Organophosphate Esters: Are These Flame Retardants and Plasticizers Affecting Children’s Health?

Purpose of Review: Organophosphate esters (OPEs) are applied to a variety of consumer products, primarily as flame retardants and plasticizers. OPEs can leach out of products over time and are consequently prevalent in the environment and frequently detected in human biomonitoring studies. Exposure during pregnancy is of particular concern as OPEs have recently been detected in placental tissues, suggesting they may be transferred to the developing infant. Also, studies have now shown that children typically experience higher exposure to several OPEs compared with adults, indicating they may be disproportionately impacted by these compounds. This review summarizes the current literature on reproductive and child health outcomes of OPE exposures and highlights areas for future research. Recent Findings: Experimental animal studies demonstrate potential for OPEs to adversely impact health, and a limited number of epidemiologic studies conducted in adult cohorts suggest that OPEs may interfere with the endocrine system. Neurodevelopment is perhaps the most well studied of children’s health endpoints, and several studies indicate that prenatal and early life OPE exposures impact both cognitive and behavioral development. Associations have also been reported with reproductive outcomes (e.g., fertilization and pregnancy loss) and with the timing of parturition and preterm birth. Cross-sectional studies also demonstrate associations between OPEs and respiratory health outcomes, allergic disease, and measures of adiposity. Summary: An expanding body of research demonstrates that OPEs are associated with adverse reproductive health and birth outcomes, asthma and allergic disease, early growth and adiposity, and neurodevelopment. Still, additional research is urgently needed to elucidate the full impact of OPEs on children’s health

Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier

Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1-/- mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1-/- mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1-/- mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis

Prenatal exposure to organophosphates and associations with birthweight and gestational length

Organophosphate esters (OPEs) are often used as flame retardants and plasticizers. Animal data suggest exposure to OPEs could impact children's growth and development, yet impacts on human birth outcomes are understudied. We evaluate impacts of OPE exposure on the timing of delivery and infant's birthweight in the Pregnancy Infection and Nutrition Study (PIN). North Carolina women enrolled in PIN in early pregnancy and participated in follow-up through delivery. Analyses were limited to mothers recruited from 2002 to 2005, whose children participated in additional follow-up in early childhood (n = 349). Mothers collected urine samples in which OPE metabolites were assessed and birth outcomes were abstracted from medical records. Bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropyl-phenyl phenyl phosphate (ip-PPP), bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP) were detected in >80% of samples. Average birthweight and gestational age were 3326 g and 39.1 weeks, respectively. As data suggest that the mechanisms of action by which OPEs impact birth outcomes may be fetal sex dependent, we conducted sex-stratified statistical analyses. Women with the highest ip-PPP concentrations delivered girls 1 week earlier than women with lower levels (95% Confidence Interval (CI): −1.85, −0.15). Women with BDCIPP levels above the median had 3.99 (95% CI: 1.08, 14.78) times the odds of delivering their daughters preterm. Similarly, higher ip-PPP levels were associated with lower birthweight, but not after standardizing for gestational age. Among males, maternal ip-PPP was associated with decreased odds of preterm birth (OR = 0.21, 95% CI: 0.06, 0.68). DPHP and BCIPHIPP levels were not associated with outcomes in either sex. Results indicate that prenatal OPE exposure may impact timing of birth, though results are imprecise. Given widespread OPE exposure and the urgent need to identify and mitigate causes of preterm birth, further investigation is warranted

Towards Reliable Automatic Protein Structure Alignment

A variety of methods have been proposed for structure similarity calculation, which are called structure alignment or superposition. One major shortcoming in current structure alignment algorithms is in their inherent design, which is based on local structure similarity. In this work, we propose a method to incorporate global information in obtaining optimal alignments and superpositions. Our method, when applied to optimizing the TM-score and the GDT score, produces significantly better results than current state-of-the-art protein structure alignment tools. Specifically, if the highest TM-score found by TMalign is lower than (0.6) and the highest TM-score found by one of the tested methods is higher than (0.5), there is a probability of (42%) that TMalign failed to find TM-scores higher than (0.5), while the same probability is reduced to (2%) if our method is used. This could significantly improve the accuracy of fold detection if the cutoff TM-score of (0.5) is used. In addition, existing structure alignment algorithms focus on structure similarity alone and simply ignore other important similarities, such as sequence similarity. Our approach has the capacity to incorporate multiple similarities into the scoring function. Results show that sequence similarity aids in finding high quality protein structure alignments that are more consistent with eye-examined alignments in HOMSTRAD. Even when structure similarity itself fails to find alignments with any consistency with eye-examined alignments, our method remains capable of finding alignments highly similar to, or even identical to, eye-examined alignments.Comment: Peer-reviewed and presented as part of the 13th Workshop on Algorithms in Bioinformatics (WABI2013

Prenatal exposure to organophosphate esters and cognitive development in young children in the Pregnancy, Infection, and Nutrition Study

Organophosphate esters (OPEs) are a class of chemicals commonly used as flame retardants and plasticizers. OPEs are applied to a wide variety of consumer products and have a propensity to leach from these products. Consequently, OPEs are ubiquitous contaminants in many human environments and human exposure is pervasive. Accumulating evidence suggests that OPEs are capable of interfering with childhood cognitive development through both neurologic- and endocrine-mediated mechanisms. However, observational evidence of cognitive effects is limited. We used data collected in the third phase of the Pregnancy, Infection, and Nutrition Study to investigate cognitive effects of prenatal exposure to OPEs. In a spot prenatal maternal urine sample, we measured the following OPE metabolites: diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). We assessed children's language and multi-faceted and overall cognitive development between two and three years of age using the MacArthur-Bates Communicative Development Inventories (MB-CDI) and the Mullen Scales of Early Learning (MSEL). We used linear regression to estimate the change in children's scores on these developmental assessments per interquartile range (IQR) increase in log-transformed, specific-gravity-corrected prenatal OPE metabolite concentrations, adjusted for maternal age, education, income, race/ethnicity, BMI, and child's sex. A total of 149 children had both OPE metabolite measurements and MB-CDI scores, and 227 children had both OPE metabolite measurements and MSEL scores. We observed that higher concentrations of ip-PPP (ng/ml) were associated with lower scores on the MSEL Cognitive Composite Score (β = −2.61; 95% CI: −5.69, 0.46), and separately on two of the four MSEL Scales that comprise the Cognitive Composite, specifically the Fine Motor Scale (β = −3.08; 95% CI: −5.26, −0.91) and the Expressive Language Scale (β = −1.21; 95% CI: −2.91, 0.49). We similarly observed that prenatal ip-PPP concentrations were inversely associated with age-standardized scores on the MB-CDI Vocabulary assessment (β = −1.19; 95% CI: −2.53, 0.16). Other OPE metabolites were not strongly associated with performance on either assessment. Our results suggest that isopropylated triarylphosphate isomers, the presumed parent compounds of ip-PPP, may adversely impact cognitive development, including fine motor skills and early language abilities. Our study contributes to the growing body of observational evidence that suggests prenatal exposure to OPEs may adversely affect cognitive development

Prenatal exposure to organophosphate esters and behavioral development in young children in the Pregnancy, Infection, and Nutrition Study

Organophosphate esters (OPEs) are commonly used as plasticizers and flame retardants in consumer products, and exposure is relatively ubiquitous in most populations studied. This may be of concern as some OPEs may be neurotoxic, endocrine-disrupting, and interfere with behavioral development; however, observational evidence is limited. We used data from the Pregnancy, Infection, and Nutrition Study, a prospective birth cohort study, to investigate associations between maternal OPE metabolite concentrations during pregnancy and behavioral development in offspring. Women provided a urine sample during pregnancy that was analyzed for concentrations of OPE metabolites, including diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). Offspring's behavioral development was assessed by the Behavioral Assessment System for Children (2nd Edition) (BASC-2) at approximately 36 months. Linear regression was used to estimate associations between tertiles in specific gravity-corrected OPE metabolite concentrations and children's scores on the BASC-2, adjusted for maternal age, maternal BMI, maternal race, maternal education, familial income, maternal depression, quality of the home environment, and sex. Higher BDCIPP concentrations were associated with higher scores on the Behavioral Symptoms Index (1st vs. 3rd tertile: β = 3.03; 95% CI = 0.40, 5.67) and Externalizing Problems (1st vs. 3rd tertile: β = 2.49; 95% CI: −0.12, 5.10) composites. Among BASC-2 scales, BDCIPP was most strongly associated with Withdrawal, Attention Problems, Depression, Hyperactivity, and Aggression. DPHP concentrations were also associated with higher scores on the Externalizing Problems and Behavioral Symptoms Index composites, but not as strongly as BDCIPP. Conversely, higher concentrations of ip-PPP were associated with fewer adverse behavioral symptoms, including an inverse association with the Internalizing Problems composite (1st vs. 3rd tertile: β = −3.74; 95% CI = −6.75, −0.74) and constituent scales. BCIPHIPP was not strongly associated with any measured behavioral outcomes. Our results suggest that greater maternal exposure to tris(1,3-dichloro-2-propyl phosphate) (TDCIPP, parent compound of BDCIPP) and, to a lesser degree, triphenyl phosphate (TPHP, parent compound of DPHP) during pregnancy is associated with adverse behavioral development in children. Our study contributes to the growing body of evidence pertaining to adverse developmental effects of prenatal OPE exposure and highlights the need for further research to characterize risks associated with this ubiquitous family of chemicals

Micro to nanostructural observations in neutron irradiated nuclear graphites PCEA and PCIB

The neutron irradiation-induced structural changes in nuclear grade graphites PCEA and PCIB were investigated using scanning electron microscopy (SEM), X-ray diffraction (XRD), Raman spectroscopy, transmission electron microscopy (TEM), selected area electron diffraction (SAED) and electron energy loss spectroscopy (EELS). The graphite samples were irradiated at the Advanced Test Reactor at the Idaho National Laboratory. Received doses ranged from 1.5 to 6.8 displacements per atom and irradiation temperatures varied between 350 °C and 670 °C. XRD and Raman measurements provided evidence for irradiation induced crystallite fragmentation, with crystallite sizes reduced by 39–55%. Analysis of TEM images was used to quantify fringe length, tortuosity, and relative misorientation of planes, and indicated that neutron irradiation induced basal plane fragmentation and curvature. EELS was used to quantify the proportion of sp2 bonding and specimen density; a slight reduction in planar-sp2 content (due to the buckling basal planes and the introduction of non-six-membered rings) agreed with the observations from TEM

Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6

Recently, bi-allelic mutations in the transcription factor RFX6 were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia. A male infant developed severe hyperglycemia (446mg/dL) within 24h of birth. Acute abdominal concerns by day five necessitated exploratory surgery that revealed duodenal atresia, gallbladder agenesis, annular pancreas and intestinal malrotation. He also exhibited chronic diarrhea and feeding intolerance, cholestatic jaundice, and subsequent liver failure. He died of sepsis at four months old while awaiting liver transplantation. The phenotype of neonatal diabetes with intestinal atresia and biliary agenesis clearly pointed to RFX6 as the causative gene; indeed, whole exome sequencing revealed a novel homozygous RFX6 mutation c.779A>C; p.Lys260Thr (K260T). This missense mutation also changes the consensus 5′ splice donor site before intron 7 and is thus predicted to cause disruption in splicing. Both parents, who were not known to be related, were heterozygous carriers. Targeted genetic testing based on consideration of phenotypic features may reveal a cause among the many genes now associated with heterogeneous forms of monogenic neonatal diabetes. Our study demonstrates the feasibility of using modern sequencing technology to identify one such rare cause. Continued research is needed to determine the possible cost-effectiveness of this approach, especially when clear phenotypic clues are absent. Further study of patients with RFX6 mutations should clarify its role in pancreatic, intestinal and enteroendocrine cellular development and explain features such as the diarrhea exhibited in our case

An efficient adaptive multigrid algorithm for predicting thin film flow on surfaces containing localised topographic features

Gravity-driven continuous thin film flow over a plane, containing well-defined single and grouped topographic features, is modelled as a Stokes flow using lubrication theory. The associated time dependent, nonlinear, coupled set of governing equations are solved using a Full Approximation Storage (FAS) Multigrid algorithm by employing automatic mesh adaptivity, the power efficiency and accuracy of which is demonstrated by comparing the results with corresponding global fine-mesh solutions.. These show that automatic grid refinement effectively restricts the use of find grids to regions of rapid flow development which, for flow over the topographies considered, includes the topography itself, the upstream Capillary ridge, downstream sure region, and the characteristic bow wave. It is shown that for the accurate solution of such flow problems, adaptive Multigridding offers increased flexibility together with a significant reduction in memory requirement. This is further demonstrated by solving the problem of transient flow over a trench topography, generated by a sinusoidally varying inlet condition