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.

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.

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.

Adsorption of per- and polyfluoroalkyl substances on biochar derived from municipal sewage sludge.

Granular activated carbon (GAC) and ion exchange resin (IXR) are widely used as adsorbents to remove PFAS from drinking water sources and effluent waste streams. However, the high cost associated with GAC and IXR generation has motivated the development of less expensive adsorbents for treatment of PFAS-impacted water. Thus, the objective of this research was to create an economically viable and sustainable PFAS adsorbent from sewage sludge. Stepwise pyrolysis at temperatures from 300 °C to 1000 °C yielded biochars whose specific surface area (SSA) and porosity increased from 41 to 148 m2/g, and from 0.062 to 0.193 cm3/g, respectively. On a per organic char basis, the SSA of the biochar was as high as 1183 m2/g, which is comparable to commercially-available activated carbons. The adsorption of perfluorooctane sulfonic acid (PFOS) on sludge biochar increased with increasing pyrolysis temperature, which was positively correlated with increasing porosity and SSA. When 1000 °C processed biochar was tested with a mixture of eight PFAS, preferential adsorption of longer carbon chain-length species was observed, indicating the importance of PFAS hydrophobic interactions with the biochar and the availability of a wide range of mesopores. The adsorption of each PFAS was dependent upon both chain length and head group, with longer chain-length species exhibiting greater adsorption than shorter chain-length species, along with greater adsorption of species with sulfonic acid head groups compared to their chain length counterparts with carboxylic acid head groups. These findings demonstrate that biochar derived from municipal solid waste can serve as a cost-effective and sustainable adsorbent for the removal of PFOS and PFAS mixtures from source waters. The circular economy benefits and waste reduction potential associated with the use of sewage sludge-derived biochar supports the development of a viable sludge-derived biochar for the removal of PFAS from water.

Metabolomic changes following GenX and PFBS exposure in developing zebrafish.

Short chain per- and polyfluoroalkyl substances (PFAS), including hexafluoropropylene oxide dimer acid (GenX) and perfluorobutane sulfonate (PFBS), are replacement chemicals for environmentally persistent, long-chain PFAS. Although GenX and PFBS have been detected in surface and ground water worldwide, few studies provide information on the metabolic alterations or risks associated with their exposures. In this study, larval zebrafish were used to investigate the toxicity of early-life exposure to GenX or PFBS. Zebrafish were chronically exposed from 4 h post-fertilization (hpf) to 6 days post-fertilization (dpf) to 150 µM GenX or 95.0 µM PFBS. Ultra-high-performance liquid chromatography paired with high-resolution mass spectrometry was used to quantify uptake of GenX and PFBS into zebrafish larvae and perform targeted and untargeted metabolomics. Our results indicate that PFBS was 20.4 % more readily absorbed into the zebrafish larvae compared to GenX. Additionally, PFBS exposure significantly altered 13 targeted metabolites and 21 metabolic pathways, while GenX exposure significantly altered 1 targeted metabolite and 17 metabolic pathways. Exposure to GenX, and to an even greater extent PFBS, resulted in a number of altered metabolic pathways in the amino acid metabolism, with other significant alterations in the carbohydrate, lipid, cofactors and vitamins, nucleotide, and xenobiotics metabolisms. Our results indicate that GenX and PFBS impact the zebrafish metabolome, with implications of global metabolic dysregulation, particularly in metabolic pathways relating to growth and development.

Repurposing Waste Chemicals for Sustainable and Durable Molecular Data Storage.

Molecular data storage offers the intriguing possibility of higher theoretical density and longer lifetimes than today's electronic memory devices. Some demonstrations have used deoxyribonucleic acid (DNA), but bottlenecks in nucleic acid synthesis continue to make DNA data storage orders of magnitude more expensive than electronic storage media. Additionally, despite its potential for long-term storage, DNA faces durability challenges from environmental degradation. In this work, we demonstrate nongenomic molecular data storage using molecular libraries redirected from chemical waste streams. This approach requires no synthetic effort and can be implemented by using molecules that have a minimal associated cost. While the technique is agnostic about the exact molecular content of its inputs, we confirmed that some sources contained poly fluoroalkyl substances (PFAS), which persist for long periods in the natural environment and could offer extremely durable information storage as well as environmental benefits. These demonstrations provide a perspective on some of the valuable possibilities for nongenomic molecular information systems.

