Intensity and type of physical activity and semen quality in healthy young men.

OBJECTIVE: To study the relationship between intensity of physical activity (PA) and semen quality in healthy young men. DESIGN: A prospective cohort study with repeated measures for each subject. SETTING: Not applicable. PATIENT(S): Healthy high school and university students who did not regularly smoke tobacco, drink alcohol, or take drugs or medicine, with normal body mass index and abdominal circumference. INTERVENTION(S): The participants underwent urologic visit, fasting blood and semen sampling, and anthropometric measurements, and filled in the International Physical Activity Questionnaire, at enrollment and after 4 and 8 months. Duration and frequency of walking, moderate-intensity, and vigorous-intensity activities in the last week were assessed, and a score was computed for total PA. MAIN OUTCOME MEASURE(S): Semen specimens were taken at each visit through masturbation, after 3-5 days of abstinence, and analyzed by an expert urologist. Sperm concentration, total and progressive motility, and proportion of spermatozoa with normal morphology were measured. Linear and generalized linear mixed models with the Poisson family were fitted to assess the relationships between PA variables and sperm parameters, after adjusting for season, time, and study arm. The shape of the relationship was modeled through restricted cubic spline regression. RESULT(S): A total of 143 male subjects, aged 18-23 years (median, 20 years), were enrolled. They had a median PA of 1,960 (95% confidence interval, 1,055-3,182) Metabolic Equivalent of Tasks in min/wk. Statistically significant differences were found for total, progressive motility, and percent of cell with normal morphology across categories of total PA; the highest medians of total (47%) and progressive motility (34%) and of the percentage of normal morphology cells (7%) were found for medium PA. Positive associations of sperm total motility and normal morphology with medium levels of PA, and negative associations with walking and vigorous-intensity activity emerged. Spline regression analysis confirmed these findings, showing an inverse U-shape relationship, with the highest value of total motility and normal morphology for medium PA, and the lowest values for lower and higher activity. CONCLUSION(S): These findings support the present recommendations to practice moderate PA for health improvement, including semen quality.

Efficacy of a Short-Term Lifestyle Change Intervention in Healthy Young Men: The FASt Randomized Controlled Trial.

The aim of this study was to investigate the impact of dietary habits and physical activity intervention on lifestyle behavior as a prevention tool supported also by personalized motivational counseling. A two-arm randomized controlled trial was carried out. A sample of 18-22-year-old students was randomly assigned to a four-month intervention based on the Mediterranean diet and moderate physical activity program (N = 66) or to a control group (N = 63). The outcomes were adherence to the Mediterranean diet, physical activity level, and nutrients intake, assessed at enrollment (t0), end of intervention (t4, 4 months after the start), and end of follow-up (t8, 8 months after the start). Adherence to the Mediterranean diet increased from t0 to t4 and t8, more in the intervention (6.83, 9.85, and 9.12, respectively) than in the control group (6.73, 7.00, 7.69, respectively) (p < 0.001). Physical activity showed a moderate increase from t0 to t4 and t8 in both groups, without significant differences between them. Significant differences were seen between the two groups in food intake changes, from t0 to t4 and t8. This randomized controlled trial showed that a moderate short-term intervention based on the Mediterranean diet and regular physical activity determined a positive change in the lifestyle of healthy, normal-weight, young men.

Polychlorinated Biphenyls and Semen Quality in Healthy Young Men Living in a Contaminated Area.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants and endocrine disruptors that have been implicated in potential damage to human semen. However, the studies conducted so far provide contrasting results. Our study aimed to investigate the associations between PCB serum and semen levels and semen quality in high school and university students living in a highly PCB-polluted area of Italy. Subjects with a normal body mass index who did not make daily use of tobacco, alcohol, drugs, or medication were selected. All participants provided a fasting blood and a semen sample. Gas chromatography-mass spectrometry was used to determine the concentrations of 26 PCB congeners. The concentrations of PCB functional groups and total PCBs were also computed. A total of 143 subjects (median age 20, range 18-22 years) were enrolled. The median total PCB concentrations were 3.85 ng/mL (range 3.43-4.56 ng/mL) and 0.29 ng/mL (range 0.26-0.32 ng/mL) in serum and semen, respectively. The analysis of the associations between sperm PCB concentration and semen parameters showed (a) negative associations between some PCB congeners, functional groups and total PCBs and sperm total motility; (b) negative associations of total PCBs with sperm normal morphology; and (c) no association of PCBs with sperm concentration. Subjects at the highest quartile of semen total PCB concentration had 19% and 23% mean reductions in total motility and normal morphology, respectively, compared to those at the lowest quartile. The analysis of the associations of serum PCB levels with sperm parameters yielded null or mixed (some positive, other negative) results. In conclusion, the present study provides evidence of a negative effect of some PCB congeners and total PCBs in semen on sperm motility and normal morphology. However, the associations between the concentration of serum and semen PCB congeners and functional groups and sperm quality parameters were inconsistent.

