Prenatal Exposure to Nitrates, Nitrites, and Nitrosatable Drugs and Preterm Births

Nitrosatable drugs react with nitrite in the stomach to form N-nitroso compounds, observed in animal models to result in adverse pregnancy outcomes such as birth defects and reduced fetal weight. Previous studies examining prenatal exposure to medications classified as nitrosatable have observed an increased risk of preterm delivery. Vitamin C is a known nitrosation inhibitor. Using data from mothers (controls) of babies without major birth defects from the National Birth Defects Prevention Study, we examined the relation between preterm births and: 1) prenatal nitrosatable drug usage; 2) dietary intake of nitrates/nitrites; 3) joint exposures to nitrosatable drugs and nitrate/nitrite intake; and 4) nitrosatable drugs and vitamin C intake among 496 case-mothers of preterm infants and 5398 control-mothers who delivered full term babies from 1997-2005. An increased risk of preterm births was observed with secondary amine exposure during the second (adjusted hazard ratio (aHR) 1.37, [95% confidence interval (CI) 1.05, 1.79]) and third (aHR 1.34, [95% CI 1.02, 1.76]) trimester. A protective effect was detected with high levels of plant nitrites (aHR 0.72, [95% CI 0.53, 0.97]). Exposure to secondary amines and high levels of nitrite were associated with preterm births, having an increased risk with first (aHR 1.84, [95% CI 1.14, 2.98]), second (aHR 1.89, [95% CI 1.17, 3.07]), and third (aHR 2.00, [95% CI 1.22, 3.29]) trimester exposure. Lower risk of moderately preterm births was observed with second trimester amide exposure in conjunction with higher levels of dietary vitamin C (aHR 1.14, [95% CI 0.66, 1.98]) compared to <85 mg/day (aHR 2.08, [95% CI 1.25, 3.47]). Prenatal exposure to nitrosatable drugs during the second and third trimester, particularly secondary amines, might increase risk of preterm delivery. In addition, nitrosatable drugs, especially secondary and tertiary amines, and higher levels of dietary nitrite (including animal, plant, and total) may increase risk of preterm births. However, dietary vitamin C intake ≥85 mg/day may attenuate the association between nitrosatable drug use during the second trimester and preterm and moderately preterm births. In this study population, daily vitamin C supplementation did not appear to confer the same benefits

Genetic Risk Factors in Lupus Nephritis and IgA Nephropathy - No Support of an Overlap

Background: IgA nephropathy (IgAN) and nephritis in Systemic Lupus Erythematosus (SLE) are two common forms of glomerulonephritis in which genetic findings are of importance for disease development. We have recently reported an association of IgAN with variants of TGFB1. In several autoimmune diseases, particularly in SLE, IRF5, STAT4 genes and TRAF1-C5 locus have been shown to be important candidate genes. The aim of this study was to compare genetic variants from the TGFB1, IRF5, STAT4 genes and TRAF1-C5 locus with susceptibility to IgAN and lupus nephritis in two Swedish cohorts. Patients and Methods: We genotyped 13 single nucleotide polymorphisms (SNPs) in four genetic loci in 1252 DNA samples from patients with biopsy proven IgAN or with SLE (with and without nephritis) and healthy age-and sex-matched controls from the same population in Sweden. Results: Genotype and allelic frequencies for SNPs from selected genes did not differ significantly between lupus nephritis patients and SLE patients without nephritis. In addition, haplotype analysis for seven selected SNPs did not reveal a difference for the SLE patient groups with and without nephritis. Moreover, none of these SPNs showed a significant difference between IgAN patients and healthy controls. IRF5 and STAT4 variants remained significantly different between SLE cases and healthy controls. In addition, the data did not show an association of TRAF1-C5 polymorphism with susceptibility to SLE in this Swedish population. Conclusion: Our data do not support an overlap in genetic susceptibility between patients with IgAN or SLE and reveal no specific importance of SLE associated SNPs for the presence of lupus nephritis.Original Publication: Mai Tuyet Vuong, Iva Gunnarsson, Sigrid Lundberg, Elisabet Svenungsson, Lars Wramner, Anders Fernström, Ann-Christine Syvanen, Lieu Thi Do, Stefan H. Jacobson and Leonid Padyukov, Genetic Risk Factors in Lupus Nephritis and IgA Nephropathy - No Support of an Overlap, 2010, PLOS ONE, (5), 5. http://dx.doi.org/10.1371/journal.pone.0010559 Licensee: Public Library of Science (PLoS) http://www.plos.org/</p