Aerobic biotransformation of 6:2 fluorotelomer sulfonate in soils from two aqueous film-forming foam (AFFF)-impacted sites.

Although 6:2 fluorotelomer sulfonate (6:2 FTS) is a common ingredient in aqueous film-forming foam (AFFF) formulations, its environmental fate at AFFF-impacted sites remains poorly understood. This study investigated the biotransformation of 6:2 FTS in microcosms prepared with soils collected from two AFFF-impacted sites; the former Loring Air Force Base (AFB) and Robins AFB. The half-life of 6:2 FTS in Loring soil was 43.3 days; while >60 mol% of initially spiked 6:2 FTS remained in Robins soil microcosms after a 224-day incubation. Differences in initial sulfate concentrations and the depletion of sulfate over the incubation likely contributed to the different 6:2 FTS biotransformation rates between the two soils. At day 224, stable transformation products, i.e., C4C7 perfluoroalkyl carboxylates, were formed with combined molar yields of 13.8 mol% and 1.2 mol% in Loring and Robins soils, respectively. Based on all detected transformation products, the biotransformation pathways of 6:2 FTS in the two soils were proposed. Microbial community analysis suggests that Desulfobacterota microorganisms may promote 6:2 FTS biotransformation via more efficient desulfonation. In addition, species from the genus Sphingomonas, which exhibited higher tolerance to elevated concentrations of 6:2 FTS and its biotransformation products, are likely to have contributed to 6:2 FTS biotransformation. This study demonstrates the potential role of biotransformation processes on the fate of 6:2 FTS at AFFF-impacted sites and highlights the need to characterize site biogeochemical properties for improved assessment of 6:2 FTS biotransformation behavior.

Biotransformation of 6:2 fluorotelomer sulfonate and microbial community dynamics in water-saturated one-dimensional flow-through columns.

Nearly all per- and polyfluoroalkyl substances (PFAS) biotransformation studies reported to date have been limited to laboratory-scale batch reactors. The fate and transport of PFAS in systems that more closely represent field conditions, i.e., in saturated porous media under flowing conditions, remain largely unexplored. This study investigated the biotransformation of 6:2 fluorotelomer sulfonate (6:2 FTS), a representative PFAS of widespread environmental occurrence, in one-dimensional water-saturated flow-through columns packed with soil obtained from a PFAS-contaminated site. The 305-day column experiments demonstrated that 6:2 FTS biotransformation was rate-limited, where a decrease in pore-water velocity from 3.7 to 2.4 cm/day, resulted in a 21.7-26.1 % decrease in effluent concentrations of 6:2 FTS and higher yields (1.0-1.4 mol% vs. 0.3 mol%) of late-stage biotransformation products (C4C7 perfluoroalkyl carboxylates). Flow interruptions (2 and 7 days) were found to enhance 6:2 FTS biotransformation during the 6-7 pore volumes following flow resumption. Model-fitted 6:2 FTS column biotransformation rates (0.039-0.041 cmw3/gs/d) were ∼3.5 times smaller than those observed in microcosms (0.137 cmw3/gs/d). Additionally, during column experiments, planktonic microbial communities remained relatively stable, whereas the composition of the attached microbial communities shifted along the flow path, which may have been attributed to oxygen availability and the toxicity of 6:2 FTS and associated biotransformation products. Genus Pseudomonas dominated in planktonic microbial communities, while in the attached microbial communities, Rhodococcus decreased and Pelotomaculum increased along the flow path, suggesting their potential involvement in early- and late-stage 6:2 FTS biotransformation, respectively. Overall, this study highlights the importance of incorporating realistic environmental conditions into experimental systems to obtain a more representative assessment of in-situ PFAS biotransformation.

A randomized controlled trial of a housing intervention to reduce endocrine disrupting chemical exposures in children.

