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Wastewater reclamation facilities are known sources of emerging contaminants associated with human health and sanitation. This study evaluated the contribution of trace organic contaminants to a previously unmonitored river by water resource reclamation facilities. Six sampling events were conducted on the Reedy River in South Carolina. Sampling locations included sites upstream and downstream of two WRRFs located on the river to examine potential contributions under drought conditions where WRRF effluents comprise a large proportion of total stream flow. Five target analytes were monitored including atrazine, carbamazepine, 17β-estradiol, perfluorooctanoic acid, and sulfamethoxazole. On a mass basis, the WRRFs contributed additional loadings of carbamazepine ranging from 5.4 g/d to 7.2 g/d (mean: 6.3 ± 0.4 g/d), PFOA ranging from 8.6 to 31.9 g/d (mean: 20.0 ± 4.9), and sulfamethoxazole ranging from 49.4 g/d to 75.1 g/d (mean: 62.1 ± 4.8). 17β-estradiol was detected once and atrazine was not detected.

Wastewater-based epidemiology (WBE) has become a valuable tool for monitoring SARS-CoV-2 infection trends throughout the COVID-19 pandemic. Population biomarkers that measure the relative human fecal contribution to normalize SARS-CoV-2 wastewater concentrations are needed for improved analysis and interpretation of community infection trends. The Centers for Disease Control and Prevention National Wastewater Surveillance System (CDC NWSS) recommends using the wastewater flow rate or human fecal indicators as population normalization factors. However, there is no consensus on which normalization factor performs best. In this study, we provided the first multistate assessment of the effects of flow rate and human fecal indicators (crAssphage, F+ Coliphage, and PMMoV) on the correlation of SARS-CoV-2 wastewater concentrations and COVID-19 cases using the CDC NWSS dataset of 182 communities across six U.S. states. Flow normalized SARS-CoV-2 wastewater concentrations produced the strongest correlation with COVID-19 cases. The correlation from the three human fecal indicators were significantly lower than flow rate. Additionally, using reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) significantly improved correlation values over samples that were analyzed with real-time reverse transcription quantitative polymerase chain reaction (rRT-qPCR). Our assessment shows that utilizing flow normalization with RT-ddPCR generate the strongest correlation between SARS-CoV-2 wastewater concentrations and COVID-19 cases.

Carbon nanomaterials are emerging contaminants released into the environment primarily through anthropogenic processes, where they primarily partition into soils and sediments. Aquatic animals that inhabit, forage, or choose prey in the benthic zone are vulnerable to dietary exposure to sediment-associated carbon nanomaterials. Since carbon nanomaterials are hydrophobic, dietary exposure may alter the availability, metabolism, storage, and transport of lipids in the intestinal lumen or at the epithelial barrier, affecting downstream biological processes. To assess the effect of single-walled carbon nanotubes (SWCNTs) on the gastrointestinal lipidome of aquatic species, a feeding experiment with adult largemouth bass (Micropterus salmoides) was conducted. After 8 weeks of exposure to SWCNTs via the diet, the intestinal abundance of ceramides and several classes of lyso- and phospholipids were significantly altered. Additionally, functional profiling with Metaboanalyst revealed changes in pathways related to fatty acid biosynthesis in exposed fish. These results suggest that though SWCNTs do not pass through the gastrointestinal epithelium, they may alter gut homeostasis through interactions with intestinal lipids.

Cancer is the second leading cause of death worldwide, with 9.6 million cancer-related deaths in 2018. Cancer incidence has increased over time, and so has the prescription rate of chemotherapeutic drugs. These pharmaceuticals, known as antineoplastic agents, enter the aquatic environment via human excretion and wastewater. The objectives of the present critical review were to investigate the risk of antineoplastics to aquatic species and to summarize the current state of knowledge regarding their levels in the environment, because many antineoplastics are not adequately removed during wastewater treatment. We conducted 2 separate literature reviews to synthesize data on the global environmental prevalence and toxicity of antineoplastics. The antineoplastics most frequently detected in the environment included cyclophosphamide, ifosfamide, tamoxifen, methotrexate, and 5-fluorouracil; all were detectable in multiple water sources, including effluent and surface waters. These antineoplastics span 3 different mechanistic classes, with cyclophosphamide and ifosfamide classified as alkylating agents, tamoxifen as a hormonal agent, and methotrexate and 5-fluorouracil as antimetabolites. Studies that characterize the risk of antineoplastics released into aquatic environments are scarce. We summarize the biological impacts of the most environmentally prevalent antineoplastics on aquatic organisms and propose an adverse outcome pathway for cyclophosphamide and ifosfamide, 2 widely prescribed drugs with a similar immunotoxic mode of action. Acute and chronic ecotoxicity studies using aquatic models are needed for risk characterization of antineoplastics. Environ Toxicol Chem 2020;39:967-985. © 2020 SETAC.

