National Institute Of Environmental Health Sciences Research Articles

Development of Potent Inhibitors of the Human Microsomal Epoxide Hydrolase

Microsomal epoxide hydrolase (mEH) hydrolyzes a wide range of epoxide containing molecules. Although involved in the metabolism of xenobiotics, recent studies associate mEH with the onset and development of some diseases. This phenomenon is partially attributed to the significant role mEH plays in hydrolyzing endogenous lipid mediators, suggesting more complex and extensive physiological functions. In order to obtain pharmacological tools to further study the biology and therapeutic potential of this enzyme target, we describe the development of highly potent inhibitors of the human mEH with IC50 values in the low nanomolar range, around 2 orders of magnitude more potent than previously obtained mEH inhibitors. Rationalization of binding through docking calculations of the inhibitors to a mEH homology model revealed that an acetamide, with a bulky aliphatic substituent at the α‐position, as well as an aryl ring 3–4 bonds away function as key pharmacophore units. No interaction was observed with the thioether moiety, suggesting it can be replaced by more metabolically stable (e.g. methylene) groups in future studies.Support or Funding InformationNational Institute of Health (NIH) R35 ES030443 and R01 GM076324‐11 grants; National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program P42 ES004699 grant; National Science Foundation Awards 1827246, 1805510 and 1627539; Computation support from Rosetta Commons and the US National Science Foundation’s XSEDE programCompound 62: The most potent mEH inhibitorFigure 1Modeling of key molecular interactions in one binding mode. Left: interactions between amide group of 62 with D226, Y299 and Y374 side chain. Right: π–π stacking between 62 and W227.Figure 2

Maternal Glyphosate Exposure Causes Autism‐like Behaviors in Offspring through Increased Expression of Soluble Epoxide Hydrolase

The number of children with autism spectrum disorder (ASD) has increased dramatically since the 1980s. Epidemiological studies suggest that exposure to pesticides (i.e., glyphosate) during pregnancy might increase the risk for ASD in offspring. Recently, we demonstrated that soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids plays a key role in the development of ASD in offspring after maternal immune activation. In the present study, we found ASD‐like behavioral abnormalities in juvenile offspring after maternal glyphosate exposure. Furthermore, we found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure. Oxylipin analysis showed decreased levels of epoxy‐fatty acids (i.e., 8(9)‐EpETrE [8,9‐epoxy‐5Z,11Z,14Z‐eicosatrienoic acid] in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure, supporting increased activity of sEH in juvenile offspring. The 16S rRNA analysis demonstrated abnormal composition of gut microbiota in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU to pregnant mothers from E5 to P21 could prevent social interaction deficits, increased grooming time in the juvenile offspring after maternal glyphosate exposure. These findings suggest that maternal glyphosate exposure causes ASD‐like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH plays a key role in ASD‐like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH would represent a promising prophylactic target for ASD in offspring after maternal glyphosate exposure.Support or Funding InformationThis study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (to K.H., 17H04243), AMED (to K.H., JP19dm0107119), the National Institute of Environmental Health Sciences (NIEHS) R01 ES002710 (to B.D.H.), NIEHS Superfund Program P42 ES004699 (to B.D.H.).

Dietary unsaturated fatty acid metabolites modulate life span and health span of C. elegans

Dietary unsaturated fatty acids are essential to physiology in different organisms. However, their mechanism remains largely unknown. Recent studies showed that the downstream metabolites play a critical role in inflammation, blood pressure regulation, pain perception, carcinogenesis, wound healing, and tissue and neural repair. However, their role in lifespan and healthspan in mammals remain largely unknown. To study the role and associated mechanism on the effect of unsaturated fatty acid metabolites on lifespan and healthspan in organism, we use C. elegans as a model organism because of the following reasons: 1) It is genetically close to humans; 2) the genome is known; 3) genetic modification is relatively easy; 4) imaging C. elegans is relatively easy, and more importantly, 5) part of the unsaturated fatty acid metabolism is conserved between humans and C. elegans. In this presentation, we will present the effect of cytochrome P450 metabolites on lifespan and healthspan on C. elegans and will discuss the potential mechanism behind such effects.Support or Funding InformationThis work was supported by the National Institute of Environmental Health Sciences (NIEHS) R00 ES024806. This work was also supported by National Science Foundation DMS‐1761320.