Few studies have considered household interventions for reducing endocrine disrupting chemical (EDC) exposures. We conducted a secondary analysis of a randomized controlled trial, originally designed to reduce lead exposure, to evaluate if the intervention lowered EDC exposures in young children. Study participants were children from the Cincinnati, Ohio area (n = 250, HOME Study). Prenatally, families received a housing intervention that included paint stabilization and dust mitigation, or as a control, injury prevention measures. At 24-months, we measured organophosphate esters (OPEs) and phthalates or their metabolites in dust and urine. We measured perfluoroalkyl substances (PFAS) in dust and serum at 24- and 36-months, respectively. We assessed associations between dust and biomarker EDCs using Spearman correlations, characterized EDC mixtures via principal components analysis, and investigated treatment effects using linear regression. To mitigate selection bias, we fit statistical models using inverse probability of retention weights. Correlations between dust EDCs and analogous biomarkers were weak-to-moderate (ρ's ≤ 0.3). The intervention was associated with 23 % (95 % CI: -38, -3) lower urinary DEHP metabolites and, in a per-protocol analysis, 34 % lower (95 % CI: -55, -2) urinary MBZP. Additionally, among Black or African American children, the intervention was associated with lower serum concentrations of several PFAS (e.g., -42 %; 95 % CI: -63, -8 for PFNA). Household interventions that include paint stabilization and dust mitigation may reduce childhood exposures to some phthalates and PFAS in Blacks/African Americans. These findings highlight the need for larger studies with tailored and sustained housing interventions.

Modulation of blood-tumor barrier transcriptional programs improves intra-tumoral drug delivery and potentiates chemotherapy in GBM.

Glioblastoma (GBM) is the most common malignant primary brain tumor. GBM has an extremely poor prognosis and new treatments are badly needed. Efficient drug delivery to GBM is a major obstacle as the blood-brain barrier (BBB) prevents passage of the majority of cancer drugs into the brain. It is also recognized that the blood-brain tumor barrier (BTB) in the growing tumor represents a challenge. The BTB is heterogeneous and poorly characterized, but similar to the BBB it can prevent therapeutics from reaching effective intra-tumoral doses, dramatically hindering their potential. Here, we identified a 12-gene signature associated with the BTB, with functions related to vasculature development, morphogenesis and cell migration. We identified CDH5 as a core molecule in this set and confirmed its over-expression in GBM vasculature using spatial transcriptomics of GBM patient specimens. We found that the indirubin-derivative, 6-bromoindirubin acetoxime (BIA), could downregulate CDH5 and other BTB signature genes, causing endothelial barrier disruption in endothelial monolayers and BBB 3D spheroids in vitro. Treatment of tumor-bearing mice with BIA enabled increased intra-tumoral accumulation of the BBB non-penetrant chemotherapeutic drug cisplatin and potentiated cisplatin-mediated DNA damage by targeting DNA repair pathways. Finally, using an injectable BIA nanoparticle formulation, PPRX-1701, we significantly improved the efficacy of cisplatin in patient-derived GBM xenograms and prolonged their survival. Overall, our work reveals potential targets at the BTB for improved chemotherapy delivery and the bifunctional properties of BIA as a BTB modulator and potentiator of chemotherapy, supporting its further development.

Environmentally relevant uptake, elimination, and metabolic changes following early embryonic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish.

Dioxin and dioxin-like compounds are ubiquitous environmental contaminants that induce toxicity by binding to the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. The zebrafish model has been used to define the developmental toxicity observed following exposure to exogenous AHR ligands such as the potent agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD). While the model has successfully identified cellular targets of TCDD and molecular mechanisms mediating TCDD-induced phenotypes, fundamental information such as the body burden produced by standard exposure models is still unknown. We performed targeted gas chromatography (GC) high-resolution mass spectrometry (HRMS) in tandem with non-targeted liquid chromatography (LC) HRMS to quantify TCDD uptake, model the elimination dynamics of TCDD, and determine how TCDD exposure affects the zebrafish metabolome. We found that 50 ppt, 10 ppb, and 1 ppb waterborne exposures to TCDD during early embryogenesis produced environmentally relevant body burdens: 38 ± 4.34, 26.6 ± 1.2, and 8.53 ± 0.341 pg/embryo, respectively, at 24 hours post fertilization. TCDD exposure was associated with the dysregulation of metabolic pathways that are associated with the AHR signaling pathway as well as pathways shown to be affected in mammals following TCDD exposure. In addition, we discovered that TCDD exposure affected several metabolic pathways that are critical for brain development and function including glutamate metabolism, chondroitin sulfate biosynthesis, and tyrosine metabolism. Together, these data demonstrate that existing exposure methods produce environmentally relevant body burdens of TCDD in zebrafish and provide insight into the biochemical pathways impacted by toxicant-induced AHR activation.

