Endocrine-disrupting chemical concentrations in follicular fluid and follicular reproductive hormone levels.

PURPOSE: To determine correlations between chemicals in follicular fluid (FF) and follicular reproductive hormone levels. METHODS: The analysis was part of a larger cohort study to determine associations between exposure to EDCs and in vitro fertilization (IVF) outcomes. FF was aspirated from a single leading follicle per participant. Demographics and data on exposure to EDCs were self-reported by the participants using a questionnaire. The concentrations of estradiol (E2), progesterone (PG), anti-Mullerian hormone (AMH), and inhibin B, as well as that of 12 phthalate metabolites and 12 phenolic chemicals were measured in each FF sample. Multivariate linear regression model was used to identify the drivers of hormone levels based on participant's age, BMI, smoking status, and chemical exposure for the monitored chemicals detected in more than 50% of the samples. Benjamini-Hochberg false discovery rate (FDR) correction was applied on the resulting p values (q value). RESULTS: FF samples were obtained from 72 women (mean age 30.9 years). Most of the phthalates and phenolic substances monitored (21/24, 88%) were identified in FF. Ten compounds (7 phthalate metabolites, 3 phenols) were found in more than 50% of samples. In addition, there were positive associations between E2 levels and mono-n-butyl phthalate (MnBP) (beta = 0.01) and mono-isobutyl phthalate (MiBP) (beta = 0.03) levels (q value < 0.05). CONCLUSION: Higher concentrations of several phthalate metabolites, present among others in personal care products, were associated with increased E2 levels in FF. The results emphasize the need to further investigate the mechanisms of action of such EDCs on hormonal cyclicity and fertility in women.

Association between parental smoking and child exposure to environmental tobacco smoke in Israel.

BACKGROUND: Environmental tobacco smoke (ETS) exposure in children can cause delayed lung development and lifelong cardiovascular damage. The aim of this study was to measure ETS exposure in children in Israel in 2020-2021 using urinary cotinine (UC) measurements and to assess correlates of ETS exposure, including parental smoking. METHODS: In the framework of the National Human Biomonitoring Program, spot urine samples and questionnaire data were collected from 166 children aged 4-12 years, during the years 2020-2021. We collected urine samples in 233 adults, 69 of whom were parents of children included in the study. Parents of participating children were asked about parental smoking, child's exposure to ETS and smoking policy at home. Cotinine and creatinine were measured in urine. Creatinine-adjusted and unadjusted urine cotinine (UC) geometric means were calculated. Associations between potential correlates and UC concentrations were analyzed in univariate and multivariate analyses. For 69 child-parent pairs, correlation between child and parental UC was analyzed. RESULTS: Based on urinary cotinine measurement, 65.2% of children of smokers are exposed to ETS, compared to 20.7% of children in non-smoking families. Greater numbers of smokers living in the home (beta = 1.27, p < 0.01), and low maternal education (beta = - 2.32, p < 0.01) were associated with higher levels of UC in a multivariate analysis. Spearman correlations showed a positive moderate correlation between UC in 69 child-parent pairs (r = 0.52, p < 0.01). CONCLUSIONS: In order to reduce child exposure to ETS, smoking parents should be urgently targeted for smoking cessation and smoke-free home interventions. Further interventions are needed to protect all children from ETS.

Influence of exposure to pesticides on telomere length and pregnancy outcome: Diethylphosphates but not Dimethylphosphates are associated with accelerated telomere attrition in a Palestinian cohort.

Exposure to environmental pesticides during pregnancy is associated with adverse health outcomes such as low birth weight and impaired neuro-development. In this study, we assessed maternal leukocyte telomere lengths (TL) in Palestinian pregnant women and compared the data with urinary organophosphate concentrations, demographic, lifestyle and dietary factors, birth weight, body length, gestational age, and head circumference. Women with high urine levels of creatinine adjusted diethylphosphate(DE)derived pesticide metabolites DEP, DETP or DEDTP had shorter telomeres (p = 0.05). Women living in proximity to agricultural fields had shorter telomeres compared to women not living in proximity to agricultural fields (p = 0.011). Regular consumption of organic food was associated with shorter telomeres (p = 0.01), whereas the consumption of other vegetables such as artichokes was rather associated with longer telomeres. By contrast, urine levels of dimethylphosphate(DM)-derived pesticide metabolites DMTP and DMDTP were associated with lower birth weight (p = 0.05) but not with shrter telomeres. In conclusion organophosphate pesticides and living in proximity to agriculture are associated with shorter TL, likely due to higher consumption of contaminated fruits and vegetables and/or the transport of pesticides to non-treatment sites. DE and DM substituted pesticides seem to have different effects on telomeres and development.

