Using Network Analysis and Predictive Functional Analysis to Explore the Fluorotelomer Biotransformation Potential of Soil Microbial Communities.

Microbial transformation of per- and polyfluoroalkyl substances (PFAS), including fluorotelomer-derived PFAS, by native microbial communities in the environment has been widely documented. However, few studies have identified the key microorganisms and their roles during the PFAS biotransformation processes. This study was undertaken to gain more insight into the structure and function of soil microbial communities that are relevant to PFAS biotransformation. We collected 16S rRNA gene sequencing data from 8:2 fluorotelomer alcohol and 6:2 fluorotelomer sulfonate biotransformation studies conducted in soil microcosms under various redox conditions. Through co-occurrence network analysis, several genera, including Variovorax, Rhodococcus, and Cupriavidus, were found to likely play important roles in the biotransformation of fluorotelomers. Additionally, a metagenomic prediction approach (PICRUSt2) identified functional genes, including 6-oxocyclohex-1-ene-carbonyl-CoA hydrolase, cyclohexa-1,5-dienecarbonyl-CoA hydratase, and a fluoride-proton antiporter gene, that may be involved in defluorination. This study pioneers the application of these bioinformatics tools in the analysis of PFAS biotransformation-related sequencing data. Our findings serve as a foundational reference for investigating enzymatic mechanisms of microbial defluorination that may facilitate the development of efficient microbial consortia and/or pure microbial strains for PFAS biotransformation.

Exposome Profiling of Environmental Pollutants in Seminal Plasma and Novel Associations with Semen Parameters.

Indicators of male fertility are in decline globally, but the underlying causes, including the role of environmental exposures, are unclear. This study aimed to examine organic chemical pollutants in seminal plasma, including both known priority environmental chemicals and less studied chemicals, to identify uncharacterized male reproductive environmental toxicants. Semen samples were collected from 100 individuals and assessed for sperm concentration, percent motility, and total motile sperm. Targeted and nontargeted organic pollutant exposures were measured from seminal plasma using gas chromatography, which showed widespread detection of organic pollutants in seminal plasma across all exposure classes. We used principal component pursuit (PCP) on our targeted panel and derived one component (driven by etriadizole) associated with total motile sperm (p < 0.001) and concentration (p = 0.03). This was confirmed by the exposome-wide association models using individual chemicals, where etriadizole was negatively associated with total motile sperm (FDR q = 0.01) and concentration (q = 0.07). Using PCP on 814 nontargeted spectral peaks identified a component that was associated with total motile sperm (p = 0.001). Bayesian kernel machine regression identified one principal driver of this association, which was analytically confirmed to be N-nitrosodiethylamine. These findings are promising and consistent with experimental evidence showing that etridiazole and N-nitrosodiethylamine may be reproductive toxicants.

High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage.

In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.

Maternal and newborn metabolomic changes associated with urinary polycyclic aromatic hydrocarbon metabolite concentrations at delivery: an untargeted approach.

INTRODUCTION: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse human health outcomes. To explore the plausible associations between maternal PAH exposure and maternal/newborn metabolomic outcomes, we conducted a cross-sectional study among 75 pregnant people from Cincinnati, Ohio. METHOD: We quantified 8 monohydroxylated PAH metabolites in maternal urine samples collected at delivery. We then used an untargeted high-resolution mass spectrometry approach to examine alterations in the maternal (n = 72) and newborn (n = 63) serum metabolome associated with PAH metabolites. Associations between individual maternal urinary PAH metabolites and maternal/newborn metabolome were assessed using linear regression adjusted for maternal and newborn factors while accounting for multiple testing with the Benjamini-Hochberg method. We then conducted functional analysis to identify potential biological pathways. RESULTS: Our results from the metabolome-wide associations (MWAS) indicated that an average of 1% newborn metabolome features and 2% maternal metabolome features were associated with maternal urinary PAH metabolites. Individual PAH metabolite concentrations in maternal urine were associated with maternal/newborn metabolome related to metabolism of vitamins, amino acids, fatty acids, lipids, carbohydrates, nucleotides, energy, xenobiotics, glycan, and organic compounds. CONCLUSION: In this cross-sectional study, we identified associations between urinary PAH concentrations during late pregnancy and metabolic features associated with several metabolic pathways among pregnant women and newborns. Further studies are needed to explore the mediating role of the metabolome in the relationship between PAHs and adverse pregnancy outcomes.