Evaluation of Neural Regulation and Microglial Responses to Brain Injury in Larval Zebrafish Exposed to Perfluorooctane Sulfonate.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are biopersistent, global pollutants. Although some in vitro and epidemiological studies have explored the neurotoxic potential of perfluorooctane sulfonate (PFOS), a prevalent PFAS congener, it is unknown how developmental PFOS exposure affects neuronal signaling, microglia development, and microglial-neuron communication. OBJECTIVES: We sought to determine the extent to which PFOS exposure disrupts brain health, neuronal activity, and microglia-neuron communication during development. In addition, although PFOS impairs humoral immunity, its impact on innate immune cells, including resident microglia, is unclear. As such, we investigated whether microglia are cellular targets of PFOS, and, if so, whether disrupted microglial development or function could contribute to or is influenced by PFOS-induced neural dysfunction. METHODS: Zebrafish were chronically exposed to either a control solution [0.1% dimethyl sulfoxide (DMSO)], 7µM PFOS, 14µM PFOS, 28µM PFOS, or 64µM perfluorooctanoic acid (PFOA). We used in vivo imaging and gene expression analysis to assess microglial populations in the developing brain and to determine shifts in the microglia state. We functionally challenged microglia state using a brain injury model and, to assess the neuronal signaling environment, performed functional neuroimaging experiments using the photoconvertible calcium indicator calcium-modulated photoactivatable ratiometric integrator (CaMPARI). These studies were paired with optogenetic manipulations of neurons and microglia, an untargeted metabolome-wide association study (MWAS), and behavioral assays. RESULTS: Developmental PFOS exposure resulted in a shift away from the homeostatic microglia state, as determined by functional and morphological differences in exposed larvae, as well as up-regulation of the microglia activation gene p2ry12. PFOS-induced effects on microglia state exacerbated microglia responses to brain injury in the absence of increased cell death or inflammation. PFOS exposure also heightened neural activity, and optogenetic silencing of neurons or microglia independently was sufficient to normalize microglial responses to injury. An untargeted MWAS of larval brains revealed PFOS-exposed larvae had neurochemical signatures of excitatory-inhibitory imbalance. Behaviorally, PFOS-exposed larvae also exhibited anxiety-like thigmotaxis. To test whether the neuronal and microglial phenotypes were specific to PFOS, we exposed embryos to PFOA, a known immunotoxic PFAS. PFOA did not alter thigmotaxis, neuronal activity, or microglial responses, further supporting a role for neuronal activity as a critical modifier of microglial function following PFOS exposure. DISCUSSION: Together, this study provides, to our knowledge, the first detailed account of the effects of PFOS exposure on neural cell types in the developing brain in vivo and adds neuronal hyperactivity as an important end point to assess when studying the impact of toxicant exposures on microglia function. https://doi.org/10.1289/EHP12861.

Chronic Exposure to Low Levels of Parabens Increases Mammary Cancer Growth and Metastasis in Mice.