Neighbourhood disadvantage and child behaviour in Montevideo, Uruguay: a mixed methods study

BackgroundThe neighbourhood context is important for child development, but little evidence exists on neighbourhood-based challenges and resources in South American cities. We used a mixed methods approach to quantify the effect of neighbourhood disadvantage on child behaviour and to empower parents to explain life in disadvantaged neighbourhoods in Montevideo, Uruguay. MethodsA study within the Salud Ambiental Montevideo (SAM) longitudinal cohort yielded a cross-sectional sample of 225 (63% of total) children aged 6–8 years with complete data. Teacher ratings of child behaviour were collected using the Connors' Teacher Rating Scale—Revised (CTRS-R) and Behavior Rating Inventory of Executive Function (BRIEF). Five indicators of neighbourhood disadvantage were collected from Montevideo census data, and combined into to a single neighbourhood disadvantage factor. In the analyses of the relation between neighbourhood disadvantage and child behaviour scores we controlled for individual-level socioeconomic indicators, child IQ, and concentrations of lead in blood. In a nested study, we conducted semi-structured interviews with ten caregivers of SAM children in low-income neighbourhoods. Parents discussed what neighbourhood means to them and what they liked and disliked about their neighbourhood, perceptions of community services, and raising children in their neighbourhood. Parents were also asked to photograph their neighbourhoods and to discuss the meaning of at least four of their photographs during the interview. FindingsOne SD increase in neighbourhood disadvantage was related to a 1% increase in prevalence ratio on scores of oppositional behaviour (p=0·048) and a 4% increase in prevalence ratio on emotional control problem ratings (p=0·006). Neighbourhood disadvantage was unrelated to hyperactive behaviours and inhibitory control scores. From the interviews, common themes emerged on the importance of playgrounds, neighbourhood disorder, fears over crime, and lack of infrastructure. Many interviewees perceived that their neighbourhoods had been safer in the past. Suggestions for improving neighbourhoods included: better waste management, increased policing, traffic regulation, and improved local clinics. InterpretationNeighbourhood disadvantage is related to child behaviour beyond the influences of individual-level socioeconomic factors. Low-income neighbourhoods in Montevideo face challenges related to local infrastructure and services. Parents advocated for improved infrastructure, health services, transportation, and safety. Future studies should test specific mechanisms behind the effects of neighbourhood disadvantage and child behaviour in Montevideo. FundingUS National Institute of Environmental Health Sciences (NIEHS) and Fogarty International (FI) Institute under grant number R21ES16523, and by NIEHS grant R21ES019949.

Appalachian Environmental Health Literacy: Building Knowledge and Skills to Protect Health.

Environmental health literacy (EHL) is an emerging, multidisciplinary field that promotes understanding of how environmental exposures can affect human health. After discussing the regional relevance of environmental health knowledge and skills, this article describes three ongoing Appalachian projects that are focused on measuring and building EHL.

Health Benefits of Sustained Air Quality Improvements in New York City: A Simulation Based on Air Pollution Levels During the COVID-19 Shutdown

New York City (NYC) experienced a sharp decline in air pollution during the COVID-19 shutdown period (March 15, 2020 to May 15, 2020) — albeit at high social and economic costs. It provided a unique opportunity to simulate a scenario in which the city-wide air quality improvement during the shutdown was sustained over the five-year period, 2021 through 2025, allowing us to estimate the potential public health benefits to children and adults and their associated economic benefits. We focused on fine particulate matter (PM2.5) and modelled potential future health benefits to children and adults. The analysis considered outcomes in children that have not generally been accounted for in clean air benefits assessments, including preterm birth, term low birthweight, infant mortality, child asthma incidence, child asthma hospital admissions and emergency department visits, autism spectrum disorder, as well as adult mortality. We estimated a city-wide 23% improvement in PM2.5 levels during the COVID-19 shutdown months compared to the average level for those months in 2015-2018 (the business as usual period). Based on the data for 2020, we extrapolated the ambient levels of PM2.5 for the following five-year period. The estimated cumulative benefits for 2021-2025 included thousands of avoided cases of illness and death, with associated economic benefits from $31.8 billion to $77 billion.This “natural experiment,” tragic though the cause, resulted in a clean air scenario that can be considered aspirational — one that could be achieved through transportation, climate, and environmental policies that support robust economic recovery with similarly reduced emissions.Funding Statement: This study was supported by the Environmental Protection Agency (EPA) RD83615401 and National Institute of Environmental Health Sciences (NIEHS) P50ES09600, The John Merck Fund (JMF), and New York Community Trust (NYCT).Declaration of Interests: The authors declare no competing interests.