Brominated flame retardants (BFRs) are environmentally persistent, are detected in humans, and some have been banned due to their potential toxicity. BFRs are developmental neurotoxicants and endocrine disruptors, however, few studies have explored their potential nephrotoxicity. We addressed this gap in the literature by determining the toxicity of three different BFRs (tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCD), and tetrabromodiphenyl ether (BDE-47)) in rat (NRK 52E) and human (HK-2 and RPTEC) tubular epithelial cells. All compounds induced time- and concentration-dependent toxicity based on decreases in MTT staining and changes in cell and nuclear morphology. The toxicity of BFRs was chemical- and cell-dependent, and human cells were more susceptible to all three BFRs based on IC50s after 48 h exposure. BFRs also had chemical- and cell-dependent effects on apoptosis as measured by increases in annexin V and PI staining. The molecular mechanisms mediating this toxicity were investigated using RNA sequencing. Principal components analysis supported the hypothesis that BFRs induce different transcriptional changes in rat and human cells. Furthermore, BFRs only shared nine differentially expressed genes in rat cells and five in human cells. Gene set enrichment analysis demonstrated chemical- and cell-dependent effects, however, some commonalities were also observed. Namely, gene sets associated with extracellular matrix turnover, the coagulation cascade, and the SNS-related adrenal cortex response were enriched across all cell lines and BFR treatments. Taken together, these data support the hypothesis that BFRs induce differential toxicity in rat and human renal cell lines that is mediated by differential changes in gene expression.

The physiology of males and females can be vastly different, complicating interpretation of toxicological and physiological data. The objectives of this study were to elucidate the sex differences in the microbiome-gastrointestinal (GI) transcriptome of adult zebrafish. We compared microbial composition and diversity in both males and females fed the same diet and housed in the same environment. There were no sex-specific differences in weight gain nor gastrointestinal morphology based on histopathology. There was no difference in gut microbial diversity, richness (Shannon and Chao1 index) nor predicted functional composition of the microbiome between males and females. Prior to post-hoc correction, male zebrafish showed higher abundance for the bacterial families Erythrobacteraceae and Lamiaceae, both belonging to the phyla Actinobacteria and Proteobacteria. At the genus level, Lamia and Altererythrobacter were more dominant in males and an unidentified genus in Bacteroidetes was more abundant in females. There were 16 unique differentially expressed transcripts in the gastrointestinal tissue between male and female zebrafish (FDR corrected, p 0.05). Relative to males, the mRNA expression for trim35-9, slc25a48, chchd3b, csad, and hsd17b3 were lower in female GI while cyp2k6, adra2c, and bckdk were higher in the female GI. Immune and lipid-related gene network expression differed between the sexes (i.e., cholesterol export and metabolism) as well as networks related to gastric motility, gastrointestinal system absorption and digestion. Such data provide clues as to putative differences in gastrointestinal physiology between male and female zebrafish. This study identifies host-transcriptome differences that can be considered when interpreting the microgenderome of zebrafish in studies investigating GI physiology and toxicology of fishes.