Computational Modeling and Design of New Inhibitors of Carbapenemases: A Discussion from the EPIC Alliance Network.

The EPIC consortium brings together experts from a wide range of fields that include clinical, molecular and basic microbiology, infectious diseases, computational biology and chemistry, drug discovery and design, bioinformatics, biochemistry, biophysics, pharmacology, toxicology, veterinary sciences, environmental sciences, and epidemiology. The main question to be answered by the EPIC alliance is the following: "What is the best approach for data mining on carbapenemase inhibitors and how to translate this data into experiments?" From this forum, we propose that the scientific community think up new strategies to be followed for the discovery of new carbapenemase inhibitors, so that this process is efficient and capable of providing results in the shortest possible time and within acceptable time and economic costs.

Comparison between Macro and Trace Element Concentrations in Human Semen and Blood Serum in Highly Polluted Areas in Italy.

Macro and trace elements are important regulators of biological processes, including those ones linked to reproduction. Among them, Ca, Cu, Fe, K, Mg, Mn, Na, Se, and Zn ensure normal spermatic functions. Hence, the aim of this study was to evaluate the concentrations of 26 macro and trace elements (Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Li, Mg, Mn, Na, Ni, Pb, Rb, Sb, Se, Sn, Sr, U, V, and Zn) in blood serum and also in semen of healthy young men, homogeneous for age, anthropometric characteristics, and lifestyle, living in three highly polluted areas in Italy. Furthermore, a comparison among three geographical areas was performed to highlight any difference in the investigated parameters and, overall, to speculate any correlations between chemical elements and semen quality. Statistically significant differences (p < 0.05) among the three areas were found for each investigated element, in both semen and serum samples, where inter-area differences were more evident in semen than in blood serum, suggesting human semen as an early environmental marker. Considering the homogeneity of three cohorts, these differences could be due more to environmental conditions in the recruiting areas, suggesting that variations in those involved in reproductive-associated pathways can have an impact on male fertility. Nevertheless, more research is needed to evaluate threshold values for sperm dysfunction and male infertility. Actually, the role of different dietary intake and environmental exposure underlying the observed differences in the recruiting areas is under further investigation for the same cohort.

Intracellular distribution of vinclozolin and its metabolites differently affects 5α-dihydrotestosterone (DHT)-induced PSA secretion in LNCaP cells.

Endocrine disruption mechanisms in prostate are an overlooked issue. The anti-androgenic properties of the fungicide vinclozolin (VIN) and its active metabolites - 2-[[(3,5- dichlorophenyl)-carbamoyl]oxy]- 2-methyl-3-butenoic acid (M1) and 3'5'-dichloro-2-hydroxy-2- methylbut-3-enanilide (M2) - were assessed on human prostate-derived cells (LNCaP); the effects were investigated also upon co-treatment with 5α-dihydrotestosterone (DHT), the physiological androgen receptor (AR)-agonist, and compared to the anti-androgenic drugs, 2-hydroxy-flutamide (2OH-FTA) and bicalutamide (BIC). Assessed endpoints were the cellular uptake and subcellular localization of VIN, M1 and M2, DHT-induced PSA gene expression and secretion. VIN, its metabolites, and the reference drugs, significantly reduced DHT-induced PSA secretion and gene expression, M2 showing the strongest downregulation. In absence of DHT, 2OH-FTA and BIC showed a very high (>98%) LNCaP uptake with a predominant intranuclear localization (BIC=80%, 2OH-FTA=70%). VIN cellular uptake was 42%: 24.7% made up by M2, mostly localized at nuclear level, differently from VIN and M1. Upon DHT co-treatment, VIN intracellular uptake increased by 28%, especially in the microsomal fraction (MF); M2 also increased mainly in MF but also, to a lower extent, in the intranuclear fraction. Finally, in a 72-hr time-course, the LNCaP uptake of VIN and its metabolites was much faster compared to purified M1 and M2. Overall, M2 resulted the leading compound for VIN endocrine-disrupting effects in LNCaP.

Oxysterols profiles in zebrafish (Danio rerio) embryos exposed to bisphenol A.