Culturally Appropriate Breast Cancer and Environmental Risk Messages: Targeting Racially and Ethnically Diverse Mothers.

The National Institute of Environmental Health Sciences (NIEHS)-funded Breast Cancer and Environment Research Program (BCERP) provides evidence-informed educational materials targeting mothers with daughters to help them engage in lifestyle changes to reduce their environmental risk of breast cancer. Building on a partnership we developed to disseminate these materials via social media, we teamed with mommy bloggers and readers to evaluate the cultural appropriateness of the information using evidence-based practices for message design. We sought to (1) identify cross-culture factors that speak to a broad group of mothers and culture-specific factors to integrate when targeting specific cultures and (2) capture cultural challenges mothers encounter when they share the information with family to understand the social context in which they receive, interpret, and act on risk-reducing messages. We conducted 50 interviews with racially and ethnically diverse bloggers/readers and thematically analyzed transcripts, comparing findings across cultures. Across cultures, mothers identified five key factors for ensuring cultural appropriateness, but with notable cultural differences: (1) incorporate diverse images, (2) provide more information specific to environmental and cultural risk, (3) heighten the message of "it's a family affair", (4) make behavioral changes feasible, and (5) use less text, more visuals. Across cultures, women experienced intergenerational communication challenges with family, which were tied to (1) lack of openness, (2) relational norms, and (3) generational resistance. Findings provide message design considerations for targeting mothers broadly or based on race/ethnicity and support the notion that the larger family system should be considered when disseminating cancer risk education.

Themes Across New Directions in Community Engagement.

The articles in this special issue on New Directions in Environmental Communication in the International Journal of Environmental Research and Public Health present new research and perspectives on engaging communities impacted by Superfund sites—the hazardous waste sites that have been identified by the U.S. Environmental Protection Agency (EPA) as needing cleanup. In particular, these articles focus on the community engagement cores (CECs) that work with affected communities as part the Superfund Research Program at the National Institute of Environmental Health Sciences (NIEHS). The purpose of this closing article is to highlight important themes evident across the eight articles in the special issue. When considered together, the findings reveal important lessons learned about community engagement and environmental communication, but also reveal that much more remains to be known. Recommendations are made for how these teams can continue to practice, reflect on, and research community engagement in ways that build toward a better understanding and implementation of best practices.

Applying community resilience theory to engagement with residents facing cumulative environmental exposure risks: lessons from Louisiana’s industrial corridor

The presence of legacy pollutants, on-going chemical manufacturing activities, and population shifts have introduced complex, cumulative exposure risks to residents of many highly industrialized communities. These "industrial corridors" present unique challenges to environmental health science professionals, public and private sector decision makers, and residents seeking to make their communities safer and healthier. Social-ecological resilience theory offers a useful framework for the design and implementation of community engagement efforts to help stakeholders take action to reduce their exposure risks. A resilience framework views the human community as a coupled social-ecological system, wherein disturbances to the equilibrium of the system - acute and/or chronic - are common rather than rare events. It recognizes three key capacities of more resilient communities. These are the abilities of community members to self-organize to address changing threat levels, to hold scientifically sound understandings of the risks, and to learn from past experiences and take action - individually or collectively - to adapt to or mitigate the hazards in their local environment. We apply this resilience theory framework to a case study from Camp Minden, Louisiana, conducted through the Louisiana State University (LSU) Superfund Research Center's Community Engagement program and supported by the National Institute of Environmental Health Sciences (NIEHS). The case illuminates a critical path by which resilience theory can be applied to guide bi-directional communication and information-gathering, and co-development of risk-reducing strategies at the community level. These are central elements of community engagement within a contentious, real-world setting. The three components of the resilience framework were supported by specific program mechanisms and activities. The capacity for self-organization among community stakeholders was furthered through the convening of a Dialogue Committee which brought together representatives of concerned residents, regulatory agencies, research scientists, and others. This collaborative problem-solving approach supported a more holistic and scientifically sound understanding of the problem through a series of interactive meetings in which members discussed site-remediation options with thermal-treatment experts and regulators, and shared how recent explosions and concerns about air quality affected them. The members co-developed selection criteria and reached consensus on two types of disposal methods that would best reduce the significant threats to public health and the local environment. We also include a brief summary of our recent randomized survey of over 550 residents of Louisiana's industrialized communities to determine the influences on household-level adaptive behaviors to reduce acute and chronic environmental exposure risks. The results of the logistic regression analysis indicate that residents with more concern and knowledge about environmental hazards, along with confidence in their ability to implement risk-reduction measures - such as checking air-quality forecasts and then limiting outside activities - were much more likely to adopt the exposure-reducing behaviors, even when controlling for socioeconomic and demographic differences among respondents. These findings shed light on the conditions under which residents of these types of communities may be more likely to take action to reduce potential environmental exposure risks, and may help in the design of public education efforts. These "lessons learned" from Louisiana communities facing cumulative environmental exposure risks suggest that application of resilience theory to the design and implementation of community engagement programs may support the longer-term effectiveness of the efforts and enhance overall environmental health resilience. In addition, they provide practical insights about how to operationalize and apply these theoretical concepts to real-world environmental health challenges faced by residents of industrialized communities throughout the world.

