Perfluoroalkyl substances (PFASs) are synthetic chemicals widely used in industrial and consumer products. The environmental spreading of PFASs raises concerns for their impact on human health. In particular, the bioaccumulation in humans due to environmental exposure has been reported also in total brain samples and PFAS exposure has been associated with neurodevelopmental disorders. In this study we aimed to investigate the specific PFAS bioaccumulation in different brain areas. Our data reported major accumulation in the brainstem region, which is richly populated by dopaminergic neurons (DNs), in brain autopsy samples from people resident in a PFAS-polluted area of Italy. Since DNs are the main source of dopamine (DA) in the mammalian central nervous system (CNS), we evaluated the possible functional consequences of perfluoro-octanoic acid (PFOA) exposure in a human model of DNs obtained by differentiation of human induced pluripotent stem cells (hiPSCs). Particularly, we analyzed the specific effect of the exposure to PFOA for 24 h, at the concentration of 10 ng/ml, at 3 different steps of dopaminergic differentiation: the neuronal commitment phase (DP1), the neuronal precursor phase (DP2) and the mature dopaminergic differentiation phase (DP3). Interestingly, compared to untreated cells, exposure to PFOA was associated with a reduced expression of Tyrosine Hydroxylase (TH) and Neurofilament Heavy (NFH), both markers of dopaminergic maturation at DP2 phase. In addition, cells at DP3 phase exposed to PFOA showed a severe reduction in the expression of the Dopamine Transporter (DAT), functionally involved in pre-synaptic dopamine reuptake. In this proof-of-concept study we show a significant impact of PFOA exposure, mainly on the most sensitive stage of neural dopaminergic differentiation, prompting the way for further investigations more directly relevant to risk assessment of these chemicals.

Context: Endothelial dysfunction seems to be the first step of the atherosclerotic process. In the past few years, it has been demonstrated that injured endothelial monolayer is restored by a premature pool of circulating progenitor cells (PCs) and a more mature one of circulating endothelial PCs (EPCs). Even though there is increasing evidence that estrogens play a beneficial role on EPCs and, even if debated, on the cardiovascular system, less is known about androgens. Objective: Our objective was to evaluate the levels of circulating PCs and EPCs in men with hypogonadotropic hypogonadism (HH) and the effect of prolonged testosterone (T) replacement therapy on these cells. Design and Setting: We conducted a prospective study on males with HH at a university andrological center. Patients: The study included 10 young HH patients (28.6 ± 3.1 yr) and 25 age-matched controls. Interventions: Idiopathic HH patients were treated with T gel therapy, 50 mg/d for 6 months. Main Outcome Measures: We assessed circulating PC and EPC concentrations and immunocytochemistry for androgen receptor expression on cultured EPCs. Results: At baseline, HH patients showed a significant reduction of both PCs and EPCs with respect to controls. T replacement therapy induced a significant increase of these cells with respect to baseline. Immunocytochemistry on cultured EPCs showed strong expression of the androgen receptor. Conclusions: Hypotestosteronemia is associated with a low number of circulating PCs and EPCs in young HH subjects. T treatment is able to induce an increase in these cells through a possible direct effect on the bone marrow.

Context: The adipose tissue (AT), which is an endocrine organ, is linked to several metabolic abnormalities. Undercarboxylated osteocalcin (ucOCN) regulates insulin and adiponectin secretion. Objective: Our objective was to investigate the involvement of OCN in obesity and to evaluate, in vitro and ex vivo, the role of AT in the modulation of this endocrine circuit. Design, Patients, and Setting: This transversal study involved 83 male subjects, divided according to the World Health Organization body mass index classification, evaluated at Padova’s Obesity Outpatient Clinic. Methods: OCN, both undercarboxylated (ucOCN) and carboxylated (cOCN) forms, was measured in serum by ELISA. OCN mRNA expression and protein production were measured by quantitative RT-PCR and immunohistochemistry during in vitro adipogenesis and in sc AT (SAT) and omental AT (OAT) from normal adult men. cOCN and ucOCN release by AT in a simple growth medium was verified by ELISA. Results: Overweight and obese patients had a lower ucOCN and ucOC/OCN ratio. In the whole cohort, ucOCN/OCN ratio was negatively correlated to body mass index (ρ = −0.233; P < 0.05). OCN mRNA was present in SAT and OAT and during all stages of adipogenesis, with higher expression in the first steps. Immunohistochemistry confirmed the expression of OCN protein. Both SAT and OAT were able to release cOCN and ucOCN. Conclusions: Our data support a pathophysiological link between ucOCN and cOCN balance and obesity. OCN is present in the first phases of adipogenesis but also in human AT ex vivo. AT releases, in vitro, both ucOCN and cOCN, suggesting a possible link between AT and OCN in the regulation of metabolism.