INTRODUCTION: Oxysterols are cholesterol oxidation products and bioactive lipids involved in developmental signalling pathways, embryonic and postembryonic tissue patterning and homeostasis. The embryonic period is a very sensitive window of exposure to bisphenol A (BPA), hence the role of BPA on the levels of oxysterols in the very early stages of zebrafish embryogenesis is a relevant novel field of investigation. OBJECTIVES: To compare the role of BPA on oxysterols levels in zebrafish embryos at 8 and 24 h post fertilization (hpf) with cytochromes P450 (CYPs)-modulating chemicals (carbamazepine, ketoconazole, and hydrogen peroxide). METHODS: Upon a dose range finding, zebrafish embryos were exposed to environmentally relevant (0.04 µM) and toxicological (17.5 µM) BPA concentrations. Seven oxysterols were profiled by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: Similarly to the CYPs-modulating chemicals, BPA caused: i) no significant changes at 8 hpf and ii) a dose-dependent increase of total oxysterols at 24 hpf, with 27-hydroxycholesterol as the most regulated oxysterol. DISCUSSION: In the first day post-fertilization of the zebrafish embryos, the role of BPA alike a CYPs-modulating chemical was confirmed by the similar oxysterol changes observed with the already known CYPs-modulating chemicals.

Oxysterols Profile in Zebrafish Embryos Exposed to Triclocarban and Propylparaben-A Preliminary Study.

Oxysterols have long been considered as simple by-products of cholesterol metabolism, but they are now fully designed as bioactive lipids that exert their multiple effects through their binding to several receptors, representing endogenous mediators potentially involved in several metabolic diseases. There is also a growing concern that metabolic disorders may be linked with exposure to endocrine-disrupting chemicals (EDCs). To date, there are no studies aimed to link EDCs exposure to oxysterols perturbation-neither in vivo nor in vitro studies. The present research aimed to evaluate the differences in oxysterols levels following exposure to two metabolism disrupting chemicals (propylparaben (PP) and triclocarban (TCC)) in the zebrafish model using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Following exposure to PP and TCC, there were no significant changes in total and individual oxysterols compared with the control group; however, some interesting differences were noticed: 24-OH was detected only in treated zebrafish embryos, as well as the concentrations of 27-OH, which followed a different distribution, with an increase in TCC treated embryos and a reduction in zebrafish embryos exposed to PP at 24 h post-fertilization (hpf). The results of the present study prompt the hypothesis that EDCs can modulate the oxysterol profile in the zebrafish model and that these variations could be potentially involved in the toxicity mechanism of these emerging contaminants.

Endocrine Disruptors and Prostate Cancer.

The role of endocrine disruptors (EDs) in the human prostate gland is an overlooked issue even though the prostate is essential for male fertility. From experimental models, it is known that EDs can influence several molecular mechanisms involved in prostate homeostasis and diseases, including prostate cancer (PCa), one of the most common cancers in the male, whose onset and progression is characterized by the deregulation of several cellular pathways including androgen receptor (AR) signaling. The prostate gland essentiality relies on its function to produce and secrete the prostatic fluid, a component of the seminal fluid, needed to keep alive and functional sperms upon ejaculation. In physiological condition, in the prostate epithelium the more-active androgen, the 5α-dihydrotestosterone (DHT), formed from testosterone (T) by the 5α-reductase enzyme (SRD5A), binds to AR and, upon homodimerization and nuclear translocation, recognizes the promoter of target genes modulating them. In pathological conditions, AR mutations and/or less specific AR binding by ligands modulate differently targeted genes leading to an altered regulation of cell proliferation and triggering PCa onset and development. EDs acting on the AR-dependent signaling within the prostate gland can contribute to the PCa onset and to exacerbating its development.

Effects of a Lifestyle Change Intervention on Semen Quality in Healthy Young Men Living in Highly Polluted Areas in Italy: The FASt Randomized Controlled Trial.

