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Developmental exposures to ultrafine particle air pollution reduces early testosterone levels and adult male social novelty preference: Risk for children's sex-biased neurobehavioral disorders.

ABSTRACT: Epidemiological studies have reported associations of air pollution exposures with various neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit and schizophrenia, all of which are male-biased in prevalence. Our studies of early postnatal exposure of mice to the ultrafine particle (UFP) component of air pollution, considered the most reactive component, provide support for these epidemiological associations, demonstrating male-specific or male-biased neuropathological changes and cognitive and impulsivity deficits consistent with these disorders. Since these neurodevelopmental disorders also include altered social behavior and communication, the current study examined the ability of developmental UFP exposure to reproduce these social behavior deficits and to determine whether any observed alterations reflected changes in steroid hormone concentrations. Elevated plus maze, social conditioned place preference, and social novelty preference were examined in adult mice that had been exposed to concentrated (10-20x) ambient UFPs averaging approximately 45 ug/m3 particle mass concentrations from postnatal day (PND) 4-7 and 10-13 for 4?h/day. Changes in serum testosterone (T) and corticosterone where measured at postnatal day (P)14 and approximately P120. UFP exposure decreased serum T concentrations on PND 14 and social nose-to-nose sniff rates with novel males in adulthood, suggesting social communication deficits in unfamiliar social contexts. Decreased sniff rates were not accounted for by alterations in fear-mediated behaviors and occurred without overt deficits in social preference, recognition or communication with a familiar animal or alterations in corticosterone. Adult T serum concentrations were positively correlated with nose to nose sniff rates. Collectively, these studies confirm another feature of male-biased neurodevelopmental disorders following developmental exposures to even very low levels of UFP air pollution that could be related to alterations in sex steroid programming of brain function.

SUBMITTER: Sobolewski M

PROVIDER: S-EPMC6456267 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Developmental exposures to ultrafine particle air pollution reduces early testosterone levels and adult male social novelty preference: Risk for children's sex-biased neurobehavioral disorders.

Sobolewski Marissa M Anderson Timothy T Conrad Katherine K Marvin Elena E Klocke Carolyn C Morris-Schaffer Keith K Allen Joshua L JL Cory-Slechta Deborah A DA

Neurotoxicology 20180823

Epidemiological studies have reported associations of air pollution exposures with various neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit and schizophrenia, all of which are male-biased in prevalence. Our studies of early postnatal exposure of mice to the ultrafine particle (UFP) component of air pollution, considered the most reactive component, provide support for these epidemiological associations, demonstrating male-specific or male-biased neuropatholo ...[more]

PMID: 30144459

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Project description:BackgroundEvidence suggests organophosphate esters (OPEs) are neurotoxic; however, the epidemiological literature remains scarce. We investigated whether prenatal exposures to OPEs were associated with child neurobehavior in the MADRES cohort.MethodsWe measured nine OPE metabolites in 204 maternal urine samples (gestational age at collection: 31.4 ± 1.8 weeks). Neurobehavior problems were assessed among 36-month-old children using the Child Behavior Checklist's (CBCL) three composite scales [internalizing, externalizing, and total problems]. We examined associations between tertiles of prenatal OPE metabolites (> 50% detection) and detect/non-detect categories (< 50% detection) and CBCL composite scales using linear regression and generalized additive models. We also examined mixtures for widely detected OPEs (n = 5) using Bayesian kernel machine regression.ResultsMaternal participants with detectable versus non-detectable levels of bis(2-methylphenyl) phosphate (BMPP) had children with 42% (95% CI: 4%, 96%) higher externalizing, 45% (-2%, 114%) higher internalizing, and 35% (3%, 78%) higher total problems. Participants in the second versus first tertile of bis(butoxethyl) phosphate (BBOEP) had children with 43% (-1%, 109%) higher externalizing scores. Bis(1-chloro-2-propyl) phosphate (BCIPP) and child sex had a statistically significant interaction in internalizing (p = 0.02) and total problems (p = 0.03) models, with 120% (23%, 295%) and 57% (6%, 134%) higher scores in the third versus first BCIPP tertile among males. Among females, detectable vs non-detectable levels of prenatal BMPP were associated with 69% higher externalizing scores (5%, 170%) while the third versus first tertile of prenatal BBOEP was associated with 45% lower total problems (-68%, -6%). Although the metabolite mixture and each CBCL outcome had null associations, we observed marginal associations between di-n-butyl phosphate and di-isobutyl phosphate (DNBP + DIBP) and higher internalizing scores (0.15; 95% CrI: -0.02, 0.32), holding other metabolites at their median.ConclusionsOur results generally suggest adverse and sex-specific effects of prenatal exposure to previously understudied OPEs on neurobehavioral outcomes in 36-month children, providing evidence of potential OPE neurotoxicity.