Marijuana smoking and outcomes of infertility treatment with assisted reproductive technologies.

What is the association of female and male partner marijuana smoking with infertility treatment outcomes with ART? Women who were marijuana smokers at enrollment had a significantly higher adjusted probability of pregnancy loss during infertility treatment with ART whereas, unexpectedly, there was a suggestion of more favorable treatment outcomes in couples where the man was a marijuana smoker at enrollment. Data on the relation of female and male partner marijuana use with outcomes of infertility treatment is scarce despite increased use and legalization worldwide. We followed 421 women who underwent 730 ART cycles while participating in a prospective cohort (the Environment and Reproductive Health Study) at a fertility center between 2004 and 2017. Among them, 200 women (368cycles) were part of a couple in which their male partner also enrolled in the study. Participants self-reported marijuana smoking at baseline. Clinical endpoints were abstracted from electronic medical records. We used generalized linear mixed models with empirical standard errors to evaluate the association of baseline marijuana smoking with ART outcomes adjusting for participants' age, race, BMI, tobacco smoking, coffee and alcohol consumption, and cocaine use. We estimated the adjusted probability of implantation, clinical pregnancy, and live birth per ART cycle, as well as the probability of pregnancy loss among those with a positive B-hCG. The 44% of the women and 61% of the men had ever smoked marijuana; 3% and 12% were marijuana smokers at enrollment, respectively. Among 317 women (395cycles) with a positive B-hCG, those who were marijuana smokers at enrollment (N = 9, cycles = 16) had more than double the adjusted probability of pregnancy loss than those who were past marijuana smokers or had never smoked marijuana (N = 308, 379cycles) (54% vs 26%; P = 0.0003). This estimate was based on sparse data. However, couples in which the male partner was a marijuana smoker at enrollment (N = 23, 41cycles) had a significantly higher adjusted probability of live birth than couples in which the male partner was a past marijuana smoker or had never smoked marijuana (N= 177, 327cycles) (48% vs 29%; P = 0.04), independently of the women's marijuana smoking status. Treatment outcomes of past marijuana smokers, male and female, did not differ significantly from those who had never smoked marijuana. Marijuana smoking was self-reported with possible exposure misclassification. Chance findings cannot be excluded due to the small number of exposed cases. The results may not be generalizable to couples from the general population. Even though marijuana smoking has not been found in past studies to impact the ability to become pregnant among pregnancy planners in the general population, it may increase the risk of pregnancy loss among couples undergoing infertility treatment. Marijuana smoking by females and males may have opposing effects on outcomes of infertility treatment with ART. The project was financed by grants R01ES009718, P30ES000002, and K99ES026648 from the National Institute of Environmental Health Sciences (NIEHS). None of the authors has any conflicts of interest to declare.

Assessing the national capacity for disaster research response (DR2) within the NIEHS Environmental Health Sciences Core Centers

IntroductionDisaster research response (DR2) is necessary to answer scientific questions about the environmental health impacts of disasters and the effectiveness of response and recovery strategies. This research explores the preparedness and capacity of National Institute of Environmental Health Sciences (NIEHS) P30 Core Centers (CCs) to conduct DR2 and engage with communities in the context of disasters.MethodsIn early 2018, we conducted an online survey of CC Directors (n = 16, 69.5% response rate) to identify their DR2 relevant scientific assets, capabilities, and activities. Summary statistics were calculated. We also conducted in-depth, semi-structured interviews with 16 (69.5%) CC Community Engagement Core directors to identify facilitators and barriers of DR2 community engagement. Interview notes were coded and thematically analyzed.ResultsSurvey: While 56% of responding CCs reported prior participation in DR2 and preparedness to repurpose funding to support DR2, less than one third reported development of a disaster-specific data collection protocol, deployment plan, or concept of operations plan, participation in an exercise to test DR2 capacity, development of academic partnerships to conduct DR2, development of a process for fast-tracking institutional review board approvals for DR2, or maintenance of formal agreements with state, local, or community-based partner(s). A number of CCs reported developing or considering developing capacity in these areas. Barriers to, and tools and resources to enhance, CC engagement in DR2 were identified. Interviews: Four key components for community engaged DR2 were identified: pre-existing community relationships, responsive research that benefits communities, coordination among researchers, and coordination with community response partners. Several roles for, benefits of, and barriers to Community Engagement Rapid Response Teams (CERRT) were described.ConclusionsCCs have significant scientific assets and community partnerships that can be leveraged for DR2; however, additional planning is necessary to ensure that these scientific assets and community partnerships are leveraged when disasters strike.