Flame Retardants and Neurodevelopment: an Updated Review of Epidemiological Literature

Purpose of Review: Flame retardant (FR) compounds can adversely impact neurodevelopment. This updated literature review summarizes epidemiological studies of FRs and neurotoxicity published since 2015, covering historical (polybrominated biphenyls [PBBs], polychlorinated biphenyls [PCBs]), contemporary (polybrominated diphenyl ethers [PBDEs], hexabromocyclododecane [HBCD], and tetrabromobisphenol A [TBBPA]), and current-use organophosphate FRs (OPFRs) and brominated FRs (2-ethylhexyl 2,3,4,5-tetrabromobezoate [EH-TBB] TBB), bis(2-ethylhexyl) tetrabromophthalate [BEH-TEBP]), focusing on prenatal and postnatal periods of exposure. Recent Findings: Continuing studies on PCBs still reveal adverse associations with child cognition and behavior. Recent studies indicate PBDEs are neurotoxic, particularly for gestational exposures with decreased cognition and increased externalizing behaviors. Findings were suggestive for PBDEs and other behavioral domains and neuroimaging. OPFR studies provide suggestive evidence of reduced cognition and more behavioral problems in children. Summary: Despite a lack of studies of PBBs, TBBPA, EH-TBB, and BEH-TEBP, and only two studies of HBCD, recent literature of PCBs, PBDEs, and OPFRs are suggestive of developmental neurotoxicity, calling for more studies of OPFRs

Gestational Exposure to Polybrominated Diphenyl Ethers and Social Skills and Problem Behaviors in Adolescents: The Home Study

Background: Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants used as flame retardants. Gestational PBDE exposure has been associated with a variety of behavior problems in children, but little is known about its impact into adolescence, particularly on social skills, which are important for achieving social competence, establishing identity, and forming lasting relationships. Objective: We investigated associations between gestational exposure to PBDEs and social skills and problem behaviors in early adolescence in a longitudinal pregnancy and birth cohort in Cincinnati, Ohio (recruited 2003–2006). Methods: We measured maternal serum concentrations of five PBDE congeners during gestation. At age 12, we measured social skills and problem behaviors scores for 243 adolescents using self- and caregiver-report on the Social Skills Improvement System (SSiS). We used multivariable linear regression models to estimate associations between maternal PBDE concentrations and SSiS scores, controlling for potential covariates. We report associations for the five congeners and a summary exposure variable (∑5BDE: the sum of BDE- 28, 47, 99, 100, and 153, n = 197). Results: We found sex-specific associations of ∑5BDE concentrations with adolescent-reported Problem Behaviors (∑5BDE × sex pint = 0.02) and caregiver-reported Social Skills (∑5BDE × sex pint = 0.02). In sex-stratified models, log10 transformed data revealed increased maternal ∑5BDE concentration among males was associated with decreased caregiver-reported Social Skills composite score (β = -10.2, 95% CI: −19.5, −1.0), increased adolescent-reported Problem Behaviors composite score (β = 12.1, 95% CI: 5.4, 18.8), and increased caregiver-reported Problem Behaviors composite score (β = 6.2, 95% CI: 0.7, 11.7). Further analysis on SSiS subscales revealed similar patterns in significant associations among males. There were no statistically significant associations in stratified models among females despite higher ∑5BDE exposure (Female GM=40.15 ng/g lipid, GSE=1.10; Male GM=35.30 ng/g lipid, GSE=1.09). Discussion: We found gestational PBDE exposure in males was associated with poorer behavioral outcomes, extending previous findings among this cohort into early adolescence