Methylparaben (MP) and propylparaben (PP) are commonly used as food, cosmetic, and drug preservatives. These parabens are detected in the majority of US women and children, bind and activate estrogen receptors (ER), and stimulate mammary tumor cell growth and invasion in vitro. Hemizygous B6.FVB-Tg (MMTV-PyVT)634Mul/LellJ female mice (n = 20/treatment) were exposed to MP or PP at levels within the US Food and Drug Administration's "human acceptable daily intake." These paraben-exposed mice had increased mammary tumor volume compared with control mice (P < 0.001) and a 28% and 91% increase in the number of pulmonary metastases per week compared with the control mice, respectively (P < 0.0001). MP and PP caused differential expression of 288 and 412 mammary tumor genes, respectively (false discovery rate < 0.05), a subset of which has been associated with human breast cancer metastasis. Molecular docking and luciferase reporter studies affirmed that MP and PP bound and activated human ER, and RNA-sequencing revealed increased ER expression in mammary tumors among paraben-exposed mice. However, ER signaling was not enriched in mammary tumors. Instead, both parabens strongly impaired tumor RNA metabolism (eg, ribosome, spliceosome), as evident from enriched KEGG pathway analysis of differential mammary tumor gene expression common to both paraben treatments (MP, P < 0.001; PP, P < 0.01). Indeed, mammary tumors from PP-exposed mice had an increased retention of introns (P < 0.05). Our data suggest that parabens cause substantial mammary cancer metastasis in mice as a function of their increasing alkyl chain length and highlight the emerging role of aberrant spliceosome activity in breast cancer metastasis.

Comprehensive analysis of alkenones by reversed-phase HPLC-MS with unprecedented selectivity, linearity and sensitivity.

Alkenones are among the most widely used paleotemperature biomarkers. Traditionally, alkenones are analyzed using gas chromatography-flame ionization detector (GC-FID), or GC-chemical ionization-mass spectrometry (GC-CI-MS). However, these methods encounter considerable challenges for samples that exhibit matrix interference or low concentrations, with GC-FID requiring tedious sample preparations and GC-CI-MS suffering from nonlinear response and a narrow linear dynamic range. Here we demonstrate that reversed-phase high pressure liquid chromatography-mass spectrometry (HPLC-MS) methods provide excellent resolution, selectivity, linearity and sensitivity for alkenones in complex matrices. We systematically compared the advantages and limitations of three mass detectors (quadrupole, Orbitrap, and quadrupole-time of flight) and two ionization modes (electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI)) for alkenone analyses. We demonstrate that ESI performs better than APCI as response factors of various unsaturated alkenones are similar. Among the three mass analyzers tested, orbitrap MS provided the lowest limit of detection (0.4, 3.8 and 8.6 pg injected masses for Orbitrap, qTOF and single quadrupole MS, respectively) and the widest linear dynamic range (600, 20 and 30 folds for Orbitrap, qTOF and single quadrupole MS, respectively). Single quadrupole MS operated in ESI mode provides accurate quantification of proxy measurements over a wide range of injection masses, and with its modest instrument cost, represents an ideal method for routine applications. Analysis of global core-top sediment samples confirmed the efficacy of HPLC-MS methods for the detection and quantification of paleotemperature proxies based on alkenones and their superiority over GC-based methods. The analytical method demonstrated in this study should also allow highly sensitive analyses of diverse aliphatic ketones in complex matrices.

Assessing aerobic biotransformation of 8:2 fluorotelomer alcohol in aqueous film-forming foam (AFFF)-impacted soils: Pathways and microbial community dynamics.

Production of 8:2 fluorotelomer alcohol (8:2 FTOH) for industrial and consumer products, including aqueous film-forming foams (AFFFs) used for firefighting, has resulted in its widespread occurrence in the environment. However, the fate of 8:2 FTOH at AFFF-impacted sites remains largely unknown. Using AFFF-impacted soils from two United States Air Force Bases, microcosm experiments evaluated the aerobic biotransformation of 8:2 FTOH (extent and byproduct formation) and the dose-response on microbial communities due to 8:2 FTOH exposure. Despite different microbial communities, rapid transformation of 8:2 FTOH was observed during a 90-day incubation in the two soils, and 7:2 secondary fluorotelomer alcohol (7:2 sFTOH) and perfluorooctanoic acid (PFOA) were detected as major transformation products. Novel transformation products, including perfluoroalkane-like compounds (1H-perfluoroheptane, 1H-perfluorohexane, and perfluoroheptanal) were identified by liquid chromatography-high resolution mass spectrometry (LC-HRMS) and used to develop aerobic 8:2 FTOH biotransformation pathways. Microbial community analysis suggests that species from genus Sphingomonas are potential 8:2 FTOH degraders based on increased abundance in both soils after exposure, and the genus Afipia may be more tolerant to and/or involved in the transformation of 8:2 FTOH at elevated concentrations. These findings demonstrate the potential role of biological processes on PFAS fate at AFFF-impacted sites through fluorotelomer biotransformation.