Glycosylation of polycyclic aromatic hydrocarbons by UDP‐glycosyltransferase 3A2 (UGT3A2) and aerodigestive tract tissues

Smoking is a primary risk factor for the development of lung and tobacco‐related cancers. There are over 70 carcinogens in tobacco smoke, and they belong to multiple chemical classes including polycyclic aromatic hydrocarbons (PAHs). The UDP‐glycosyltransferase (UGT) family of enzymes play a key role in the detoxification of several major tobacco carcinogens by glucuronidation, using UDP‐glucuronic acid as cosubstrate. While the UGT 1As, 2As, and 2Bs are well known to detoxify simple and complex PAHs, the UGT3A subfamily has been understudied in the detoxification of PAHs. UGT3A2 uses UDP‐glucose and UDP‐xylose as cosubstrates and is active against 1‐hydroxypyrene, a biomarker for PAH exposure. Our previous research has shown that UGT3A2 is expressed in the aerodigestive tract and is active against simple hydroxylated PAHs. The purpose of the present study was to determine the kinetic parameters of UGT3A2 against complex PAHs and determine glycosylation in aerodigestive tract tissues using UDP‐glucose and UDP‐xylose. Microsomes prepared from UGT3A2 overexpressing HEK293 cells exhibited glycosylation activity against complex PAHs including benzo[a]pyrene (B[a]P)‐7,8‐diol, B[a]P‐9,10‐diol, DB[a, l]P‐11,12‐diol, and 5‐methylchrysene‐1,2‐diol, with Km's ranging from 96 to 1250 μM using UDP‐glucose. The Km's were significantly lower when using UDP‐xylose, with Km's ranging from 120 to 168 μM for the same substrates. The Vmax/Km ratio of UDP‐xylose/UDP‐glucose ranged from 0.71 to 4.0. To determine the physiological significance and relevance of UDP‐xylose‐ and UDP‐glucose‐dependent glycosylation, activity assays were performed in tissues where UGT3A2 is expressed using 1‐hydroxypyrene as substrate. Using UDP‐glucose as the cosubstrate, glycosylation rates of 3.5, 5.2, and 13 pmol·min−1·mg−1 were observed for liver, intestine and kidney microsomes, respectively. The rates were higher using UDP‐xylose, with rates of 22, 9.3, and 20 pmol·min−1·mg−1 for liver, intestine and kidney, respectively. The glycosylation rate ratio for UDP‐xylose/UDP‐glucose ranged from 1.6 to 6.3 in the three tissues, with liver exhibiting the highest ratio. In addition, detectable glycosylation activity was observed in various aerodigestive tract tissues including esophagus, tonsil, bronchus, floor of mouth, tongue, trachea, and larynx, with tonsil exhibiting the highest relative activity with both UDP‐sugars. Incubations with UDP‐xylose resulted in higher levels of glycosylation activity than that observed with UDP‐glucose in esophagus, tonsil, floor of mouth, and larynx. These data suggest that UGT3A2 is playing an important role in the detoxification of PAHs in tobacco target tissues, with UDP‐xylose being the preferred cosubstrate in most tissues.Support or Funding InformationThis study is supported by the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health to P Lazarus (Grant R01‐ES025460), a NIEHS Research Supplement to Promote Diversity in Health‐Related Research to AG Vergara (Grant R01‐ES025460‐02S1), and a grant from the Health Sciences and Services Authority of Spokane, WA (Grant WSU002292).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Environmental justice screening tools: Implications for nursing.

