Dynamic proteomic and phosphoproteomic atlas of corticostriatal axons in neurodevelopment.

Mammalian axonal development begins in embryonic stages and continues postnatally. After birth, axonal proteomic landscape changes rapidly, coordinated by transcription, protein turnover, and post-translational modifications. Comprehensive profiling of axonal proteomes across neurodevelopment is limited, with most studies lacking cell-type and neural circuit specificity, resulting in substantial information loss. We create a Cre-dependent APEX2 reporter mouse line and map cell-type-specific proteome of corticostriatal projections across postnatal development. We synthesize analysis frameworks to define temporal patterns of axonal proteome and phosphoproteome, identifying co-regulated proteins and phosphorylations associated with genetic risk for human brain disorders. We discover proline-directed kinases as major developmental regulators. APEX2 transgenic reporter proximity labeling offers flexible strategies for subcellular proteomics with cell type specificity in early neurodevelopment, a critical period for neuropsychiatric disease.

Residential proximity to roadways and placental-associated stillbirth: a case-control study.

We conducted a retrospective case-control study of 1,097 women in Massachusetts and Rhode Island, USA, to examine the association between stillbirth related to placental abruption or placental insufficiency and maternal exposure to traffic-related air pollution. We utilized distance to nearest roadway proximity metrics as a proxy for traffic-related air pollution exposure. No meaningful increase in the overall odds of placental-associated stillbirths was observed (adjusted OR: 1.1, 95% CI: 0.5-2.8). However, mothers living within 50 m of a roadway had a 60% increased odds of experiencing a stillbirth related to placental abruption compared to mothers living greater than 200 m away. This suggestive finding was imprecise due to the small case number in the highest exposure category (95% CI: 0.6-4.0). Future studies of placental abruption with more precise exposure assessments are warranted.

A tree-planting decision support tool for urban heat mitigation.

Heat poses an urgent threat to public health in cities, as the urban heat island (UHI) effect can amplify exposures, contributing to high heat-related mortality and morbidity. Urban trees have the potential to mitigate heat by providing substantial cooling, as well as co-benefits such as reductions in energy consumption. The City of Boston has attempted to expand its urban canopy, yet maintenance costs and high tree mortality have hindered successful canopy expansion. Here, we present an interactive web application called Right Place, Right Tree-Boston that aims to support informed decision-making for planting new trees. To highlight priority regions for canopy expansion, we developed a Boston-specific Heat Vulnerability Index (HVI) and present this alongside maps of summer daytime land surface temperatures. We also provide information about tree pests and diseases, suitability of species for various conditions, land ownership, maintenance tips, and alternatives to tree planting. This web application is designed to support decision-making at multiple spatial scales, to assist city officials as well as residents who are interested in expanding or maintaining Boston's urban forest.

Reproductive and developmental health effects of prenatal exposure to tetrachloroethylene-contaminated drinking water.

Tetrachloroethylene (PCE) is a common contaminant in both occupational and community settings. High exposure levels in the workplace have been shown to have adverse impacts on reproduction and development but few epidemiological studies have examined these effects at the lower levels commonly seen in community settings. We were presented with a unique opportunity to examine the reproductive and developmental effects of prenatal exposure to PCE-contaminated drinking water resulting from the installation of vinyl-lined water pipes in Massachusetts and Rhode Island from the late 1960s through 1980. This review describes the methods and findings of two community-based epidemiological studies, places their results in the context of the existing literature, and describes the strengths and challenges of conducting epidemiological research on a historical pollution episode. Our studies found that prenatal exposure to PCE-contaminated drinking water is associated with delayed time-to-pregnancy, and increased risks of placental abruption, stillbirths stemming from placental dysfunction, and certain birth defects. No associations were observed with pregnancy loss, birth weight, and gestational duration. Important strengths of this research included the availability of historical data on the affected water systems, a relatively high exposure prevalence and wide range of exposure levels, and little opportunity for recall bias and confounding. Challenges arose mainly from the retrospective nature of the exposure assessments. This research highlights the importance of considering pregnant women and their developing fetuses when monitoring, regulating, and remediating drinking water contaminants.

Assessing the contributions of metals in environmental media to exposure biomarkers in a region of ferroalloy industry.