BACKGROUND: Human semen quality is affected by lifestyle and environmental factors. OBJECTIVE: To evaluate the short-term effects of a diet and physical activity intervention on semen quality of healthy young men living in highly polluted areas of Italy. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial was conducted. Healthy young men were assigned to an intervention or a control group. INTERVENTION: A 4-mo Mediterranean diet and moderate physical activity program. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcomes were sperm concentration, motility and morphology, concentration of round cells, and semen total antioxidant capacity. Secondary outcomes were adherence to Mediterranean diet and physical activity. All outcomes were measured twice, at the enrollment (t0) and at the end of the intervention (t4). RESULTS AND LIMITATIONS: A total of 263 individuals attended all visits, and underwent examinations and laboratory analyses: 137 in the intervention group and 126 in the control group. The adherence to Mediterranean diet and physical activity level increased more in the intervention group than in the control group from t0 to t4. Sperm concentration, total and progressive motility, and proportion of normal morphology cells increased in the intervention group but decreased in the control group, with statistically significant differences between the two groups at t4. The total antioxidant capacity increased in the intervention group but decreased in the control group, from t0 to t4. CONCLUSIONS: Study results showed that an intervention based on Mediterranean diet and regular physical activity can determine an improvement of semen quality in healthy young men. PATIENT SUMMARY: Our study aimed to evaluate the effect of a lifestyle intervention on semen quality of healthy young men. We assigned the 263 enrolled individuals to an intervention or a control group. The intervention group followed a 4-mo Mediterranean diet and moderate physical activity program, at the end of which the participants showed an improvement of semen quality parameters.

Left atrial appendage thrombosis in a patient with Friedreich Ataxia-related cardiomyopathy, left ventricular systolic dysfunction, and atrial fibrillation.

Friedreich ataxia is the most common form of hereditary ataxia. Heart involvement in Friedreich ataxia is common and can include increased left ventricular wall thickness, atrial fibrillation, and in the later stages, a reduction of left ventricular ejection fraction. We present the case of a 45-year-old man with a history of paroxysmal atrial fibrillation and a congestive heart failure, hypertension, age ⩾ 75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, and female sex (CHA2DS2-VASc) score of only 1 (because of reduced left ventricular ejection fraction) who presented with pneumonia and was also found to have atrial fibrillation with a rapid ventricular response. Despite already being on long-term therapy with a non-vitamin K-antagonist oral anticoagulant, a transesophageal echocardiogram showed a mobile floating thrombus in the left atrial appendage. In accordance with previous necropsy evidence of thrombosis and thromboembolism in Friedreich ataxia subjects who likely have had only non-sex-related CHA2DS2-VASc score ⩽1, this case suggests that the risk of thromboembolism in Friedreich ataxia subjects with atrial fibrillation may not be adequately predicted by the sole CHA2DS2-VASc score.

Antioxidative Molecules in Human Milk and Environmental Contaminants.

Breastfeeding provides overall beneficial health to the mother-child dyad and is universally recognized as the preferred feeding mode for infants up to 6-months and beyond. Human milk provides immuno-protection and supplies nutrients and bioactive compounds whose concentrations vary with lactation stage. Environmental and dietary factors potentially lead to excessive chemical exposure in critical windows of development such as neonatal life, including lactation. This review discusses current knowledge on these environmental and dietary contaminants and summarizes the known effects of these chemicals in human milk, taking into account the protective presence of antioxidative molecules. Particular attention is given to short- and long-term effects of these contaminants, considering their role as endocrine disruptors and potential epigenetic modulators. Finally, we identify knowledge gaps and indicate potential future research directions.

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction.

Flavonoids are plant bioactives that are recognized as hormone-like polyphenols because of their similarity to the endogenous sex steroids 17ß-estradiol and testosterone, and to their estrogen- and androgen-like activity. Most efforts to verify flavonoid binding to nuclear receptors (NRs) and explain their action have been focused on ERα, while less attention has been paid to other nuclear and non-nuclear membrane androgen and estrogen receptors. Here, we investigate six flavonoids (apigenin, genistein, luteolin, naringenin, quercetin, and resveratrol) that are widely present in fruits and vegetables, and often used as replacement therapy in menopause. We performed comparative computational docking simulations to predict their capability of binding nuclear receptors ERα, ERß, ERRß, ERRγ, androgen receptor (AR), and its variant ART877A and membrane receptors for androgens, i.e., ZIP9, GPRC6A, OXER1, TRPM8, and estrogens, i.e., G Protein-Coupled Estrogen Receptor (GPER). In agreement with data reported in literature, our results suggest that these flavonoids show a relevant degree of complementarity with both estrogen and androgen NR binding sites, likely triggering genomic-mediated effects. It is noteworthy that reliable protein-ligand complexes and estimated interaction energies were also obtained for some suggested estrogen and androgen membrane receptors, indicating that flavonoids could also exert non-genomic actions. Further investigations are needed to clarify flavonoid multiple genomic and non-genomic effects. Caution in their administration could be necessary, until the safe assumption of these natural molecules that are largely present in food is assured.

Risk-benefit in food safety and nutrition - Outcome of the 2019 Parma Summer School.

Risk-benefit assessment is the comparison of the risk of a situation to its related benefits, i.e. a comparison of scenarios estimating the overall health impact. The risk-benefit analysis paradigm mirrors the classical risk analysis one: risk-benefit assessment goes hand-in-hand with risk-benefit management and risk-benefit communication. The various health effects associated with food consumption, together with the increasing demand for advice on healthy and safe diets, have led to the development of different research disciplines in food safety and nutrition. In this sense, there is a clear need for a holistic approach, including and comparing all of the relevant health risks and benefits. The risk-benefit assessment of foods is a valuable approach to estimate the overall impact of food on health. It aims to assess together the negative and positive health effects associated with food intake by integrating chemical and microbiological risk assessment with risk and benefit assessment in food safety and nutrition. The 2019 Parma Summer School on risk-benefit in food safety and nutrition had the objective was to provide an opportunity to learn from experts in the field of risk-benefit approach in food safety and nutrition, including theory, case studies, and communication of risk-benefit assessments plus identify challenges for the future. It was evident that whereas tools and approaches have been developed, more and more case studies have been performed which can form an inherent validation of the risk-benefit approach. Executed risk-benefit assessment case studies apply the steps and characteristics developed: a problem formulation (with at least 2 scenarios), a tiered approach until a decision can be made, one common currency to describe both beneficial and adverse effects (DALYs in most instances). It was concluded that risk-benefit assessment in food safety and nutrition is gaining more and more momentum, while also many challenges remain for the future. Risk-benefit is on the verge of really enrolling into the risk assessment and risk analysis paradigm. The interaction between risk-benefit assessors and risk-benefit managers is pivotal in this, as is the interaction with risk-benefit communicators.

Modulation of Human Sperm Mitochondrial Respiration Efficiency by Plant Polyphenols.

Plant bioactives, such as polyphenols, can differentially affect (positively or negatively) sperm quality, depending on their concentration. These molecules have been proposed as natural scavengers of reactive oxygen species (ROS) for male infertility treatment. However, few data are available about their effects on the molecular mechanisms related to sperm quality and, in particular, to sperm mitochondrial function. We investigated the effects of quercetin, naringenin, genistein, apigenin, luteolin, and resveratrol at the concentration of 0.1-1000 nM on mitochondrial respiration efficiency. Upon chemical exposure, spermatozoa were swollen in a hypotonic solution and used for polarographic assays of mitochondrial respiration. All tested compounds, except for apigenin, caused a significant increase in the mitochondrial respiration efficiency at the concentration of 0.1 nM, and a significant decrease starting from concentrations of 10 nM. The analysis of oxygen consumption rate in the active and in the resting state of mitochondrial respiration suggested different mechanisms by which the tested compounds modulate mitochondrial function. Therefore, by virtue of their ability to stimulate the respiration active state, quercetin, genistein, and luteolin were found to improve mitochondrial function in asthenozoospermic samples. Our results are relevant to the debate on the promises and perils of natural antioxidants in nutraceutical supplementation.

Assessing correlations between short-term exposure to atmospheric pollutants and COVID-19 spread in all Italian territorial areas.

The spread of SARS-CoV-2, the beta coronavirus responsible for the current pneumonia pandemic outbreak, has been speculated to be linked to short-term and long-term atmospheric pollutants exposure. The present work has been aimed at analyzing the atmospheric pollutants concentrations (PM10, PM2.5, NO2) and spatio-temporal distribution of cases and deaths (specifically incidence, mortality and lethality rates) across the whole Italian national territory, down to the level of each individual territorial area, with the goal of checking any potential short-term correlation between these two phenomena. The data analysis has been limited to the first quarter of 2020 to reduce the lockdown-dependent biased effects on the atmospheric pollutant levels as much as possible. The analysis looked at non-linear, monotonic correlations using the Spearman non-parametric correlation index. The statistical significance of the Spearman correlations has also been evaluated. The results of the statistical analysis suggest the hypothesis of a moderate-to-strong correlation between the number of days exceeding the annual regulatory limits of PM10, PM2.5 and NO2 atmospheric pollutants and COVID-19 incidence, mortality and lethality rates for all the 107 territorial areas in Italy. A weak-to-moderate correlation seems to exist when considering the 36 territorial areas in four of the most affected regions (Lombardy, Piedmont, Emilia-Romagna and Veneto). Overall, PM10 and PM2.5 showed a higher non-linear correlation than NO2 with incidence, mortality and lethality rates. As to particulate matters, PM10 profile has been compared with the incidence rate variation that occurred in three of the most affected territorial areas in Northern Italy (i.e., Milan, Brescia, and Bergamo). All areas showed a similar PM10 time trend but a different incidence rate variation, that was less severe in Milan compared with Brescia and Bergamo.