Environmental justice (EJ) means socially and economically disadvantaged communities and citizens are entitled to an equally clean environment and resources to enjoy. EJ communities are mostly located close to polluters such as Superfund sites, coal-fired power plants and landfills and are more likely to be exposed to higher levels of environmental hazards than the U.S. population on average. It is often a difficult task to identify EJ communities and the environmental hazards in the communities without using specific EJ screening tools. Therefore, the goal of this manuscript is to introduce public health nurses to map-based EJ screening tools. This will help public health nurses to identify EJ communities and take appropriate actions. Public Health Nurses can also use other relevant web sites, such as the U.S. Environmental Protection Agency (EPA), National Institute of Environmental Health Sciences (NIEHS) and Toxicology Data Network (TOXNET) as resources concerning potential health effects of pollutants. Using the provided tools in this paper, nurses should be able to identify EJ communities and be united to recognize barriers of EJ communities and become promoters for EJ advocacy in practice, leadership and education.

Marijuana smoking and markers of testicular function among men from a fertility centre.

Is marijuana smoking associated with semen quality, sperm DNA integrity or serum concentrations of reproductive hormones among subfertile men? Men who had ever smoked marijuana had higher sperm concentration and count and lower serum FSH concentrations than men who had never smoked marijuana; no differences were observed between current and past marijuana smokers. Studies of marijuana abuse in humans and animal models of exposure to marijuana suggest that marijuana smoking adversely impacts spermatogenesis. Data is less clear for moderate consumption levels and multiple studies have found higher serum testosterone concentrations among marijuana consumers. This longitudinal study included 662 subfertile men enroled at the Massachusetts General Hospital Fertility Center between 2000 and 2017. The men provided a total of 1143 semen samples; 317 men also provided blood samples in which we measured reproductive hormones. Use of marijuana and other drugs was self-reported at baseline. Standard protocols were followed for measuring semen quality, sex hormones and DNA integrity. We used linear mixed effect models with a random intercept to evaluate the associations of self-reported marijuana smoking at enrolment with semen parameters from subsequently collected samples, and linear regression models for sperm DNA integrity and serum reproductive hormones, while adjusting for confounders including smoking and cocaine use. Men who had ever smoked marijuana (N = 365) had significantly higher sperm concentration (62.7 (95% confidence interval: 56.0, 70.3) million/mL) than men who had never smoked marijuana (N = 297) (45.4 (38.6, 53.3) million/mL) after adjusting for potential confounders (P = 0.0003). There were no significant differences in sperm concentration between current (N = 74) (59.5 (47.3, 74.8) million/mL) and past marijuana smokers (N = 291) (63.5 (56.1, 72.0) million/mL; P = 0.60). A similar pattern was observed for total sperm count. Furthermore, the adjusted prevalence of sperm concentration and total sperm motility below WHO reference values among marijuana smokers was less than half that of never marijuana smokers. Marijuana smokers had significantly lower follicle stimulating hormone (FSH) concentrations than never marijuana smokers (-16% (-27%, -4%)) and there were no significant differences between current and past marijuana smokers (P = 0.53). Marijuana smoking was not associated with other semen parameters, with markers of sperm DNA integrity or with reproductive hormones other than FSH. Chance findings cannot be excluded due to the multiple comparisons. Our results may not be generalisable to men from the general population. Marijuana smoking was self-reported and there may be misclassification of the exposure. These findings are not consistent with a deleterious effect of marijuana on testicular function. Whether these findings are reflective of the previously described role of the endocannabinoid system in spermatogenesis or a spurious association requires confirmation in further studies. The project was funded by grants R01ES009718 and P30ES000002 from the National Institute of Environmental Health Sciences (NIEHS). None of the authors has any conflicts of interest to declare. N/A.

Development of the Texas A&M Superfund Research Program Computational Platform for Data Integration, Visualization, and Analysis

The National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program (SRP) aims to support university-based multidisciplinary research on human health and environmental issues related to hazardous substances and pollutants. The Texas A&M Superfund Research Program comprehensively evaluates the complexities of hazardous chemical mixtures and their potential adverse health impacts due to exposure through a number of multi-disciplinary projects and cores. One of the essential components of the Texas A&M Superfund Research Center is the Data Science Core, which serves as the basis for translating the data produced by the multi-disciplinary research projects into useful knowledge for the community via data collection, quality control, analysis, and model generation. In this work, we demonstrate the Texas A&M Superfund Research Program computational platform, which houses and integrates large-scale, diverse datasets generated across the Center, provides basic visualization service to facilitate interpretation, monitors data quality, and finally implements a variety of state-of-the-art statistical analysis for model/tool development. The platform is aimed to facilitate effective integration and collaboration across the Center and acts as an enabler for the dissemination of comprehensive ad-hoc tools and models developed to address the environmental and health effects of chemical mixture exposure during environmental emergency-related contamination events.