Microbial Reductive Dechlorination by a Commercially Available Dechlorinating Consortium Is Not Inhibited by Perfluoroalkyl Acids (PFAAs) at Field-Relevant Concentrations.

Perfluoroalkyl acids (PFAAs) have been shown to inhibit biodegradation (i.e., organohalide respiration) of chlorinated ethenes. The potential negative impacts of PFAAs on microbial species performing organohalide respiration, particularly Dehalococcoides mccartyi (Dhc), and the efficacy of in situ bioremediation are a critical concern for comingled PFAA-chlorinated ethene plumes. Batch reactor (no soil) and microcosm (with soil) experiments, containing a PFAA mixture and bioaugmented with KB-1, were completed to assess the impact of PFAAs on chlorinated ethene organohalide respiration. In batch reactors, PFAAs delayed complete biodegradation of cis-1,2-dichloroethene (cis-DCE) to ethene. Maximum substrate utilization rates (a metric for quantifying biodegradation rates) were fit to batch reactor experiments using a numerical model that accounted for chlorinated ethene losses to septa. Fitted values for cis-DCE and vinyl chloride biodegradation were significantly lower (p < 0.05) in batch reactors containing ≥50 mg/L PFAAs. Examination of reductive dehalogenase genes implicated in ethene formation revealed a PFAA-associated change in the Dhc community from cells harboring the vcrA gene to those harboring the bvcA gene. Organohalide respiration of chlorinated ethenes was not impaired in microcosm experiments with PFAA concentrations of 38.7 mg/L and less, suggesting that a microbial community containing multiple strains of Dhc is unlikely to be inhibited by PFAAs at lower, environmentally relevant concentrations.

Associations of a Prenatal Serum Per- and Polyfluoroalkyl Substance Mixture with the Cord Serum Metabolome in the HOME Study.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous and persistent chemicals associated with multiple adverse health outcomes; however, the biological pathways affected by these chemicals are unknown. To address this knowledge gap, we used data from 264 mother-infant dyads in the Health Outcomes and Measures of the Environment (HOME) Study and employed quantile-based g-computation to estimate covariate-adjusted associations between a prenatal (∼16 weeks' gestation) serum PFAS mixture [perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)] and 14,402 features measured in cord serum. The PFAS mixture was associated with four features: PFOS, PFHxS, a putatively identified metabolite (3-monoiodo-l-thyronine 4-O-sulfate), and an unidentified feature (590.0020 m/z and 441.4 s retention time; false discovery rate <0.20). Using pathway enrichment analysis coupled with quantile-based g-computation, the PFAS mixture was associated with 49 metabolic pathways, most notably amino acid, carbohydrate, lipid and cofactor and vitamin metabolism, as well as glycan biosynthesis and metabolism (P(Gamma) <0.05). Future studies should assess if these pathways mediate associations of prenatal PFAS exposure with infant or child health outcomes, such as birthweight or vaccine response.

Does Using Corsi-Rosenthal Boxes to Mitigate COVID-19 Transmission Also Reduce Indoor Air Concentrations of PFAS and Phthalates?