As the prevalence of obesity has steadily increased on a global scale, research has shifted to explore potential contributors to this pandemic beyond overeating and lack of exercise. Environmental chemical contaminants, known as obesogens, alter metabolic processes and exacerbate the obese phenotype. Diethylhexyl phthalate (DEHP) is a common chemical plasticizer found in medical supplies, food packaging, and polyvinyl materials, and has been identified as a probable obesogen. This study investigated the hypothesis that co-exposure to DEHP and overfeeding would result in decreased lipid mobilization and physical fitness in Danio rerio (zebrafish). Four treatment groups were randomly assigned: Regular Fed (control, 10 mg/fish/day with 0 mg/kg DEHP), Overfed (20 mg/fish/day with 0 mg/kg DEHP), Regular Fed + DEHP (10 mg/fish/day with 3 mg/kg DEHP), Overfed + DEHP (20 mg/fish/day with 3 mg/kg DEHP). After 24 weeks, swim tunnel assays were conducted on half of the zebrafish from each treatment to measure critical swimming speeds (U

OBJECTIVES Approximately 2½ billion people worldwide rely on solid/biomass fuel as fuel for cooking/heating the home. Environmental exposure to the smoke associated with biomass fuel burning has been associated respiratory diseases, cardiac disorders, and altered blood pressure. Therefore, a systematic review and meta-analysis was conducted to study this relationship across multiple studies. METHODS Searches were performed using PRISMA guidelines for articles using Web of Science, PubMed, Toxline, and Web of Science of peer reviewed papers with no beginning time restriction until February 2017. The search yielded 10 manuscripts after application of inclusion criteria, which encompassed 93 724 participants. Outcomes included (a) the proportion of people with a clinical diagnosis of hypertension in an exposed (vs. unexposed) population or (b) correlation coefficients examining degree of exposure and systolic/diastolic blood pressure. RESULTS The four studies reporting effect sizes for hypertension (N = 92 042) had a weighted mean effect size of r = .12 [-0.02, 0.27], z = 1.66, p = 0.097. The six studies reporting effect sizes for systolic and diastolic blood pressure (N = 1682) had weighted mean effect sizes of r = .15 [0.06, 0.24], p = 0.001, and r = .09 [0.03, 0.15], p = 0.002, respectively. CONCLUSION These analyses revealed that there is a small-but-significant relationship between biomass fuel exposure and an increase in both systolic and diastolic blood pressure, but the relationship between biomass fuel and hypertension specifically remains unclear.

Wastewater reclamation facilities are known sources of emerging contaminants associated with human health and sanitation. This study evaluated the contribution of trace organic contaminants to a previously unmonitored river by water resource reclamation facilities. Six sampling events were conducted on the Reedy River in South Carolina. Sampling locations included sites upstream and downstream of two WRRFs located on the river to examine potential contributions under drought conditions where WRRF effluents comprise a large proportion of total stream flow. Five target analytes were monitored including atrazine, carbamazepine, 17β-estradiol, perfluorooctanoic acid, and sulfamethoxazole. On a mass basis, the WRRFs contributed additional loadings of carbamazepine ranging from 5.4 g/d to 7.2 g/d (mean: 6.3 ± 0.4 g/d), PFOA ranging from 8.6 to 31.9 g/d (mean: 20.0 ± 4.9), and sulfamethoxazole ranging from 49.4 g/d to 75.1 g/d (mean: 62.1 ± 4.8). 17β-estradiol was detected once and atrazine was not detected.

Introduction: Insecticide-treated mosquito nets (ITNs) are highly effective for the control of malaria. Yet widely distributed ITNs have been repurposed as fishing nets throughout the world. Objectives: Herein we present a synthesis of the current knowledge of ITN fishing and the toxicity of pyrethroids and discuss the potential implications of widespread fishing with ITNs. We further review effective management strategies in tropical fisheries to explore a framework for managing potential ITN fishing impacts. Discussion: Pyrethroids are toxic to fish and aquatic environments, and fishing with ITNs may endanger the health of fisheries. Furthermore, although human toxicity to the pyrethroid insecticides that impregnate ITNs is traditionally thought to be low, recent scientific advances have shown that pyrethroid exposure is associated with a host of human health issues, including neurocognitive developmental disorders, diabetes, and cardiovascular disease. Although it is known that ITN fishing is widespread, the implications for both fisheries and human communities is understudied and may be severe. https://doi.org/10.1289/EHP7001