Anogenital distance is associated with semen quality but not reproductive hormones in 1106 young men from the general population.

Is anogenital distance (AGD) associated with semen quality and reproductive hormones in men from the general population? Short AGD measured from the anus to the base of scrotum (AGDAS) was associated with reduced sperm counts and morphology but not with sperm motility or reproductive hormones. AGD is longer in males than in females. In rodents, AGD is a well-established and sensitive marker of disruption during the masculinization programming window in utero and it has been suggested to be so in humans as well. Therefore, the average AGD would be expected to be shorter in men with poor semen quality, which some studies have confirmed while others have not. This cross-sectional population-based study was of 1106 men included between 2012 and 2016. Men from the general Danish population (median age 19 years), unselected with regard to fertility status and semen quality, delivered a semen sample, had a blood sample drawn, which was analyzed for concentrations of reproductive hormones, and answered a comprehensive questionnaire. They also had a physical examination performed including determination of AGD measured as the distance between anus and scrotum (AGDAS) and penis (AGDAP). Odds ratios (OR) and 95% CI were estimated for a man having abnormal semen parameters according to the World Health Organization's reference values or a low/high concentration of reproductive hormones (defined as the lowest or highest 10%) depending on AGD. AGD was categorized in four strata: ≤10th percentile, 10th-30th percentile, 30th-50th percentile and >50th percentile. Men with the 10% shortest AGDAS had a more than doubled risk (OR: 2.19, 95% CI: 1.40-3.42) of being in the subfertile range for either sperm concentration (<15 million/mL) or sperm morphology (<4%) compared to men with AGDAS above the median (reference). Men in the 10th-30th percentile also had an increased OR of 1.48 (95% CI: 1.06-2.08) but not men in the 30th-50th percentile (OR: 1.14, 95% CI: 0.81-1.62). AGDAP was only weakly related to semen quality. AGD was not associated with testicular volume or any of the reproductive hormones. Limitations include the potential non-differential misclassification of reproductive outcomes based on a single semen and blood sample and some between-examiner differences in AGD measurements which introduces noise and may result in an underestimation of observed associations. Our study of men from the general population confirmed associations between AGD and semen quality, supporting the hypothesis that AGD in humans could be a marker of fetal testicular development. This suggests that the low semen quality in Danish men may partly be explained by prenatal factors. The study has received financial support from the ReproUnion (L.P.); the Research fund of Rigshospitalet, Copenhagen University Hospital (N.J.); Grants R01ES016863-04 and R01ES016863-02S4; National Institute of Environmental Health Sciences (NIEHS) and National Institute of Environmental Health Sciences grant (P30ES023515) (S.S.); the European Union (Contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); the Danish Ministry of Health; the Danish Environmental Protection Agency; A.P. Møller and wife Chastine McKinney Møllers foundation; and Svend Andersens Foundation. None of the funders had any role in the study design, collection, analysis or interpretation of data, writing of the paper or publication decisions. The authors have nothing to declare. N/A.

CLARITY-BPA academic laboratory studies identify consistent low-dose Bisphenol A effects on multiple organ systems.

Bisphenol A (BPA) is a high-production chemical used in a variety of applications worldwide. While BPA has been documented as an endocrine-disrupting chemical (EDC) having adverse health-related outcomes in multiple studies, risk assessment for BPA has lagged due to reliance on guideline toxicology studies over academic ones with end-points considered more sensitive and appropriate. To address current controversies on BPA safety, the United States National Institute of Environmental Health Sciences (NIEHS), the National Toxicology Program (NTP) and the Food and Drug Administration (FDA) established the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) using the NCTR Sprague-Dawley rats. The goal of CLARITY-BPA is to perform a traditional regulatory toxicology study (Core study) in conjunction with multiple behavioural, molecular and cellular studies by academic laboratories focused on previously identified BPA-sensitive organ systems (Academic studies). Combined analysis of the data from both study types will be undertaken by the NTP with the aim of resolving uncertainties on BPA toxicity. To date, the Core study has been completed and a draft report released. Most of the academic studies have also been finalized and published in peer-reviewed journals. In light of this important milestone, the PPTOX-VI meeting held in the Faroe Islands, 27-30 May 2018 devoted a plenary session to CLARITY-BPA with presentations by multiple investigators with the purpose of highlighting key outcome. This MiniReview synthesizes the results of three academic studies presented at this plenary session, evaluates recently published findings by other CLARITY-BPA academic studies to provide an early combined overview of this emerging data and places this in the context of the Core study findings. This co-ordinated effort revealed a plethora of significant BPA effects across multiple organ systems and BPA doses with non-monotonic responses across the dose range utilized. Remarkably consistent across most studies, including the Core study, are low-dose effects (2.5, 25 and 250μg BPA/kg body-weight). Collectively, the findings highlighted herein corroborate a significant body of evidence that documents adverse effects of BPA at doses relevant to human exposures and emphasizes the need for updated risk assessment analysis.