The COVID-19 pandemic brought new emphasis on indoor air quality. However, few studies have investigated the impact of air filtration, a COVID-mitigation approach, on indoor air concentrations of semivolatile organic compounds (SVOCs). Using a quasi-experimental design, we quantified the impact of a relatively low-cost "do-it-yourself" air filter (Corsi-Rosenthal Box; CR Box) on indoor air concentrations of 42 PFAS and 24 other SVOCs. We sampled air before (October-November 2021) and during (February-March 2022) deployment of CR Boxes in 17 rooms located in an occupied Providence, Rhode Island office building. We measured sound levels in rooms with CR Boxes operating and not operating. While CR Boxes were deployed, concentrations of seven PFAS (N-EtFOSE, N-EtFOSA, FBSA, PFBS, PFHxS, PFOS, PFNA) were 28-61% lower and concentrations of five phthalates (DMP, DEP, DiBP, BBzP, DCHP) were 29-62% lower. Concentrations of five PFAS and one phthalate increased 23-44% during the intervention period, but the 95% CI of most of these estimates included the null. Daytime sound levels increased 5.0 dB when CR Boxes were operating. These results indicate that CR Boxes reduced exposure to several lower-volatility phthalates and sulfonated PFAS previously reported to be found in office building materials and products, with potentially distracting increases in sound levels.

Biotransformation of 8:2 Fluorotelomer Alcohol in Soil from Aqueous Film-Forming Foams (AFFFs)-Impacted Sites under Nitrate-, Sulfate-, and Iron-Reducing Conditions.

The environmental fate of per- and polyfluoroalkyl substances (PFAS) in aqueous film-forming foams (AFFFs) remains largely unknown, especially under the conditions representative of natural subsurface systems. In this study, the biotransformation of 8:2 fluorotelomer alcohol (8:2 FTOH), a component of new-generation AFFF formulations and a byproduct in fluorotelomer-based AFFFs, was investigated under nitrate-, iron-, and sulfate-reducing conditions in microcosms prepared with AFFF-impacted soils. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-resolution mass spectrometry (HRMS) were employed to identify biotransformation products. The biotransformation was much slower under sulfate- and iron-reducing conditions with >60 mol % of initial 8:2 FTOH remaining after ∼400 days compared to a half-life ranging from 12.5 to 36.5 days under nitrate-reducing conditions. Transformation products 8:2 fluorotelomer saturated and unsaturated carboxylic acids (8:2 FTCA and 8:2 FTUA) were detected under all redox conditions, while 7:2 secondary fluorotelomer alcohol (7:2 sFTOH) and perfluorooctanoic acid (PFOA) were only observed as transformation products under nitrate-reducing conditions. In addition, 1H-perfluoroheptane (F(CF2)6CF2H) and 3-F-7:3 acid (F(CF2)7CFHCH2COOH) were identified for the first time during 8:2 FTOH biotransformation. Comprehensive biotransformation pathways for 8:2 FTOH are presented, which highlight the importance of accounting for redox condition and the related microbial community in the assessment of PFAS transformations in natural environments.

Influence of Residual Nonaqueous-Phase Liquids (NAPLs) on the Transport and Retention of Perfluoroalkyl Substances.

Per- and polyfluoralkyl substances (PFAS) are known to accumulate at interfaces, and the presence of nonaqueous-phase liquids (NAPLs) could influence the PFAS fate in the subsurface. Experimental and mathematical modeling studies were conducted to investigate the effect of a representative NAPL, tetrachloroethene (PCE), on the transport behavior of PFAS in a quartz sand. Perfluorooctanesulfonate (PFOS), perfluorononanoic acid (PFNA), a 1:1 mixture of PFOS and PFNA, and a mixture of six PFAS (PFOS, PFNA, perfluorooctanoic acid (PFOA), perfluoroheptanoic acid (PFHpA), perfluorohexanesulfonate (PFHxS), and perfluorobutanesulfonate (PFBS)) were used to assess PFAS interactions with PCE-NAPL. Batch studies indicated that PFAS partitioning into PCE-NAPL (Knw < 0.1) and adsorption on 60-80 mesh Ottawa sand (Kd < 6 × 10-5 L/g) were minimal. Column studies demonstrated that the presence of residual PCE-NAPL (∼16% saturation) delayed the breakthrough of PFOS and PFNA, with minimal effects on the mobility of PFBS, PFHpA, PFHxS, and PFOA. Breakthrough curves (BTCs) obtained for PFNA and PFOS alone and in mixtures were nearly identical, indicating the absence of competitive adsorption effects. A mathematical model that accounts for NAPL-water interfacial sorption accurately reproduced PFAS BTCs, providing a tool to predict PFAS fate and transport in co-contaminated subsurface environments.