Improving the Risk Assessment of Pesticides through the Integration of Human Biomonitoring and Food Monitoring Data: A Case Study for Chlorpyrifos.

The risk assessment of pesticide residues in food is a key priority in the area of food safety. Most jurisdictions have implemented pre-marketing authorization processes, which are supported by prospective risk assessments. These prospective assessments estimate the expected residue levels in food combining results from residue trials, resembling the pesticide use patterns, with food consumption patterns, according to internationally agreed procedures. In addition, jurisdictions such as the European Union (EU) have implemented large monitoring programs, measuring actual pesticide residue levels in food, and are supporting large-scale human biomonitoring programs for confirming the actual exposure levels and potential risk for consumers. The organophosphate insecticide chlorpyrifos offers an interesting case study, as in the last decade, its acceptable daily intake (ADI) has been reduced several times following risk assessments by the European Food Safety Authority (EFSA). This process has been linked to significant reductions in the use authorized in the EU, reducing consumers' exposure progressively, until the final ban in 2020, accompanied by setting all EU maximum residue levels (MRL) in food at the default value of 0.01 mg/kg. We present a comparison of estimates of the consumer's internal exposure to chlorpyrifos based on the urinary marker 3,5,6-trichloro-2-pyridinol (TCPy), using two sources of monitoring data: monitoring of the food chain from the EU program and biomonitoring of European citizens from the HB4EU project, supported by a literature search. Both methods confirmed a drastic reduction in exposure levels from 2016 onwards. The margin of exposure approach is then used for conducting retrospective risk assessments at different time points, considering the evolution of our understanding of chlorpyrifos toxicity, as well as of exposure levels in EU consumers following the regulatory decisions. Concerns are presented using a color code, and have been identified for almost all studies, particularly for the highest exposed group, but at different levels, reaching the maximum level, red code, for children in Cyprus and Israel. The assessment uncertainties are highlighted and integrated in the identification of levels of concern.

MRI guided focused ultrasound (MRgFUS) treatment for uterine fibroids among women with and without abdominal scars.

INTRODUCTION: MRI guided focused ultrasound (MRgFUS) is a noninvasive technique for treating uterine fibroids. The presence of abdominal scars can limit the number of women eligible for the procedure, due to absorbance of beam energy. The goals of this study were to assess the number of women that fit the procedure and to compare outcomes among women with or without abdominal scars. MATERIAL AND METHODS: A prospective cohort study of all women that were interested in MRgFUS in a single University-Affiliated Hospital between November 2012 and December 2019. Rates of women that were referred to further screening, fulfilled selection criteria and underwent the procedure were compared between patients with or without abdominal scars. We evaluated the treatment parameters of the two groups and used linear regression model predict non-perfused volume (NPV) at the end of the process. RESULTS: Out of 701 patients, 21.8% were suitable for MRgFUS. Women with scars had significant lower NPV compared with women without scars (60% versus 82.4%, p = 0.021). No serious adverse events were reported in both groups. Linear regression models showed that fibroids' volume, stopping the treatment due to severe pain and the presence of abdominal scars had a statistically significantly negative effect on NPV (betas: -11.51, -6.96, and -6.29, p-values: <0.001, 0.003, and 0.007 respectively), while number of sonication had a statistically significantly positive effect on NPV (beta = 5.98, p = 0.011). CONCLUSION: Regardless of strict inclusion criteria, MRgFUS treatment is less efficient among women with abdominal scars, although still feasible for those who are interested in noninvasive option.

The dynamic optotype (Dyop): a novel visual acuity test for use in children.

PURPOSE: To evaluate the "dynamic optotype" (Dyop), a simple visual acuity test based on a dynamic target that requires minimal knowledge of symbols and letters. METHODS: A total of 160 consecutive, systemically healthy children, 4-17 years of age were prospectively recruited from the Pediatric Ophthalmology Unit of Meir Medical Center. Children were tested with the Dyop visual acuity test and the Early Treatment Diabetic Retinopathy Study (ETDRS) Lea numbers chart. The results of both tests were compared. The eye with the poorest acuity was tested with the new Dyop eye chart and the Lea numbers chart. The order of the testing was reversed between children. The logMAR visual acuity scores for each eye chart were compared. RESULTS: We found a strong linear correlation (r = 0.88) between visual acuity measures. The mean difference in visual acuity was -0.01 (95% CI, -0.02 to 0.01). The 95% limits of agreement were ±1.2 lines. The logMAR equivalent mean difference was about less than 1 letter. The Dyop test underestimated visual acuity relative to the Lea numbers chart. CONCLUSIONS: The results of this study support the Dyop eye chart as a valid measure of visual acuity in children 4-17 years of age, with visual acuity ranging from 20/16 to 20/200.

Unconventional oil and gas development and health outcomes: A scoping review of the epidemiological research.

BACKGROUND: Hydraulic fracturing together with directional and horizontal well drilling (unconventional oil and gas (UOG) development) has increased substantially over the last decade. UOG development is a complex process presenting many potential environmental health hazards, raising serious public concern. AIM: To conduct a scoping review to assess what is known about the human health outcomes associated with exposure to UOG development. METHODS: We performed a literature search in MEDLINE and SCOPUS for epidemiological studies of exposure to UOG development and verified human health outcomes published through August 15, 2019. For each eligible study we extracted data on the study design, study population, health outcomes, exposure assessment approach, statistical methodology, and potential confounders. We reviewed the articles based on categories of health outcomes. RESULTS: We identified 806 published articles, most of which were published during the last three years. After screening, 40 peer-reviewed articles were selected for full text evaluation and of these, 29 articles met our inclusion criteria. Studies evaluated pregnancy outcomes, cancer incidence, hospitalizations, asthma exacerbations, sexually transmitted diseases, and injuries or mortality from traffic accidents. Our review found that 25 of the 29 studies reported at least one statistically significant association between the UOG exposure metric and an adverse health outcome. The most commonly studied endpoint was adverse birth outcomes, particularly preterm deliveries and low birth weight. Few studies evaluated the mediating pathways that may underpin these associations, highlighting a clear need for research on the potential exposure pathways and mechanisms underlying observed relationships. CONCLUSIONS: This review highlights the heterogeneity among studies with respect to study design, outcome of interest, and exposure assessment methodology. Though replication in other populations is important, current research points to a growing body of evidence of health problems in communities living near UOG sites.

A hybrid model for evaluating exposure of the general population in Israel to air pollutants.

Exposure to air pollution is associated with a wide range of health effects, including increased respiratory symptoms, cancer, reproductive and birth defects, and premature death. Air quality measurements by standardized measuring equipment, although accurate, can only provide an estimate for part of the population, with decreasing accuracy further away from the monitoring sites. Estimating pollution levels over large geographical domains requires the use of air quality models which ideally incorporate air quality measurements. In order to estimate actual exposure of the population to air pollution (population-weighted concentrations of air pollutants), there is a need to combine data from air quality models with population density data. Here we present the results of exposure estimates for the entire population of Israel using a chemical transport model combined with measurements from the national monitoring network. We evaluated the individual exposure levels for the entire population to several air pollutants based on census tract units. Using this hybrid model, we found that the entire population of Israel is exposed to concentrations of PM10 and PM2.5 that exceed the target values but are below the environmental values according to the Israeli Clean Air Law. In addition, we found and that over 1.5 million residents are exposed to NOx at concentrations higher than the target values. This data may help decision makers develop targeted interventions to reduce the concentrations of specific pollutants, based on population-weighted exposure.

Newborn infant urinary cotinine and birth outcomes in the Jerusalem Environment Mother and Child Cohort Study.

BACKGROUND: Environmental tobacco smoke (ETS) exposure during pregnancy can cause preterm delivery and childhood cancer. The aim of this study was to measure ETS exposure in pregnant women and in newborn infants in Israel using urinary cotinine measurements, to assess predictors of ETS exposure in these vulnerable groups, and to assess associations with birth effects (birth weight, birth length, head circumference) in newborn infants. METHODS: We analyzed urinary cotinine and creatinine in 265 non-smoking pregnant women and 97 newborns, and analyzed associations with self-reported exposure to ETS, paternal smoking, sociodemographic variables and with birth outcomes (birth weight, birth length, head circumference). RESULTS: 37.7% of pregnant women and 29.0% of infants had urinary cotinine concentrations above the level of quantification (LOQ) of 1 µg/L, whereas 63.8% and 50.5%, respectively, had urinary cotinine concentrations above the level of detection (LOD) of 0.5 µg/L. Median unadjusted and creatinine adjusted urinary concentrations of cotinine in pregnant women were 0.7 µg/L, and 0.9 µg/g creatinine, respectively, and in newborn infants were 0.5 µg/L, and 1.3 µg/g creatinine, respectively. We did not find an association between maternal and infant urinary cotinine level. Maternal (but not infant) urinary cotinine was significantly associated with paternal smoking (p < 0.05). Infant (but not maternal) cotinine above the LOQ was negatively associated with birth weight (p < 0.05). CONCLUSIONS: In this high socioeconomic cohort, almost a third of newborn infants born to non-smoking mothers had quantifiable levels of urinary cotinine. This is the first study showing that newborns with quantifiable urinary cotinine levels have lower birth weight.

Socioeconomic inequalities in exposure to environmental tobacco smoke in children in Israel.

BACKGROUND: Environmental tobacco smoke (ETS) exposure in infants and children causes more frequent and severe asthma attacks, respiratory infections, ear infections, and sudden infant death syndrome. The aim of this study was to measure ETS exposure in children in Israel (ages 4-11 years) using urinary cotinine measurements, in order to compare exposure levels to other international populations, and to assess predictors of ETS exposure in children in Israel. METHODS: A subset of children who participated in the National Health and Nutrition Survey (RAV- MABAT) in 2015-2016 were invited to participate in the Second Israel Biomonitoring Survey. We analyzed urinary cotinine and creatinine concentrations in 103 children. Parents of study participants were interviewed in person on children's exposure to ETS at home and in other environments and on sociodemographic variables. We calculated creatinine-adjusted and unadjusted urinary cotinine geometric means in children and analyzed associations in univariable and multivariable analyses, between sociodemographic variables and parental - reported exposure, and urinary cotinine concentrations. RESULTS: Based on urinary creatinine measurement, over 60% of children are exposed to ETS (compared to <40% based on parental report). Linear regression showed a positive association between urinary cotinine concentration and reported ETS exposure (p = 0.001). Mean cotinine concentration among children whose parents reported that they are exposed to ETS at home (5.1 µg/l) was significantly higher than the concentration among children whose parents reported they are not exposed to ETS at home (1.6 µg/l, p < 0.001). There was an inverse relationship between total family income and urinary cotinine concentration (p < 0.05). In a multivariable model adjusted for ethnicity and other factors, family income was a significant predictor of urinary cotinine level (p = 0.04, slope = -0.49). Geometric mean creatinine adjusted concentrations in children in the current study were higher than in children in Canada and selected European countries. CONCLUSIONS: We found evidence of widespread exposure to ETS in children in the study. There is an urgent need to protect children in Israel from exposure to ETS.

Exposure to environmental tobacco smoke in non - smoking adults in Israel: results of the second Israel biomonitoring survey.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) increases the risk of heart and respiratory disease, cancer, and premature mortality in non-smoking individuals. Results from the first Israel Biomonitoring Study in 2011 showed that over 60% of non-smoking adults are exposed to ETS. The purpose of the current study was to assess whether policies to restrict smoking in public places have been associated with reductions in exposure to ETS, and to examine predictors of exposure. METHODS: We analyzed urinary cotinine and creatinine concentrations in 194 adult participants in the National Health and Nutrition (RAV MABAT) Survey in 2015-2016. Study participants were interviewed in person on smoking status and exposure to ETS. We calculated creatinine-adjusted and unadjusted urinary cotinine geometric means and medians among smokers and non-smokers. We analyzed associations in univariable analyses, between socio-demographic variables and self - reported exposure, and urinary cotinine concentrations. RESULTS: There was no reduction in geometric mean urinary cotinine levels in non-smokers in the current study (1.7 µg/g) compared to that in 2011 (1.6 µg/g). Median cotinine levels among the non - smoking Arab participants were higher in comparison to the Jewish and other participants (2.97 versus 1.56 µg/l, p = 0.035). Participants who reported that they were exposed to ETS at home had significantly higher median levels of creatinine adjusted urinary cotinine than those reporting they were not exposed at home (4.19 µg/g versus 2.9 µg/g, p = 0.0039). CONCLUSIONS: Despite additional restrictions on smoking in public places in 2012-2016, over 60% of non-smoking adults in Israel continue to be exposed to ETS. Urinary cotinine levels in non-smokers have not decreased compared to 2011. Results indicate higher exposure to ETS in Arab study participants and those reporting ETS exposure at home. There is an urgent need: (1) to increase enforcement on the ban on smoking in work and public places; (2) for public health educational programs and campaigns about the adverse health effects of ETS; and (3) to develop and disseminate effective interventions to promote smoke free homes. Periodic surveys using objective measures of ETS exposure (cotinine) are an important tool for monitoring progress, or lack thereof, of policies to reduce exposure to tobacco smoke in non-smokers.

The bone marrow is patrolled by NK cells that are primed and expand in response to systemic viral activation.

The bone marrow hosts NK cells whose distribution, motility and response to systemic immune challenge are poorly understood. At steady state, two-photon microscopy of the bone marrow in Ncr1gfp/+ mice captured motile NK cells interacting with dendritic cells. NK cells expressed markers and effector molecules of mature cells. Following poly (I:C) injection, RNA-Seq of NK cells revealed three phases of transcription featuring immune response genes followed by posttranscriptional processes and proliferation. Functionally, poly (I:C) promoted upregulation of granzyme B, enhanced cytotoxicity in vitro and in vivo, and, in the same individual cells, triggered proliferation. Two-photon imaging revealed that the proportion of sinusoidal NK cells decreased, while at the same time parenchymal NK cells accelerated, swelled and divided within the bone marrow. MVA viremia induced similar responses. Our findings demonstrate that the bone marrow is patrolled by mature NK cells that rapidly proliferate in response to systemic viral challenge while maintaining their effector functions.

Strategies for patient empowerment through the promotion of medicines in Israel: regulatory framework for the pharmaceutical industry.

The correct and rational use of medications can have a positive direct impact on disease outcomes, as well on the utilization of the health system resources. Unfortunately, 50% of the patients do not take their medications as prescribed, largely due to lack of patients' understanding of their medical condition, as well as the lack of reliable medicine information.There are multiple strategies implemented in many countries to tackle this challenge including: disease awareness campaigns (DAC) to raise the public awareness to specific diseases, direct-to-consumer advertisement (DTCA) to raise the public awareness to prescription medicines, specific treatments and over-the-counter (OTC) products to improve the accessibility of patients to specific medicines.Prior to 2013, the Israeli policy prohibited prescribing medication advertising and prevented the flow of information from pharmaceutical companies to the patient. In the last five years, the Pharmaceutical division in the Israeli Ministry of Health, as part of the "empowering the patient" agenda, has taken new innovative approaches to raise public awareness to diseases, medications and appropriate usage, as well as promotion of information to improve patient adherence to the prescribed medication.This paper elaborates on the aforementioned strategies implemented in developed countries, and specifically focuses on newly implemented strategies and regulations in Israel regarding pre- and post-prescription information, to improve patient appropriate utilization and adherence to medication.

MicroRNA-142 controls thymocyte proliferation.

T-cell development is a spatially and temporally regulated process, orchestrated by well-defined contributions of transcription factors and cytokines. Here, we identify the noncoding RNA miR-142 as an additional regulatory layer within murine thymocyte development and proliferation. MiR-142 deficiency impairs the expression of cell cycle-promoting genes in mature mouse thymocytes and early progenitors, accompanied with increased levels of cyclin-dependent kinase inhibitor 1B (Cdkn1b, also known as p27Kip1 ). By using CRISPR/Cas9 technology to delete the miR-142-3p recognition element in the 3'UTR of cdkn1b, we confirm that this gene is a novel target of miR-142-3p in vivo. Increased Cdkn1b protein expression alone however was insufficient to cause proliferation defects in thymocytes, indicating the existence of additional critical miR-142 targets. Collectively, we establish a key role for miR-142 in the control of early and mature thymocyte proliferation, demonstrating the multifaceted role of a single miRNA on several target genes.

CD74 is a novel transcription regulator.

CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor. Macrophage migration inhibitory factor binding to CD74 induces its intramembrane cleavage and the release of its cytosolic intracellular domain (CD74-ICD), which regulates cell survival. In the present study, we characterized the transcriptional activity of CD74-ICD in chronic lymphocytic B cells. We show that following CD74 activation, CD74-ICD interacts with the transcription factors RUNX (Runt related transcription factor) and NF-κB and binds to proximal and distal regulatory sites enriched for genes involved in apoptosis, immune response, and cell migration. This process leads to regulation of expression of these genes. Our results suggest that identifying targets of CD74 will help in understanding of essential pathways regulating B-cell survival in health and disease.

M-sec regulates polarized secretion of inflammatory endothelial chemokines and facilitates CCL2-mediated lymphocyte transendothelial migration.

Activation of endothelial cells by IL-1ß triggers the expression of multiple inflammatory cytokines and leukocyte-attracting chemokines. The machineries involved in the secretion of these inducible proteins are poorly understood. With the use of genome-wide transcriptional analysis of inflamed human dermal microvascular endothelial cells, we identified several IL-1ß-induced candidate regulators of these machineries and chose to focus our study on TNF-α-induced protein 2 (myeloid-secretory). The silencing of myeloid-secretory did not affect the ability of inflamed endothelial cells to support the adhesion and crawling of effector T lymphocytes. However, the ability of these lymphocytes to complete transendothelial migration across myeloid-secretory-silenced human dermal microvascular endothelial cells was inhibited significantly. These observed effects on lymphocyte transendothelial migration were recovered completely when exogenous promigratory chemokine CXCL12 was overlaid on the endothelial barrier. A polarized secretion assay suggested that the silencing of endothelial myeloid-secretory impairs T effector transendothelial migration by reducing the preferential secretion of endothelial-produced CCL2, a key transendothelial migration-promoting chemokine for these lymphocytes, into the basolateral endothelial compartment. Myeloid-secretory silencing also impaired the preferential secretion of other endothelial-produced inflammatory chemokines, as well as cytokines, such as IL-6 and GM-CSF, into the basolateral endothelial compartment. This is the first evidence of a novel inflammation-inducible machinery that regulates polarized secretion of endothelial CCL2 and other inflammatory chemokines and cytokines into basolateral endothelial compartments and facilitates the ability of endothelial CCL2 to promote T cell transendothelial migration.

Analysis of the transcriptional networks underpinning the activation of murine macrophages by inflammatory mediators.

Macrophages respond to the TLR4 agonist LPS with a sequential transcriptional cascade controlled by a complex regulatory network of signaling pathways and transcription factors. At least two distinct pathways are currently known to be engaged by TLR4 and are distinguished by their dependence on the adaptor molecule MyD88. We have used gene expression microarrays to define the effects of each of three variables--LPS dose, LPS versus IFN-ß and -γ, and genetic background--on the transcriptional response of mouse BMDMs. Analysis of correlation networks generated from the data has identified subnetworks or modules within the macrophage transcriptional network that are activated selectively by these variables. We have identified mouse strain-specific signatures, including a module enriched for SLE susceptibility candidates. In the modules of genes unique to different treatments, we found a module of genes induced by type-I IFN but not by LPS treatment, suggesting another layer of complexity in the LPS-TLR4 signaling feedback control. We also observe that the activation of the complement system, in common with the known activation of MHC class 2 genes, is reliant on IFN-γ signaling. Taken together, these data further highlight the exquisite nature of the regulatory systems that control macrophage activation, their likely relevance to disease resistance/susceptibility, and the appropriate response of these cells to proinflammatory stimuli.