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Background: this study was performed under the umbrella of the Health Extended Alliance for Innovative Therapies, Advanced Lab Research, and Integrated Approaches of Precision Medicine (HEAL ITALIA) partnership and funded under the National Recovery and Resilience Plan, Mission 4 Component 2 Investment 1.3, and by the European Union. Objectives: the overall objective of the HEAL project is to identify innovative and effective therapeutic approaches to reduce disease burden. The present research falls within Spoke 7: Prevention Strategies: Integrated and gender medicine approaches for prevention strategies based on environmental, lifestyle, and clinical biometric data. Obesity represents a primary risk factor worldwide for the onset of numerous life-threatening diseases, including metabolic, cardiovascular, and neurological diseases. Environmental and gender-related factors influence obesity development. However, the molecular mechanisms underlying the effects of those agents on different organs of the human body are not fully understood yet. Methods: here, we present a study protocol aimed at shedding light on (i) the complex interplays among adipose tissue, brain and gut in obesity, and (ii) the effects of specific dietary components and environmental metabolism-disrupting compounds on those interactions. To this purpose, we combined ex vivo, in vitro, and in vivo approaches to gain additional knowledge about the molecular mechanisms underlying connections between organs. Conclusions: the data provided by this study will contribute to defining new targets for therapeutic and/or preventive interventions, thereby allowing more personalized approaches to nutrition. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is a worldwide public health problem. Experimental animal and in vitro studies suggest that the exposure to BPA and phthalates are associated to a higher risk of obesity. Objective: The objective of the study was to determine urinary excretion of bisphenol A and phthalates in obese and normal weight children. Methods: A case-control study was conducted in 122 children. Sixty-six obese children, 36 girls (mean age 8.41 ± 1.27 years), and 30 boys (mean age 8.51 ± 1.33 years) and 56 normal weight children, 27 girls (mean age 7.64 ± 1.49 years), and 29 boys (mean age 7.77 ± 1.56 years) were studied. Urinary BPA and bis(2-ethylhexyl) phthalate (DEHP) metabolites (MEHP, MEHHP, and MEOHP) were measured, respectively, by gas chromatography and high-performance liquid chromatography. Individual determinants of exposure were evaluated through "ad hoc" questionnaires. Results: BPA and DEHP metabolites were detectable in obese and normal weight children. Obese girls showed significantly higher BPA concentrations in comparison with normal weight girls (means 10.77, 95% CI = 7.02–16.53 vs. 5.50, 95% CI = 3.93–7.71 μg/g creatinine, respectively, p < 0.02). The first step of DEHP metabolic rate was significantly higher in obese girls compared with controls (p < 0.05). DEHP metabolites correlated significantly with leptin concentrations in obese girls (p < 0.03). A higher risk of obesity was found in children with BPA levels above the median values with the habit to eat food packaged (OR = 11.09, 95% CI = 1.28–95.78). Conclusions: These findings show that a higher exposure to BPA is associated with the risk of obesity in girls. Further studies are needed to unveil the cause-effect relationship. [ABSTRACT FROM AUTHOR]

Phthalates and bisphenol A (BPA) are plasticizers used in many industrial products that can act as endocrine disruptors and lead to metabolic diseases. During the LIFE PERSUADED project, we measured the urinary concentrations of BPA and Di(2-ethylhexyl)phthalate (DEHP) metabolites in 900 Italian women representative of the Italian female adult population (living in the north, centre, and south of Italy in both rural and urban areas). The whole cohort was exposed to DEHP and BPA with measurable levels above limit of detection in more than 99% and 95% of the samples, respectively. The exposure patterns differed for the two chemicals in the three macro-areas with the highest urinary levels for DEHP in south compared to central and northern Italy and for BPA in northern compared to central and southern Italy. BPA levels were higher in women living in urban areas, whereas no difference between areas was observed for DEHP. The estimated daily intake of BPA was 0.11 μg/kg per day, about 36-fold below the current temporary tolerable daily intake of 4 μg/kg per day established by the EFSA in 2015. The analysis of cumulative exposure showed a positive correlation between DEHP and BPA. Further, the reduction of exposure to DEHP and BPA, through specific legislative measures, is necessary to limit the harmfulness of these substances. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a plasticizer with endocrine disrupting properties particularly relevant for children health. Recently BPA has been associated with metabolic dysfunctions but no data are yet available in specific, long-term studies. This study aimed to evaluate BPA modes of action and hazards during animal juvenile life-stage, corresponding to childhood. Immature Sprague-Dawley rats of both sexes were orally treated with 0 (vehicle only—olive oil), 2, 6, and 18 mg/kg bw per day of BPA for 28 days, from weaning to sexual maturity. Dose levels were obtained from the PERSUADED biomonitoring study in Italian children. Both no-observed-adverse-effect-level (NOAEL)/low-observed-adverse-effect-level (LOAEL) and estimated benchmark dose (BMD) approaches were applied. General toxicity, parameters of sexual development, endocrine/reproductive/functional liver and kidney biomarkers, histopathology of target tissues, and gene expression in hypothalamic-pituitary area and liver were studied. No mortality or general toxicity occurred. Sex-specific alterations were observed in liver, thyroid, spleen, leptin/adiponectin serum levels, and hypothalamic-pituitary gene expression. Thyroid homeostasis and liver were the most sensitive targets of BPA exposure in the peripubertal phase. The proposed LOAEL was 2 mg/kg bw, considering as critical effect the liver endpoints, kidney weight in male and adrenal histomorphometrical alterations and osteopontin upregulation in female rats. The BMD lower bounds were 0.05 and 1.33 mg/kg bw in males and females, considering liver and thyroid biomarkers, respectively. Overall, BPA evaluation at dose levels derived from children biomonitoring study allowed to identify sex-specific, targeted toxicological effects that may have significant impact on risk assessment for children. [ABSTRACT FROM AUTHOR]

Phthalates and bisphenol A (BPA), plasticizers used in several products of daily life, are considered as endocrine disrupters, therefore children exposure is particularly relevant. The LIFE PERSUADED project aims to define the following: (a) the evaluation of internal levels of DEHP’s metabolites and BPA in Italian children and their mothers, (b) the association of the exposure with puberty development and obesity diseases, and (c) the effects of exposure in juvenile in vivo model. The cross-sectional study has involved 2160 mother-child pairs, including males and females, children and adolescents, from urban and rural areas of North, Center, and South Italy. A structured questionnaire and a food diary are designed to evaluate the association between lifestyle variables potentially related to DEHP/BPA exposure and internal levels, through univariate and multivariate analyses. Two pilot case-control studies are carried out on idiopathic premature thelarche and precocious puberty (30 girls each group, aged 2-7 years) and idiopathic obesity (30 boys and 30 girls, aged 6-10 years), matched to healthy controls. BPA and DEHP’s metabolites are analyzed in urine samples from all recruited subjects. Clinical and toxicological biomarkers are evaluated in serum of case-control subjects. Moreover, the toxicity study is carried out in a juvenile rodent model exposed to mixtures of BPA and DEHP at dose levels recorded in children population. The scientific results of LIFE PERSUADED will contribute to risk assessment of BPA and DEHP. [ABSTRACT FROM AUTHOR]