Developmental exposure to DDT or DDE alters sympathetic innervation of brown adipose in adult female mice.

BACKGROUND: Exposure to the bioaccumulative pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) has been associated with increased risk of insulin resistance and obesity in humans and experimental animals. These effects appear to be mediated by reduced brown adipose tissue (BAT) thermogenesis, which is regulated by the sympathetic nervous system. Although the neurotoxicity of DDT is well-established, whether DDT alters sympathetic innervation of BAT is unknown. We hypothesized that perinatal exposure to DDT or DDE promotes thermogenic dysfunction by interfering with sympathetic regulation of BAT thermogenesis. METHODS: Pregnant C57BL/6 J mice were administered environmentally relevant concentrations of DDTs (p,p'-DDT and o,p'-DDT) or DDE (p,p'-DDE), 1.7 mg/kg and 1.31 mg/kg, respectively, from gestational day 11.5 to postnatal day 5 by oral gavage, and longitudinal body temperature was recorded in male and female offspring. At 4 months of age, metabolic parameters were measured in female offspring via indirect calorimetry with or without the ß3 adrenergic receptor agonist, CL 316,243. Immunohistochemical and neurochemical analyses of sympathetic neurons innervating BAT were evaluated. RESULTS: We observed persistent thermogenic impairment in adult female, but not male, mice perinatally exposed to DDTs or p,p'-DDE. Perinatal DDTs exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDTs nor p,p'-DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDTs-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDTs, but not p,p'-DDE, and 48 and 43% fewer synapses in stellate ganglia of mice exposed to either DDTs or p,p'-DDE, respectively, compared to control. CONCLUSIONS: These data demonstrate that perinatal exposure to DDTs or p,p'-DDE impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT.

Delineating the Relationship between Nanoparticle Attachment Efficiency and Fluid Flow Velocity.

The ability to fundamentally describe nanoparticle (NP) transport in the subsurface underpins environmental risk assessment and successful material applications, including advanced remediation and sensing technologies. Despite considerable progress, our understanding of NP deposition behavior remains incomplete as there are conflicting reports regarding the effect of fluid flow velocity on attachment efficiency. To directly address this and more accurately describe NP attachment behavior, we have developed a novel protocol using a quartz crystal microbalance with dissipation monitoring (QCM-D) to separate and individually observe deposition mechanisms (diffusion and sedimentation), providing in situ, real-time information about particle diffusion (from the bulk liquid to solid surface). Through this technique, we have verified that the approaching velocity of NPs via diffusion increases (0.8-6.7 µm/s) with increasing flow velocity (6.1-106.0 µm/s), leading to an increased NP kinetic energy, thus affecting deposition processes. Further, in the presence of a secondary energy minimum associated with organic surface coatings, secondary minimum deposition decreases and primary minimum deposition increases with the flow velocity. NPs deposited at the primary minimum are relatively more resistant to hydrodynamic energies (including detachment associated energies), resulting in an increase of observed attachment efficiencies. Taken together, this work not only describes a novel method to delineate and quantify physical processes underpinning particle behavior but also provides direct measurements regarding key factors defining the relationship(s) of flow velocity and particle attachment. Such insight is valuable for next-generation fate and transport model accuracy, especially under unfavorable attachment regimes, which is a current and critical need for subsurface material applications and implication paradigms.

Aqueous Film-Forming Foams Exhibit Greater Interfacial Activity than PFOA, PFOS, or FOSA.

