibitor everolimus in hepatocellular carcinoma through the activation of a miR-375/oncogenes circuit.

Primary or acquired resistant mechanisms prevent the employment of individualized therapy with target drugs like the mTOR inhibitor everolimus (EVE) in hepatocellular carcinoma (HCC). The current study evaluated the effect of 1,25(OH)2Vitamin D (VitD) treatment on EVE sensitivity in established models of HCC cell lines resistant to everolimus (EveR). DNA content and colony formation assays, which measure the proliferative index, revealed that VitD pre-treatment re-sensitizes EveR cells to EVE treatment. The evaluation of epithelial and mesenchymal markers by western blot and immunofluorescence showed that VitD restored an epithelial phenotype in EveR cells, in which prolonged EVE treatment induced transition to mesenchymal phenotype. Moreover, VitD treatment prompted hepatic miRNAs regulation, evaluated by liver miRNA finder qPCR array. In particular, miR-375 expression was up-regulated by VitD in EveR cells, in which miR-375 was down-regulated compared to parental cells, with consequent inhibition of oncogenes involved in drug resistance and epithelial-mesenchymal transition (EMT) such as MTDH, YAP-1 and c-MYC. In conclusion, the results of the current study demonstrated that VitD can re-sensitize HCC cells resistant to EVE treatment triggering miR-375 up-regulation and consequently down-regulating several oncogenes responsible of EMT and drug resistance.

Influence of Bisphenol A on Type 2 Diabetes Mellitus.

Bisphenol A (BPA) is an organic synthetic compound employed to produce plastics and epoxy resins. It is used as a structural component in polycarbonate beverage bottles and as coating for metal surface in food containers and packaging. The adverse effects of BPA on human health are widely disputed. BPA has been recently associated with a wide variety of medical disorders and, in particular, it was identified as potential endocrine-disrupting compound with diabetogenic action. Most of the clinical observational studies in humans reveal a positive link between BPA exposure, evaluated by the measurement of urinary BPA levels, and the risk of developing type 2 diabetes mellitus. Clinical studies on humans and preclinical studies on in vivo, ex vivo, and in vitro models indicate that BPA, mostly at low doses, may have a role in increasing type 2 diabetes mellitus developmental risk, directly acting on pancreatic cells, in which BPA induces the impairment of insulin and glucagon secretion, triggers inhibition of cell growth and apoptosis, and acts on muscle, hepatic, and adipose cell function, triggering an insulin-resistant state. The current review summarizes the available evidences regarding the association between BPA and type 2 diabetes mellitus, focusing on both clinical and preclinical studies.

The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma.

Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms.

Carprofen analogues as sirtuin inhibitors: enzyme and cellular studies.

The best of both: SIRT1/2 inhibitors were developed by combining chemical features of selisistat (SIRT1-selective inhibitor; blue) and carprofen (anti-inflammatory drug; red). The most potent compound (shown) increased acetyl-p53 and acetyl-α-tubulin levels, and induced slight apoptosis at 50 µM in U937 cells, differently from selisistat and carprofen.