Wastewater-based epidemiology has been used to measure SARS-CoV-2 prevalence in cities worldwide as an indicator of community health, however, few longitudinal studies have followed SARS-CoV-2 in wastewater in small communities from the start of the pandemic or evaluated the influence of tourism on viral loads. Therefore the objective of this study was to use measurements of SARS-CoV-2 in wastewater to monitor viral trends and variants in a small island community over a twelve-month period beginning May 1, 2020, before the community re-opened to tourists. Wastewater samples were collected weekly and analyzed to detect and quantify SARS-CoV-2 genome copies. Sanger sequencing was used to determine genome sequences from total RNA extracted from wastewater samples positive for SARS-CoV-2. Visitor data was collected from the local Chamber of Commerce. We performed Poisson and linear regression to determine if visitors to the Cedar Key Chamber of Commerce were positively associated with SARS-CoV-2-positive wastewater samples and the concentration of SARS-CoV-2 RNA. Results indicated that weekly wastewater samples were negative for SARS-CoV-2 until mid-July when positive samples were recorded in four of five consecutive weeks. Additional positive results were recorded in November and December 2020, as well as January, March, and April 2021. Tourism data revealed that the SARS-CoV-2 RNA concentration in wastewater increased by 1.06 Log

Water contaminated with plastic debris and leached plasticizers can be ingested or taken up by aquatic invertebrates and vertebrates alike, exerting adverse effects on multiple tissues including the gastrointestinal tract. As such, gut microbiomes of aquatic animals are susceptible targets for toxicity. Recent studies conducted in teleost fishes report that microplastics and plasticizers (e.g., phthalates, bisphenol A) induce gastrointestinal dysbiosis and alter microbial diversity in the gastrointestinal system. Here we synthesize the current state of the science regarding plastics, plasticizers, and their effects on microbiomes of fish. Literature suggests that microplastics and plasticizers increase the abundance of opportunistic pathogenic microorganisms (e.g. Actinobacillus, Mycoplasma and Stenotrophomonas) in fish and reveal that gamma-proteobacteria are sensitive to microplastics. Recommendations moving forward for the research field include (1) environmentally relevant exposures to improve understanding of the long-term impacts of microplastic and plasticizer contamination on the fish gastrointestinal microbiome; (2) investigation into the potential impacts of understudied polymers such as polypropylene, polyamide and polyester, and (3) studies with elastomers such as rubbers that are components of tire materials, as these chemicals often dominate plastic debris. Focus on both microplastics and the gut microbiota is intensifying in environmental toxicology, and herein lies an opportunity to improve evaluation of global ecological impacts associated with plastic contamination. This is important as the microbiota is intimately tied to an individual's health and fragmentation of microbial community networks and gut dysbiosis can result in disease susceptibility and early mortality events.

Aquaculture is the fastest growing food-production sector and is vital to food security, habitat restoration and endangered species conservation. One of the continued challenges to the industry is our ability to manage aquatic disease agents that can rapidly decimate operations and are a constant threat to sustainability. Such threats also evolve as microbes acquire resistance and/or new pathogens emerge. The advent of nanotechnology has transformed our approach to fisheries disease management with advances in water disinfection, food conversion, fish health and management systems. In this review, several nano-enabled technology successes will be discussed as they relate to the challenges associated with disease management in the aquaculture sector, with a particular focus on fishes. Future perspectives on how nanotechnology can offer functional approaches for improving disinfection and innovating at the practical space of early warning systems will be discussed. Finally, the importance of "safety by design" approaches to the development of novel commercial nano-enabled products will be emphasized.

To improve physical characteristics of plastics such as flexibility and durability, producers enrich materials with phthalates such as di-2-(ethylhexyl) phthalate (DEHP). DEHP is a high production volume chemical associated with metabolic and immune disruption in animals and humans. To reveal mechanisms implicated in phthalate-related disruption in the gastrointestinal system, male and female zebrafish were fed DEHP (3 ppm) daily for two months. At the transcriptome level, DEHP significantly upregulated gene networks in the intestine associated with helper T cells’ (Th1, Th2, and Th17) specific pathways. The activation of gene networks associated with adaptive immunity was linked to the suppression of networks for tight junction, gap junctional intercellular communication, and transmembrane transporters, all of which are precursors for impaired gut integrity and performance. On a class level, DEHP exposure increasedBacteroidiaandGammaproteobacteriaand decreasedVerrucomicrobiaein both the male and female gastrointestinal system. Further, in males there was a relative increase inFusobacteriiaandBetaproteobacteriaand a relative decrease inSaccharibacteria. Predictive algorithms revealed that the functional shift in the microbiome community, and the metabolites they produce, act to modulate intestinal adaptive immunity. This finding suggests that the gut microbiota may contribute to the adverse effects of DEHP on the host by altering metabolites sensed by both intestinal and immune Th cells. Our results suggest that the microbiome–gut–immune axis can be modified by DEHP and emphasize the value of multiomics approaches to study microbiome–host interactions following chemical perturbations