Perfluoroalkyl acids spontaneously concentrate at air-water and non-aqueous phase liquid (NAPL)-water interfaces, which can influence their retention during subsurface transport. This work presents measurements of air- and NAPL-water interfacial tension for synthetic groundwater containing perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorooctanesulfonamide (FOSA), or aqueous film-forming foam (AFFF) formulations at concentrations ranging from 0.1 to greater than 1000 mg/L. The NAPLs tested included dodecane, tetrachloroethylene, and jet fuel. AFFF formulations were less efficient at lowering interfacial tension than PFOA, FPOS, or FOSA substances below 100 mg/L, while above 100 mg/L, these formulations were more effective, achieving tensions of less than 3 mN/m. Infiltration of solutions with such low tension could lead to mobilization of residual NAPL. Equations based on interfacial tension measurements show that concentrations of PFOA, PFOS, and FOSA at the air-water interface were from 2 to 16 times greater than at the NAPL-water interface below 100 mg/L and were 10-50 times greater for AFFF below 20 mg/L. Calculations for unsaturated soil estimate that up to 87% of PFOS mass was at the air-water interface and less than 4% at the dodecane-water interface for bulk-water concentrations below 1 mg/L.

Development and Validation of a Two-Stage Kinetic Sorption Model for Polymer and Surfactant Transport in Porous Media.

Understanding the sorption processes is critical to the successful design and implementation of a variety of technologies in subsurface application. Most transport models assume minimal interactions between adsorbed species and, thus, are unable to accurately describe the formation of adsorbed bilayers. To address this limitation, a two-stage kinetic sorption model is developed and incorporated into a one-dimensional advective-dispersive-reactive transport simulator. The model is evaluated using data obtained from column experiments conducted with a representative polymer [gum arabic (GA)] and a nonionic surfactant [Witconol 2722 (WT)] under a range of experimental conditions. Model simulations demonstrate that the first-stage polymer/surfactant-surface sorption rate is at least 1 order of magnitude greater than the second-stage rate, associated with bilayer formation, indicating that the first-stage reaction is more favorable. The reversibility of the second-stage sorption process is found to be compound-specific, with irreversible sorption observed for GA and prolonged tailing observed for WT. This study demonstrates that the developed two-stage kinetic model is superior to a two-stage equilibrium-based model in its replication of two-leg breakthrough curves observed in core flood experiments; the normalized root-mean-square error between measurement and regressed model simulations was reduced by an average of 41% with the kinetic approach.

In Situ Sequestration of Perfluoroalkyl Substances Using Polymer-Stabilized Powdered Activated Carbon.

Remediation of groundwater impacted by per- and polyfluoroalkyl substances (PFAS) is particularly challenging due to the resistance of the molecule to oxidation because of the strength of the carbon-fluorine bond and the need to achieve low nanogram per liter drinking water targets. Previous studies have shown that activated carbon is an effective sorbent for removal of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in conventional water treatment systems. The objective of this study was to evaluate the in situ delivery and sorptive capacity of an aqueous suspension containing powdered activated carbon (PAC) stabilized with polydiallyldimethylammonium chloride (polyDADMAC). Batch reactor studies demonstrated substantial adsorption of PFOA and PFOS by polyDADMAC-stabilized PAC, which yielded Freundlich adsorption coefficients of 156 and 629 L/g-n, respectively. In columns packed with 40-50 mesh Ottawa sand, injection of a PAC (1000 mg/L) + polyDADMAC (5000 mg/L) suspension created a sorptive region that increased subsequent PFOA and PFOS retention by 3 orders of magnitude relative to untreated control columns, consistent with the mass of retained PAC. Experiments conducted in a heterogeneous aquifer cell further demonstrated the potential for stabilized-PAC to be an effective in situ treatment option for PFAS-impacted groundwater.

Accumulation of six PFAS compounds by woody and herbaceous plants: potential for phytoextraction.