Project description:Epidemiology studies have linked exposure to pollutant particles to increased cardiovascular mortality and morbidity, however, the mechanism remains unknown. In this study, we hypothesized that the ultrafine fraction of ambient pollutant particles would cause endothelial cells dysfunction. We profiled gene expression of human pulmonary artery endothelial cells (HPAEC) exposed to ultrafine Chapel Hill particles (UFP) (100μg/ml) or vehicle for 4h with Affymetrix HG U133 Plus 2.0 chips (N = 4 each). Using an unpaired t-test (p <0.01, 5% false discovery rate) we found 426 unique genes to be differentially expressed with 320 upregulated genes and 106 downregulated genes. Among these genes, we noted upregulation of genes related to coagulation-inflammation circuitry including tissue factor (F3), coagulation factor II receptor-like 2 (F2RL2, PAR3), interleukin (IL)-6 and IL-8. Upregulation of these genes were independently confirmed by RT-PCR and/or protein release. Genes related to the CXC chemokine family that have been implicated in the pathogenesis of vascular disease were upregulated, including MCP-1 (2.60 fold), IL-8 (2.47 fold), CXCL1 (1.41 fold), CXCL2 (1.95 fold), CXCL3 (2.28 fold) and CXCR4 (1.30 fold). In addition, genes related to clotting independent signaling of F3 were also differentially expressed, including FOS, JUN and NFKBIA. Treatment of HPAEC with UFP for 16 hours increased the release of IL6 and IL8 by 1.9-fold and 1.8-fold respectively. Pretreatment of HPAEC with a blocking antibody against F3 attenuated IL6 and IL8 release by 30% and 70% respectively. Thus using gene profiling, we uncovered that UFP may induce vascular endothelial cells to express genes related to clotting and angiogenesis. These results provide a novel hypothesis that PM may cause cardiovascular adverse health effects via induction of tissue factor in vascular endothelial cells which then triggers clotting dependent and independent downstream signaling. Keywords: particle treatment

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Project description:The selective recovery of ultrafine, <10 μm, particles remains a significant challenge in the minerals industry. Indeed, these particles often report to tailings impoundments, resulting in under-utilization of mined resources and the need for tailings dams. Recently, a technique has been developed offering the potential to selectively recover particles down to <1 μm in size. This technique, originally inspired by oil agglomeration, uses a high internal-phase water in oil emulsion as a binder to selectively agglomerate hydrophobic particles. Due to the significant concentration of the dispersed aqueous phase, ~95%, the continuous organic phase forms a network of very thin, permeable films, estimated to be 60 nm thick. These are stabilized by an emulsifier. In the high shear field of the agglomeration process, the binder is fragmented into smaller hydrophobic portions, delivering its thin film coating to the adhering hydrophobic particles. Permeation of water across the thin films eliminates the viscous hydrodynamic resistance, permitting sub-micron particle recovery to occur at rates similar to those for particles considerably larger in size. This recovery occurs within seconds under intense mixing. In this study, a model system consisting of magnetite, with a Sauter mean diameter of 11.4 μm, was agglomerated using the water in oil emulsion binder. The binder, which contained the emulsifier sorbitan monooleate, appeared to also act as a collector for the magnetite, thus no separate particle conditioning step was required. Curiously, however, the binder requirements were higher than expected. Further investigations concerning the stability of the binder revealed that the magnetite particles were causing rapid binder degradation. Therefore, prior to agglomeration using the binder, the particles were conditioned with sorbitan monooleate to render them hydrophobic. This pre-conditioning led to significant reductions in the binder dosage required to achieve agglomeration. Moreover, the resulting dosage matched that predicted by a model silica system for the same specific hydrophobic surface area, thus allowing a model to be validated based on the required binder dosage for a known hydrophobic surface area. Examination of binder stability in the presence of conditioned magnetite revealed that the now hydrophobic particles stabilized the binder.

Dataset Information

Developmental exposures to ultrafine particle air pollution reduces early testosterone levels and adult male social novelty preference: Risk for children's sex-biased neurobehavioral disorders.

Publications

Developmental exposures to ultrafine particle air pollution reduces early testosterone levels and adult male social novelty preference: Risk for children's sex-biased neurobehavioral disorders.

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