The microbiome plays an essential role in the health and onset of diseases in all animals, including humans. The microbiome has emerged as a central theme in environmental toxicology because microbes interact with the host immune system in addition to its role in chemical detoxification. Pathophysiological changes in the gastrointestinal tissue caused by ingested chemicals and metabolites generated from microbial biodegradation can lead to systemic adverse effects. The present critical review dissects what we know about the impacts of environmental contaminants on the microbiome of aquatic species, with special emphasis on the gut microbiome. We highlight some of the known major gut epithelium proteins in vertebrate hosts that are targets for chemical perturbation, proteins that also directly cross-talk with the microbiome. These proteins may act as molecular initiators for altered gut function, and we propose a general framework for an adverse outcome pathway that considers gut dysbiosis as a major contributing factor to adverse apical endpoints. We present 2 case studies, nanomaterials and hydrocarbons, with special emphasis on the Deepwater Horizon oil spill, to illustrate how investigations into the microbiome can improve understanding of adverse outcomes. Lastly, we present strategies to functionally relate chemical-induced gut dysbiosis with adverse outcomes because this is required to demonstrate cause-effect relationships. Further investigations into the toxicant-microbiome relationship may prove to be a major breakthrough for improving animal and human health. Environ Toxicol Chem 2018;37:2758-2775. © 2018 SETAC.

Nano-titanium dioxide (TiO2 ) is the most widely used form of nanoparticles in commercial industry and comes in 2 main configurations: rutile and anatase. Rutile TiO2 is used in ultraviolet (UV) screening applications, whereas anatase TiO2 crystals have a surface defect that makes them photoreactive. There are numerous reports in the literature of photo-induced toxicity to aquatic organisms following coexposure to anatase nano-TiO2 and UV. All natural freshwater contains varying amounts of natural organic matter (NOM), which can drive UV attenuation and quench reactive oxygen species (ROS) in aquatic ecosystems. The present research examined how NOM alters the photo-induced toxicity of anatase nano-TiO2 . Daphnia magna neonates were coexposed to NOM and photoexcited anatase nano-TiO2 for 48 h. Natural organic matter concentrations as low as 4 mg/L reduced anatase nano-TiO2 toxicity by nearly 100%. These concentrations of NOM attenuated UV by

As nanomaterials are used in a wide array of applications, investigations regarding health impacts associated with inhalation are a concern. Reports show that exposure to single-walled carbon nanotubes (SWCNTs) can induce fibrosis, allergic-type reactions, and pathogen susceptibility. Airway clearance is known to play a primary role in these disease states, yet SWCNT detection in biological systems is challenging. Common techniques, such as electron microscopy, lack spatial resolution and specificity to delineate SWCNTs in carbon-based organisms. Here we validated a near-infrared fluorescence imaging (NIRFI) system to track and semi-quantify SWCNTs over 21 days in tissues of mice exposed intratracheally to 1 dose of SWCNTs. In tandem, we optimized a NIRF-based spectrometry method to quantify SWCNTs, showing that NIRFI was consistent with SWCNT burdens quantified by NIRF spectroscopy in whole lung tissue homogenates. Finally, NIRFI was utilized to localize SWCNTs on lung tissue sections used for pathological analysis. Results revealed that SWCNTs remained in the lung over 21 days and were consistent with alveolar wall restructuring and granuloma formation. This study is the first to quantify SWCNTs in mouse lungs using both semi-quantitative tracking and quantitative mass measurements using NIRF, highlighting this as a sensitive and specific technique for assessing SWCNT clearance in vivo.