Per and polyfluoroalkyl substances (PFAS) consist of a large group of compounds used to make products more resistant to stains, grease, and water and for fire suppression. They have been widely detected in the environment and exposure has been linked to adverse human health effects. Phytoremediation could be used to remediate PFAS-impacted sites, but there is little information on herbaceous and woody plant species uptake of PFAS compounds from soil. A greenhouse study evaluated the potential for eight herbaceous and seven woody plant species to absorb PFAS compounds. Six PFAS compounds: PFPeA, PFHxA, PFOA, PFBS, PFHxS, and PFOS were added weekly to irrigation water, and the plants grown for up to 14 weeks after an initial establishment period. Significant accumulation of all PFAS compounds occurred in at least one plant species. Mass recovery in above-ground tissue by the best performing plant ranged from a low of 3.8% for PFOS by Festuca rubra to a high of 42% for PFPeA by Schedonorus arundinaceus. Hyperaccumulation, defined as tissue/soil concentrations >10/1, was observed for all six PFAS compounds in at least one plant species. These results demonstrate the potential use of phytoremediation as a tool for remediating PFAS-contaminated sites.

Metabolomics of childhood exposure to perfluoroalkyl substances: a cross-sectional study.

INTRODUCTION: Exposure to perfluoroalkyl substances (PFAS), synthetic and persistent chemicals used in commercial and industrial processes, are associated with cardiometabolic dysfunction and related risk factors including reduced birth weight, excess adiposity, and dyslipidemia. Identifying the metabolic changes induced by PFAS exposure could enhance our understanding of biological pathways underlying PFAS toxicity. OBJECTIVE: To identify metabolic alterations associated with serum concentrations of four PFAS in children using a metabolome-wide association study. METHODS: We performed untargeted metabolomic profiling by liquid chromatography with ultra-high-resolution mass spectrometry, and separately quantified serum concentrations of perfluorooctanoic acid, perfluorooctanesulfonic acid, perfluorononanoic acid, and perfluorohexanesulfonic acid (PFHxS) for 114 8-year old children from Cincinnati, OH. We evaluated associations between each serum PFAS concentration and 16,097 metabolic features using linear regression adjusted for child age, sex, and race with a false discovery rate < 20%. We annotated PFAS-associated metabolites and conducted pathway enrichment analyses. RESULTS: Serum PFAS concentrations were associated with metabolic features annotated primarily as lipids and dietary factors. Biological pathways associated with all four PFAS included arginine, proline, aspartate, asparagine, and butanoate metabolism. CONCLUSIONS: In this cross-sectional study, childhood serum PFAS concentrations were correlated with metabolic pathways related to energy production and catabolism. Future studies should determine whether these pathways mediate associations between PFAS exposure and childhood cardiometabolic health.

Metabolome-wide association study of anti-epileptic drug treatment during pregnancy.

Pregnant women with epilepsy (PWWE) require continuous anti-epileptic drug (AED) treatment to avoid risk to themselves and fetal risks secondary to maternal seizures, resulting in prolonged AED exposure to the developing embryo and fetus. The objectives of this study were to determine whether high-resolution metabolomics is able to link the metabolite profile of PWWE receiving lamotrigine or levetiracetam for seizure control to associated pharmacodynamic (PD) biological responses. Untargeted metabolomic analysis of plasma obtained from 82 PWWE was completed using high-resolution mass spectrometry. Biological alterations due to lamotrigine or levetiracetam monotherapy were determined by a metabolome-wide association study that compared patients taking either drug to those who did not require AED treatment. Metabolic changes associated with AED use were then evaluated by testing for drug-dose associated metabolic variations and pathway enrichment. AED therapy resulted in drug-associated metabolic profiles recognizable within maternal plasma. Both the parent compounds and major metabolites were detected, and each AED was correlated with other metabolic features and pathways. Changes in metabolites and metabolic pathways important to maternal health and linked to fetal neurodevelopment were detected for both drugs, including changes in one­carbon metabolism, neurotransmitter biosynthesis and steroid metabolism. In addition, decreased levels of 5-methyltetrahydrofolate and tetrahydrofolate were detected in women taking lamotrigine, which is consistent with recent findings showing increased risk of autism spectrum disorder traits in PWWE using AED. These results represent a first step in development of pharmacometabolomic framework with potential to detect adverse AED-related metabolic changes during pregnancy.

Exposure to Persistent Organic Pollutants (POPs) and Their Relationship to Hepatic Fat and Insulin Insensitivity among Asian Indian Immigrants in the United States.