Clear Evidence of Cell Phone RF Radiation Cancer Risk [Health Matters

During 26-28 March 2018, the National Institute of Environmental Health Sciences (NIEHS) National Toxicology Program (NTP), a part of the U.S. National Institutes of Health, convened a three-day technical reports peer-review panel meeting in Research Triangle Park, North Carolina, to review the NTP's draft reports on its carcinogenesis studies of cell-phone RF radiation in mice and rats [1].

Maternal and paternal preconception exposure to bisphenols and size at birth.

Are maternal and paternal preconception urinary bisphenol A (BPA) or bisphenol S (BPS) concentrations associated with offspring birth size? Maternal-but not paternal-preconception urinary BPA concentrations were associated with lower birth size among couples seeking fertility evaluation. Prenatal BPA exposure has been previously associated with reduced birth size in some but not all epidemiologic studies. However, the potential effect of BPA exposure before conception in either parent is unknown. Data on BPS is practically absent. Ongoing prospective preconception cohort of women and men seeking fertility evaluation between 2005 and 2016 in a large fertility center in an academic hospital in Boston, MA, USA. We examined the association between maternal and paternal preconception, as well as maternal prenatal urinary BPA and BPS concentrations, and size at birth among 346 singletons from couples recruited in the Environment and Reproductive Health (EARTH) Study using multivariable linear regression. Infant birth weight and head circumference were abstracted from delivery records. Mean preconception and prenatal exposures were estimated by averaging urinary ln-BPA and ln-BPS concentrations in multiple maternal and paternal urine samples collected before pregnancy, and maternal pregnancy samples collected in each trimester. Maternal preconception urinary BPA concentrations were inversely associated with birth weight and head circumference in adjusted models: each ln-unit increase was associated with a decrease in birth weight of 119 g (95% CI: -212, -27), and a head circumference decrease of 0.72 cm (95% CI: -1.3, -0.1). Additional adjustment by gestational age or prenatal BPA exposure modestly attenuated results. Women with higher prenatal BPA concentrations had infants with lower mean birth weight (-75 g, 95% CI: -153, 2) although this did not achieve statistical significance. Paternal preconception urinary BPA concentrations were not associated with either birth weight or head circumference. No consistent patterns emerged for BPS concentrations measured in either parent. We observed a strong negative association between maternal-but not paternal-preconception BPA concentrations and offspring birth size among a subfertile population. Although these results are overall consistent with prior studies on prenatal BPA exposure, these findings may not be generalizable to women without fertility concerns. This study suggests that the unexplored maternal preconception period may be a sensitive window for BPA effects on birth outcomes. Work supported by Grants (ES R01 009718, ES 022955 and ES 000002) from the National Institute of Environmental Health Sciences (NIEHS). C.M. was supported by a post-doctoral fellowship award from the Canadian Institutes of Health Research. There are no competing interests to declare.

Expanding the Concept of Translational Research: Making a Place for Environmental Health Sciences.

Summary:The National Institute of Environmental Health Sciences (NIEHS) introduces a new translational research framework that builds upon previous biomedical models to create a more comprehensive and integrated environmental health paradigm. The framework was developed as a graphical construct that illustrates the complexity of designing, implementing, and tracking translational research in environmental health. We conceptualize translational research as a series of concentric rings and nodes, defining “translation” as movement either from one ring to another or between nodes on a ring. A “Fundamental Questions” ring expands upon the research described in other frameworks as “basic” to include three interrelated concepts critical to basic science research: research questions, experimental settings, and organisms. This feature enables us to capture more granularity and thus facilitates an approach for categorizing translational research and its growth over time. We anticipate that the framework will help researchers develop compelling long-term translational research stories and accelerate public health impacts by clearly mapping out opportunities for collaborations. By using this paradigm, researchers everywhere will be better positioned to design research programs, identify research partners based on cross-disciplinary research needs, identify stakeholders who are likely to use the research for environmental decision-making and intervention, and track progress toward common goals. https://doi.org/10.1289/EHP3657