Polybrominated Diphenyl Ether (PBDE) and Poly- and Perfluoroalkyl Substance (PFAS) Exposures During Pregnancy and Maternal Depression

Background: Experimental studies in rodents suggest that polybrominated diphenyl ethers (PBDEs) and poly- and perfluoroalkyl substances (PFAS) may contribute to depressive symptoms. Few studies have examined the impact of these chemicals on depression in adults. Objective: To examine the associations between serum PBDE and PFAS concentrations during pregnancy and repeated measures of depressive symptoms in women assessed from pregnancy to 8 years postpartum. Methods: This study was based on 377 women from the Health Outcomes and Measures of the Environment Study, a birth cohort in Cincinnati, OH (USA). PBDEs (BDE-28, -47, -99, -100, -153, and ∑PBDEs) and PFAS (perfluorooctanoate [PFOA], perfluorooctane sulfonate [PFOS], perfluorohexane sulfonate [PFHxS], perfluorononanoate [PFNA]) were quantified in maternal serum at 16 ± 3 weeks gestation. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI-II) at ~20 weeks gestation and up to seven times during postpartum visits (4 weeks, 1, 2, 3, 4, 5, and 8 years). We used linear mixed models to estimate covariate-adjusted associations between chemical concentrations and repeated measures of BDI-II. Multinomial logistic regression models were used to estimate the relative risk ratios of having a medium or high depression trajectory. Results: We found that a 10-fold increase in BDE-28 at 16 ± 3 weeks gestation was associated with significantly increased BDI-II scores (β = 2.5 points, 95% confidence interval [CI] 0.8, 4.2) from pregnancy to 8 years postpartum. Significant positive associations were also observed with BDE-47, -100, -153, and ∑PBDEs. A 10-fold increase in ∑PBDEs was associated with a 4.6-fold increased risk (95% CI 1.8, 11.8) of a high trajectory for BDI-II compared to a low trajectory. We observed no significant associations between PFAS and BDI-II scores

Childhood Exposure to Per- And Polyfluoroalkyl Substances (PFAS) And Neurobehavioral Domains in Children at Age 8 Years

Background: Toxicological studies have raised concerns regarding the neurotoxic effects of per- and polyfluoroalkyl substances (PFAS). However, observational evidence from human studies investigating the association between childhood PFAS and neurobehavior is limited and remains unclear. Objectives: To examine whether childhood PFAS concentrations are associated with neurobehavior in children at age 8 years and whether child sex modifies this relationship. Methods: We used data from 208 mother-child dyads in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort (Cincinnati, OH, USA). We quantified PFAS in child serum at 3 and 8 years. We assessed neurobehavioral domains using the Behavior Assessment System for Children-2 at 8 years. We used multiple informant models to estimate score changes per ln-increase in repeated PFAS concentrations. Results: Childhood PFAS were not associated with Externalizing or Internalizing Problems at 8 years. However, we noted effect measure modification by sex, with higher scores in Externalizing Problems among males per ln-unit increase in perfluorononanoate (PFNA) at 3 years (β = 4.3 points, 95% CI: 1.0, 7.7) while females had lower scores (β = −2.8 points, 95% CI: −4.7, −1.0). More Internalizing Problems were observed among males per ln-unit increase in concurrent PFNA concentrations (β = 3.7 points, 95% CI: 0.7, 6.8), but not in females (β = −1.7 points, 95% CI: −4.6, 1.2). Childhood PFNA concentrations were associated with lower scores for attention problems and activity of daily living. Conclusion: While findings do not consistently support an association between childhood PFAS serum concentrations and neurobehavior, child sex may play a role in this relationship