Persistent organic pollutants (POPs), such as dichlorodiphenyltrichloroethane (DDT) and other organochlorine compounds, are abundant in the environment and in foodstuffs from the Indian subcontinent. These environmental contaminants have been associated with a higher risk of diabetes in numerous studies. Asian Indians are well known to have a high risk of diabetes compared with other populations, and this risk is also found in migrant populations of Asian Indians in the United States, Europe, and elsewhere. We hypothesized that high plasma concentrations of POPs in Asian Indian migrants are linked to a variety of diabetes-related pathologies and explored the mechanism for the induction of these effects. We measured 30 environmental pollutants in plasma samples obtained from 147 participants in the Metabolic syndrome and Atherosclerosis in South Asians Living in America pilot study using a gas chromatography-tandem mass spectrometry analytical method that uses less than 0.5 mL of plasma. We found that plasma levels of o,p'-DDT and p,p'-DDT were independently associated with both body mass index (BMI) and waist circumference. Doubling the levels of the sums of these DDTs was associated with insulin insensitivity (-0.38 Matsuda index, p = 0.001), increased adiposity (1.26 kg/m2 BMI and 3.58 cm waist circumference increase, p < 0.0001), circulating insulin (12.9 mIU/L, p = 0.002), hepatic fat (-0.051 HU, p = 0.001), as well as increased odds of obesity (OR = 2.17, p < 0.001, BMI-based; OR = 2.37, p = 0.001, waist-based), prediabetes (OR = 1.55, p = 0.02), diabetes (OR = 1.72, p = 0.01), and fatty liver (OR = 1.66, p = 0.01) in multivariable models accounting for confounding by age, sex, years in the US, education, and fish protein. Furthermore, levels of DDTs were associated with increased hepatic fat and circulating insulin, independent of obesity and confounders. These findings suggest that exposure to DDTs may contribute to the risk of metabolic disease among Asian Indians by affecting hepatic fat levels independent of obesity.

Multigenerational metabolic profiling in the Michigan PBB registry.

Although polychlorinated biphenyls and polybrominated biphenyls are no longer manufactured the United States, biomonitoring in human populations show that exposure to these pollutants persist in human tissues. The objective of this study was to identify metabolic variations associated with exposure to 2,2'4,4',5,5'-hexabromobiphenyl (PBB-153) and 2,2'4,4',5,5'-hexachlorobiphenyl (PCB-153) in two generations of participants enrolled in the Michigan PBB Registry (http://pbbregistry.emory.edu/). Untargeted, high-resolution metabolomic profiling of plasma collected from 156 individuals was completed using liquid chromatography with high-resolution mass spectrometry. PBB-153 and PCB-153 levels were measured in the same individuals using targeted gas chromatography-tandem mass spectrometry and tested for dose-dependent correlation with the metabolome. Biological response to these exposures were evaluated using identified endogenous metabolites and pathway enrichment. When compared to lipid-adjusted concentrations for adults in the National Health and Nutrition Examination Survey (NHANES) for years 2003-2004, PCB-153 levels were consistent with similarly aged individuals, whereas PBB-153 concentrations were elevated (p<0.0001) in participants enrolled in the Michigan PBB Registry. Metabolic alterations were correlated with PBB-153 and PCB-153 in both generations of participants, and included changes in pathways related to catecholamine metabolism, cellular respiration, essential fatty acids, lipids and polyamine metabolism. These pathways were consistent with pathophysiological changes observed in neurodegenerative disease and included previously identified metabolomic markers of Parkinson's disease. To determine if the metabolic alterations detected in this study are replicated other cohorts, we evaluated correlation of PBB-153 and PCB-153 with plasma fatty acids measured in NHANES. Both pollutants showed similar associations with fatty acids previously linked to PCB exposure. Thus, the results from this study show metabolic alterations correlated with PBB-153 and PCB-153 exposure can be detected in human populations and are consistent with health outcomes previously reported in epidemiological and mechanistic studies.