Residential proximity to ferroalloy production has been associated with increased manganese exposure, which can adversely affect health, particularly among children. Little is known, however, about which environmental samples contribute most to internal levels of manganese and other ferroalloy metals. We aimed to characterize sources of exposure to metals and evaluate the ability of internal biomarkers to reflect exposures from environmental media. In 717 Italian adolescents residing near ferromanganese industry, we examined associations between manganese, lead, chromium, and copper in environmental samples (airborne particles, surface soil, indoor/outdoor house dust) and biological samples (blood, hair, nails, saliva, urine). In multivariable regression analyses adjusted for child age and sex, a 10% increase in soil Mn was associated with increases of 3.0% (95% CI: 1.1%, 4.9%) in nail Mn and 1.6% (95% CI: -0.2%, 3.4%) in saliva Mn. Weighted-quantile-sum (WQS) regression estimated that higher soil and outdoor dust Mn accounted for most of the effect on nail Mn (WQS weights: 0.61 and 0.22, respectively, out of a total of 1.0). Higher air and soil Mn accounted for most of the effect on saliva Mn (WQS weights: 0.65 and 0.29, respectively). These findings can help inform biomarker selection in future epidemiologic studies and guide intervention strategies in exposed populations.

Modeled exposure to tetrachloroethylene-contaminated drinking water and the occurrence of birth defects: a case-control study from Massachusetts and Rhode Island.

BACKGROUND: Residents of Massachusetts and Rhode Island were exposed to tetrachloroethylene-contaminated drinking water from 1968 through the early 1990s when it leached from the vinyl lining of asbestos cement water distribution pipes. While occupational exposure to solvents during pregnancy has consistently been linked to an increased risk of certain birth defects, mixed results have been observed for environmental sources of exposure, including contaminated drinking water. The present case-control study was undertaken to examine further the association between prenatal exposure to tetrachloroethylene-contaminated drinking water and the risk of central nervous system defects, oral clefts and hypospadias. METHODS: Cases were comprised of live- and stillborn infants delivered between 1968 and 1995 to mothers who resided in 28 Massachusetts and Rhode Island cities and towns with some PCE-contaminated water supplies. Infants with central nervous system defects (N = 268), oral clefts (N = 112) and hypospadias (N = 94) were included. Controls were randomly selected live-born, non-malformed infants who were delivered during the same period and geographic area as cases (N = 771). Vital records and self-administered questionnaires were used to gather identifying information, birth defect diagnoses, and other relevant data. PCE exposure during the first trimester was estimated using water distribution system modeling software that incorporated a leaching and transport model. Prenatal PCE exposure was dichotomized as "high" or "low" exposure at the level corresponding to an estimated average concentration of 40 µg/L, the criterion for remediation when PCE contamination was discovered in 1980. RESULTS: Mothers with "high" levels of exposure to PCE-contaminated drinking water during the first trimester (> 40 µg/L) had increased odds of having a child with spina bifida (OR: 2.0, 95% CI: 0.8-5.4), cleft lip with or without cleft palate (OR: 3.8, 95% CI: 1.2-12.3) and hypospadias (OR: 2.1, 95% CI:0.5-8.3). No increases in the odds of other defects were observed in relation to "high" exposure levels. CONCLUSIONS: The results of the present study suggest that mothers with "high" PCE exposure levels during the first trimester have increased odds of having a child with spina bifida, cleft lip with or without cleft palate, and hypospadias. These findings support several prior studies that observed an increased risk of selected birth defects following prenatal exposure to solvents in occupational and environmental settings. Even though PCE contamination from vinyl lined pipes was remediated many years ago, it remains a widespread contaminant across the U.S and so environmental regulations must be guided by a precautionary perspective that safeguards pregnant women and their offspring.

Modeled exposure to tetrachloroethylene-contaminated drinking water and the risk of placenta-related stillbirths: a case-control study from Massachusetts and Rhode Island.

BACKGROUND: Residents of Massachusetts and Rhode Island were exposed to tetrachloroethylene (PCE)-contaminated drinking water from 1968 through the early 1990s when the solvent was used to apply a vinyl liner to drinking water mains to address taste and odor problems. Few studies have examined the risk of fetal death among women exposed to solvent-contaminated drinking water. Two previous investigations found moderate increases in the risk of stillbirth among highly exposed women; however, these results were based on a small number of cases. The present case-control study was undertaken to examine further this association with a large number of stillbirths. METHODS: Cases were comprised of stillborn infants delivered between 1968 and 1995 to mothers who resided in 28 Massachusetts and Rhode Island cities and towns with some affected water mains (N = 296). Cases were included if the cause of death was placental abruption and/or placental insufficiency. Controls were randomly selected live-born infants who were delivered in the same time period and geographic area (N = 783). Data on confounding variables were gathered from vital records and questionnaires. PCE exposure was estimated using a leaching and transport model integrated into water system software. RESULTS: Mothers with any PCE exposure had a 1.7-fold increase in the adjusted odds of placenta-related stillbirth (95% CI: 1.2-2.4). The adjusted odds ratio (OR) increased as a woman's exposure level increased: in comparison to unexposed mothers, ORs were 1.5 (95% CI: 1.0-2.3) for low exposure (> 0-median), 1.7 (95% CI: 1.1-2.5) for moderate exposure (>median-90th percentile) and 1.9 (95% CI: 1.1-3.2) for high exposure (>90th percentile) (p value for trend = 0.02). A similar pattern was observed when PCE exposure was dichotomized at 40 µg/L, the suggested action guideline for remediation (OR = 1.5, 95% CI: 1.1-2.2 and OR = 2.6, 95% CI: 1.4-4.8, respectively, for PCE exposure <=40 µg/L and > 40 µg/L) (p value for trend = .003). CONCLUSIONS: We observed a linear dose-dependent increase in the odds of stillbirth due to placental abruption and placental insufficiency with prenatal exposure to PCE contaminated drinking water. Because PCE remains a common drinking water contaminant, these findings highlight the importance of considering pregnant women when monitoring, regulating and remediating drinking water supplies.

Feasibility of testing a coaching training intervention for CNAs in nursing homes.

The study aim was to describe the feasibility of conducting a coaching training intervention on use of level of assistance strategies for Certified Nursing Assistants (CNAs) in nursing homes. CNAs received either traditional or coaching training. Feasibility of coaching training was evaluated by determining: acceptability, through use of a Post-Intervention Evaluation Form; fidelity, by adherence to protocol; recruitment and retention, by ease of obtaining the sample and retention rates; and ability to randomize within each home without contamination. CNAs' mean satisfaction score of the coach training was high (4.5 out of 5). Eighteen of 22 comments on the evaluation form were positive. At least six dyads were recruited within the 60-day benchmark in each home. CNA and resident retention rates were 89.47% and 85%, respectively. Eighty-nine percent of intervention group CNAs shared study information, demonstrating contamination. The coaching training intervention is feasible. Findings revealed areas to improve the intervention.

Potential Effectiveness of Point-of-Use Filtration to Address Risks to Drinking Water in the United States.

Numerous contemporary incidents demonstrate that conventional control strategies for municipal tap water have limited ability to mitigate exposures to chemicals whose sources are within distribution systems, such as lead, and chemicals that are not removed by standard treatment technologies, such as perfluorooctanoic acid (PFOA)/perfluorooctanesulfonic acid (PFOS). In these situations, point-of-use (POU) controls may be effective in mitigating exposures and managing health risks of chemicals in drinking water, but their potential utility has not been extensively examined. As an initial effort to fill this information gap, we conducted a critical review and analysis of the existing literature and data on the effectiveness of POU drinking water treatment technologies for reducing chemical contaminants commonly found in tap water in the United States. We found that many types of water treatment devices available to consumers in the United States have undergone laboratory testing and often certification for removal of chemical contaminants in tap water, but in most cases their efficacy in actual use has yet to be well characterized. In addition, the few studies of POU devices while "in use" focus on traditional contaminants regulated under the Safe Drinking Water Act, but do not generally consider nontraditional contaminants of concern, such as certain novel human carcinogens, industrial chemicals, pesticides, pharmaceuticals, personal care products, and flame retardants. Nevertheless, the limited information available at present suggests that POU devices can be highly effective when used prophylactically and when deployed in response to contamination incidents. Based on these findings, we identify future areas of research for assessing the ability of POU filters to reduce health-related chemical contaminants distributed through public water systems and private wells.

Pilot Testing a Coaching Intervention to Improve Certified Nursing Assistants' Dressing of Nursing Home Residents.

The purpose of the current study was to identify initial effects of a coaching training intervention using Level of Assistance (LoA) strategies compared with traditional lecture techniques on the appropriateness of LoA use by certified nursing assistants (CNAs) and independence of dressing of nursing home residents with dementia. Seventeen CNA-resident dyads participated in this pilot randomized controlled trial (RCT). Control and experimental group CNAs received a 25-minute traditional lecture. Experimental group CNAs also underwent three coaching sessions over 4 weeks. There were significant between-group differences in the percentage of dyads who had improved scores for appropriateness of LoA use and dressing independence from pretest to posttest (experimental: n = 9, 100%; control: n = 8, 50%; p = 0.029). However, there were no statistically significant median differences between groups in appropriateness of LoA use by CNAs and resident dressing independence scores. There were significant within-group median improvements in appropriateness of LoA use (p = 0.004) and independence of dressing scores (p = 0.004) between pretest and posttest in the experimental group, but not in the control group. This initial pilot RCT supports coach training as a method to improve appropriate use of LoA strategies by CNAs and independence of resident dressing. [Res Gerontol Nurs. 2017; 10(6):267-276.].