Maternal dietary intake of nitrates, nitrites and nitrosamines and selected birth defects in offspring: a case-control study

BACKGROUND: Dietary intake of nitrates, nitrites, and nitrosamines can increase the endogenous formation of N-nitroso compounds in the stomach. Results from animal studies suggest that these compounds might be teratogenic. We examined the relationship between maternal dietary intake of nitrates, nitrites (including plant and animal sources as separate groups), and nitrosamines and several types of birth defects in offspring. METHODS: For this population-based case–control study, data from a 58-question food frequency questionnaire, adapted from the short Willett Food Frequency Questionnaire and administered as part of the National Birth Defects Prevention Study (NBDPS), were used to estimate daily intake of dietary nitrates, nitrites, and nitrosamines in a sample of 6544 mothers of infants with neural tube defects (NTD)s, oral clefts (OC)s, or limb deficiencies (LD)s and 6807 mothers of unaffected control infants. Total daily intake of these compounds was divided into quartiles based on the control mother distributions. Odds ratios (OR)s and 95% confidence intervals (CI)s were estimated using logistic regression; estimates were adjusted for maternal daily caloric intake, maternal race-ethnicity, education, dietary folate intake, high fat diet (> 30% of calories from fat), and state of residence. RESULTS: While some unadjusted ORs for NTDS had 95% (CI)s that excluded the null value, none remained significant after adjustment for covariates, and the effect sizes were small (adjusted odds ratios [aOR] <1.12). Similar results were found for OCs and LDs with the exception of animal nitrites and cleft lip with/without cleft palate (aORs and CIs for quartile 4 compared to quartile 1 =1.24; CI=1.05-1.48), animal nitrites and cleft lip (4th quartile aOR=1.32; CI=1.01-1.72), and total nitrite and intercalary LD (4th quartile aOR=4.70; CI=1.23-17.93). CONCLUSIONS: Overall, odds of NTDs, OCs or LDs did not appear to be significantly associated with estimated dietary intake of nitrate, nitrite, and nitrosamines

Avian Influenza Virus Surveillance in Wild Birds in Georgia: 2009-2011

The Caucasus, at the border of Europe and Asia, is important for migration and over-wintering of wild waterbirds. Three flyways, the Central Asian, East Africa-West Asia, and Mediterranean/Black Sea flyways, converge in the Caucasus region. Thus, the Caucasus region might act as a migratory bridge for influenza virus transmission when birds aggregate in high concentrations in the post-breeding, migrating and overwintering periods. Since August 2009, we have established a surveillance network for influenza viruses in wild birds, using five sample areas geographically spread throughout suitable habitats in both eastern and western Georgia. We took paired tracheal and cloacal swabs and fresh feces samples. We collected 8343 swabs from 76 species belonging to 17 families in 11 orders of birds, of which 84 were real-time RT-PCR positive for avian influenza virus (AIV). No highly pathogenic AIV (HPAIV) H5 or H7 viruses were detected. The overall AIV prevalence was 1.6%. We observed peak prevalence in large gulls during the autumn migration (5.3-9.8%), but peak prevalence in Black-headed Gulls in spring (4.2-13%). In ducks, we observed increased AIV prevalence during the autumn post-moult aggregations and migration stop-over period (6.3%) but at lower levels to those observed in other more northerly post-moult areas in Eurasia. We observed another prevalence peak in the overwintering period (0.14-5.9%). Serological and virological monitoring of a breeding colony of Armenian Gulls showed that adult birds were seropositive on arrival at the breeding colony, but juveniles remained serologically and virologically negative for AIV throughout their time on the breeding grounds, in contrast to gull AIV data from other geographic regions. We show that close phylogenetic relatives of viruses isolated in Georgia are sourced from a wide geographic area throughout Western and Central Eurasia, and from areas that are represented by multiple different flyways, likely linking different host sub-populations

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery