Italian Children Exposure to Bisphenol A: Biomonitoring Data from the LIFE PERSUADED Project

A human biomonitoring (HBM) study on bisphenol A (BPA) in Italian children and adolescents was performed within the LIFE PERSUADED project, considering the residing areas, sex and age. The median urinary BPA level was 7.02 mu g/L, with children living in the South of Italy or in urban areas having higher levels than those residing in the North or in rural areas. Children aged 4-6 years had higher BPA levels than those aged 7-10 and 11-14 years, but no differences were detected between sexes. The exposure in Italian children was higher compared to children from other countries, but lower than the HBM guidance value (135 mu g/L). The estimated daily intake was 0.17 mu g/kg body weight (bw) per day, about 24-fold below the temporary Tolerable Daily Intake of 4 mu g/kg bw per day established by the European Food Safety Authority. However, this threshold was exceeded in 1.44% of the enrolled children, raising concern about the overall exposure of Italian young population

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

Background Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDL-cholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality. Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major candidate genes for monogenic hypercholesterolemia (LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1). Results A total of 213 variants were detected in 1076 subjects. About 90% of them had a pathogenic or likely pathogenic variants. More than 94% of patients carried pathogenic variants in LDLR gene, 27 of which were novel. Pathogenic variants in APOB and PCSK9 were exceedingly rare. We found 4 true homozygotes and 5 putative compound heterozygotes for pathogenic variants in LDLR gene, as well as 5 double heterozygotes for LDLR/APOB pathogenic variants. Two patients were homozygous for pathogenic variants in LDLRAP1 gene resulting in autosomal recessive hypercholesterolemia. One patient was found to be heterozygous for the ApoE variant p.(Leu167del), known to confer an FH phenotype. Conclusions This study shows the molecular characteristics of the FH patients identified in Italy over the last two years. Full phenotypic characterization of these patients and cascade screening of family members is now in progress

Familial hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN)

BACKGROUND AND AIMS: Primary dyslipidemias are a heterogeneous group of disorders characterized by abnormal levels of circulating lipoproteins. Among them, familial hypercholesterolemia is the most common lipid disorder that predisposes for premature cardiovascular disease. We set up an Italian nationwide network aimed at facilitating the clinical and genetic diagnosis of genetic dyslipidemias named LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network). METHODS: Observational, multicenter, retrospective and prospective study involving about 40 Italian clinical centers. Genetic testing of the appropriate candidate genes at one of six molecular diagnostic laboratories serving as nationwide DNA diagnostic centers. RESULTS AND CONCLUSIONS: From 2012 to October 2016, available biochemical and clinical information of 3480 subjects with familial hypercholesterolemia identified according to the Dutch Lipid Clinic Network (DLCN) score were included in the database and genetic analysis was performed in 97.8% of subjects, with a mutation detection rate of 92.0% in patients with DLCN score 656. The establishment of the LIPIGEN network will have important effects on clinical management and it will improve the overall identification and treatment of primary dyslipidemias in Italy

Rodent Model of Gender-Affirming Hormone Therapies as Specific Tool for Identifying Susceptibility and Vulnerability of Transgender People and Future Applications for Risk Assessment

Transgenders (TGs) are individuals with gender identity and behaviour different from the social norms; they often undergo gender-affirming hormone therapy (HT). HT for TG men involves testosterone treatment and, for TG women, oestrogen plus androgen-lowering agents. Due—but not limited—to the lifelong lasting HT, usually TG people experience several physical and behavioural conditions leading to different and specific susceptibility and vulnerability in comparison to general population, including the response to chemical contaminants present in daily life. In particular, the exposure to the widespread endocrine disrupters (EDs) may affect hormonal and metabolic processes, leading to tissue and organ damage. Since the endocrine system of TG people is overstimulated by HT and, often, the targets overlap with ED, it is reasonable to hypothesize that TG health deserves special attention. At present, no specific tools are available to study the toxicological effects of environmental contaminants, including EDs, and the potential long-term consequences of HT on TG people. In this context, the development of adequate and innovative animal models to mimic gender-affirming HT have a high priority, since they can provide robust data for hazard identification in TG women and men, leading to more reliable risk assessment

Toxicogenomic analysis of placenta samples from mice exposed to different doses of BPA

Bisphenol A (BPA), a widespread Endocrine Disrupter mainly used in food contact plastics, may induce adverse effects especially on susceptible lifestages, first of all pregnancy. The present study considered placental development as a potential target of BPA and investigated potential differences in the modes of action of two doses of BPA by a toxicogenomic approach. Pregnant CD-1 mice were administered with vehicle, 0.5 (BPA05) or 50 mg/kg (BPA50) body weight (bw)/die of BPA, from gestational day (GD) 1 to GD11. At GD12 dams were sacrificed and transcriptomic analysis was performed on placenta samples. Histological, histomorphometrical and immunohistochemical analyses were also performed to phenotypically anchor transcriptional changes associated with BPA exposure. The interpretation and description of the overall data are included in a manuscript under revision [1]. Here we describe the experimental design and the analysis performed on the gene expression data which are publicly available through the Gene Expression Omnibus (GEO) database with accession number GSE63852

Sex-Specific Effects of Short-Term Oral Administration of Food-Grade Titanium Dioxide Nanoparticles in the Liver and Kidneys of Adult Rats

Titanium dioxide (TiO2) nanomaterial is used in several items (implant materials, pills composition, cosmetics, etc.). Although TiO2 is no longer considered safe as a food additive, the general population is exposed daily through different routes, and information is lacking on some aspects of animal and human health. This study evaluated liver and kidney toxicity of food-grade TiO2 nanoparticles (NPs) (primary size 2 NPs are known to affect the gastric mucosa, short-term exposure induced sex-specific effects: general toxicity parameters were predominantly altered in female rats, whereas the liver appeared to be more affected than the kidneys in male rats, which also showed overexpression of NPY and SPP1. In the kidneys, the TiO2 NP effects were quantitatively similar but qualitatively different in the two sexes. In conclusion, careful consideration should be paid to the presence of TiO2 NPs in other items that can lead to human exposure

In Vitro Assessment and Toxicological Prioritization of Pesticide Mixtures at Concentrations Derived from Real Exposure in Occupational Scenarios

Humans are daily exposed to multiple residues of pesticides with agricultural workers representing a subpopulation at higher risk. In this context, the cumulative risk assessment of pesticide mixtures is an urgent issue. The present study evaluated, as a case study, the toxicological profiles of thirteen pesticide mixtures used for grapevine protection, including ten active compounds (sulfur, potassium phosphonate, metrafenone, zoxamide, cyflufenamid, quinoxyfen, mancozeb, folpet, penconazole and dimethomorph), at concentrations used on field. A battery of in vitro tests for cell viability and oxidative stress endpoints (cytotoxicity, apoptosis, necrosis, ROS production, mitochondrial membrane potential, gene expression of markers for apoptosis and oxidative stress) was performed on two cellular models representative of main target organs of workers’ and population exposure: pulmonary A549 and hepatic HepG2 cell lines. All the endpoints provided evidence for effects also at the lower concentrations used. The overall data were integrated into the ToxPI tool obtaining a toxicity ranking of the mixtures, allowing to prioritize effects also among similarly composed blends. The clustering of the toxicological profiles further provided evidence of common and different modes of action of the mixtures. The approach demonstrated to be suitable for the purpose and it could be applied also in other contexts