Non-targeted analysis (NTA) and suspect screening analysis (SSA): a review of examining the chemical exposome.

Non-targeted analysis (NTA) and suspect screening analysis (SSA) are powerful techniques that rely on high-resolution mass spectrometry (HRMS) and computational tools to detect and identify unknown or suspected chemicals in the exposome. Fully understanding the chemical exposome requires characterization of both environmental media and human specimens. As such, we conducted a review to examine the use of different NTA and SSA methods in various exposure media and human samples, including the results and chemicals detected. The literature review was conducted by searching literature databases, such as PubMed and Web of Science, for keywords, such as "non-targeted analysis", "suspect screening analysis" and the exposure media. Sources of human exposure to environmental chemicals discussed in this review include water, air, soil/sediment, dust, and food and consumer products. The use of NTA for exposure discovery in human biospecimen is also reviewed. The chemical space that has been captured using NTA varies by media analyzed and analytical platform. In each media the chemicals that were frequently detected using NTA were: per- and polyfluoroalkyl substances (PFAS) and pharmaceuticals in water, pesticides and polyaromatic hydrocarbons (PAHs) in soil and sediment, volatile and semi-volatile organic compounds in air, flame retardants in dust, plasticizers in consumer products, and plasticizers, pesticides, and halogenated compounds in human samples. Some studies reviewed herein used both liquid chromatography (LC) and gas chromatography (GC) HRMS to increase the detected chemical space (16%); however, the majority (51%) only used LC-HRMS and fewer used GC-HRMS (32%). Finally, we identify knowledge and technology gaps that must be overcome to fully assess potential chemical exposures using NTA. Understanding the chemical space is essential to identifying and prioritizing gaps in our understanding of exposure sources and prior exposures. IMPACT STATEMENT: This review examines the results and chemicals detected by analyzing exposure media and human samples using high-resolution mass spectrometry based non-targeted analysis (NTA) and suspect screening analysis (SSA).

Low-temperature persulfate activation by powdered activated carbon for simultaneous destruction of perfluorinated carboxylic acids and 1,4-dioxane.

Carbonaceous materials have emerged as a method of persulfate activation for remediation. In this study, persulfate activation using powdered activated carbon (PAC) was demonstrated at temperatures relevant to groundwater (5-25 °C). At room temperature, increasing doses of PAC (1-20 g L-1) led to increased persulfate activation (3.06 × 10-6s-1 to 2.10 × 10-4 with 1 and 20 g L-1 PAC). Activation slowed at lower temperatures (5 and 11 °C); however, substantial (>70 %) persulfate activation was achieved. PAC characterization showed that persulfate is activated at the surface of the PAC, as indicated by an increase in the PAC C:O ratio. Similarly, electron paramagnetic resonance (EPR) spectroscopy studies with a spin trapping agents (5,5-dimethyl-1-pyrroline N-oxide (DMPO)) and 2,2,6,6-tetramethylpiperidine (TEMP) revealed that singlet oxygen was not the main oxidizing species in the reaction. DMPO was oxidized to form 5,5-dimethylpyrrolidone-2(2)-oxyl-(1) (DMPOX), which forms in the presence of strong oxidizers, such as sulfate radicals. The persulfate/PAC system is demonstrated to simultaneously degrade both perfluorooctanoic acid (PFOA) and 1,4-dioxane at room temperature and 11 °C. With a 20 g L-1 PAC and 75 mM persulfate, 80 % and 70 % of the PFOA and 1,4-dioxane, respectively, degraded within 6 h at room temperature. At 11 °C, the same PAC and persulfate doses led to 57% dioxane degradation and 54 % PFOA degradation within 6 h. Coupling PAC with persulfate offers an effective, low-cost treatment for simultaneous destruction of 1,4-dioxane and PFOA.