Residential Proximity to Roadways and Ischemic Placental Disease in a Cape Cod Family Health Study.

Exposure to air pollution may adversely impact placental function through a variety of mechanisms; however, epidemiologic studies have found mixed results. We examined the association between traffic exposure and placental-related obstetric conditions in a retrospective cohort study on Cape Cod, MA, USA. We assessed exposure to traffic using proximity metrics (distance of residence to major roadways and length of major roadways within a buffer around the residence). The outcomes included self-reported ischemic placental disease (the presence of at least one of the following conditions: preeclampsia, placental abruption, small-for-gestational-age), stillbirth, and vaginal bleeding. We used log-binomial regression models to estimate risk ratios (RR) and 95% confidence intervals (CI), adjusting for potential confounders. We found no substantial association between traffic exposure and ischemic placental disease, small-for-gestational-age, preeclampsia, or vaginal bleeding. We found some evidence of an increased risk of stillbirth and placental abruption among women living the closest to major roadways (RRs comparing living <100 m vs. ≥200 m = 1.75 (95% CI: 0.82-3.76) and 1.71 (95% CI: 0.56-5.23), respectively). This study provides some support for the hypothesis that air pollution exposure adversely affects the risk of placental abruption and stillbirth; however, the results were imprecise due to the small number of cases, and may be impacted by non-differential exposure misclassification and selection bias.

Childhood and adolescent fish consumption and adult neuropsychological performance: An analysis from the Cape Cod Health Study.

OBJECTIVE: This exploratory analysis examines the relationship between childhood and adolescent fish consumption and adult neuropsychological performance. DESIGN: Data from a retrospective cohort study that assessed fish consumption from age 7 to 18years via questionnaire were analyzed. A subset of the population underwent domain-specific neuropsychological assessment. Functions evaluated included omnibus intelligence, academic achievement, language, visuospatial skills, learning and memory, attention and executive function, fine motor coordination, mood, and motivation to perform. SETTING: Eight towns in the Cape Cod region of Massachusetts, USA, an area characterized by high fish consumption and an active seafood industry. SUBJECTS: A cohort of 1245 subjects was recruited based on Massachusetts birth records from 1969 to 1983. Sixty-five participants from the original cohort underwent neuropsychological testing in adulthood (average age=30years). RESULTS: Participant report of consuming fish at least twice per month was associated with better performance on tests of visual learning, memory, and attentional abilities. However, self-report of consuming fish at rates higher than twice per month was not associated with improved abilities. No statistically significant associations were observed between type of fish consumed (e.g., species known to be high in methylmercury content) and test outcomes. CONCLUSIONS: The results suggest that moderate fish consumption during childhood and adolescence may be associated with some cognitive benefits and that consumption of fish during this exposure window may potentially influence adult neuropsychological performance. Future prospective studies should take into account this time period of exposure.

Childhood Fish Consumption and Learning and Behavioral Disorders.

Fish is a major source of nutrients critical for brain development during early life. The importance of childhood fish consumption is supported by several studies reporting associations of n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation with better behavior and school performance. However, fish may have a different effect than n-3 PUFA alone due to the neurotoxic effects of methylmercury, a frequent contaminant. We investigated associations of childhood fish consumption with learning and behavioral disorders in birth cohort study of the neurotoxic effects of early life exposure to solvent-contaminated drinking water. Childhood (age 7-12 years) fish consumption and learning and behavioral problems were reported in self-administered questionnaires (age 23-41 at questionnaire completion). Fish consumption was not meaningfully associated with repeating a grade, tutoring, attending summer school, special class placement, or low educational attainment. However, participants who ate fish several times a week had an elevated odds of Attention Deficit Disorder/Attention Deficit Hyperactivity Disorder (odds ratio: 5.2; 95% confidence interval: 1.5-18) compared to participants who did not eat fish. While these findings generally support the safety of the observed level of fish consumption, the absence of a beneficial effect may be attributed to insufficient fish intake or the choice of relatively low n-3 PUFA fish.

Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium.

Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal adenosis remains elusive. Here we report that DES induces vaginal adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Müllerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5' sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate.

The development of cervical and vaginal adenosis as a result of diethylstilbestrol exposure in utero.

Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow-up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Müllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models that can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses their molecular pathogenesis.