Dietary exposure to chemicals alters the diversity of microbiome communities and can lead to pathophysiological changes in the gastrointestinal system. The organochlorine pesticide dieldrin is a persistent environmental contaminant that bioaccumulates in fatty tissue of aquatic organisms. The objectives of this study were to determine whether environmentally-relevant doses of dieldrin altered gastrointestinal morphology and the microbiome of zebrafish. Adult zebrafish at similar to 4 months of age were fed a measured amount of feed containing either a solvent control or one of two doses of dieldrin (measured at 16, and 163.5 ng/g dry weight) for 4 months. Dieldrin body burden levels in zebrafish after four-month exposure were 0 (control), 11.47 +/- 1.13 ng/g (low dose) and 18.32 +/- 1.32 ng/g (high dose) wet weight [mean +/- std]. Extensive histopathology at the whole organism level revealed that dieldrin exposure did not induce notable tissue pathology, including the gastrointestinal tract. A repeated measure mixed model analysis revealed that, while fish gained weight over time, there were no dieldrin-specific effects on body weight. Fecal content was collected from the gastrointestinal tract of males and 16S rRNA gene sequencing conducted. Dieldrin at a measured feed dose of 16 ng/g reduced the abundance of Firmicutes, a phylum involved in energy resorption. At the level of class, there was a decrease in abundance of Clostridia and Betaproteobacteria, and an increase in Verrucomicrobiae species. We used a computational approach called predicted relative metabolomic turnover (PRMT) to predict how a shift in microbial community composition affects exchange of metabolites. Dieldrinwas predicted to affect metabolic turnover of uroporphyrinogen I and coproporphyrinogen I [enzyme]-cysteine, hydrogen selenide, selenite, and methyl-selenic acid in the fish gastrointestinal system. These pathways are related to bacterial heme biosynthesis and selenium metabolism. Our study demonstrates that dietary exposures to dieldrin can alter microbiota composition over 4 months, however the long-term consequences of such impacts are not well understood.

Increased use of antidepressants has led to an increase in their detection in final treated wastewater effluents and receiving streams. Antidepressants are intended to modify human behavior by altering brain chemistry, and because of the high functional conservation of antidepressant target receptors in vertebrates, aquatic organisms may be at risk. The antidepressant bupropion is designed to alter brain norepinephrine and dopamine concentrations in humans. The objective of the present study was to understand if alteration of dopaminergic neurotransmitter concentrations in the hybrid striped bass (Morone saxatilis × Morone chrysops) brain by bupropion would alter this predator's ability to capture prey. The authors exposed hybrid striped bass to bupropion in a static system for 6 d, followed by a 6-d recovery period. During the present study's 12-d experiment, each hybrid striped bass was fed 4 unexposed fathead minnows every 3 d, and the time it took the hybrid striped bass to consume each of those 4 fathead minnows was quantified. After each feeding event, hybrid striped bass brains were harvested and analyzed for changes in several brain neurotransmitter concentrations, including serotonin, norepinephrine, dopamine, and many of their metabolites. Although bupropion altered the concentration of dopamine and many of the dopaminergic neurotransmitter metabolite concentrations in the brains on day 3 of the exposure, it did not alter the time to capture prey. This suggests that alteration of dopaminergic neurotransmitter concentrations in the hybrid striped bass brain does not alter a predator's ability to capture prey. Environ Toxicol Chem 2016;35:2058-2065. © 2016 SETAC.

Microbiome community structure is intimately involved in key biological functions in the gastrointestinal (GI) system including nutrient absorption and lipid metabolism. Recent evidence suggests that disruption of the GI microbiome is a contributing factor to metabolic disorders and obesity. Poor diet and chemical exposure have been independently shown to cause disruption of the GI microbiome community structure and function. We hypothesized that the addition a chemical exposure to overfeeding exacerbates adverse effects on the GI microbiome community structure and function. To test this hypothesis, adult zebrafish were fed a normal feeding regime (Control), an overfeeding regime (OF), or an overfeeding regime contaminated with diethylhexyl phthalate (OF + DEHP), a suspected obesogen-inducing chemical. After 60 days, fecal matter was collected for sequencing, identification, and quantification of the GI microbiome using the 16s rRNA hypervariable region. Analysis of beta diversity indicated distinct microbial profiles between treatments with the largest divergence between Control and OF + DEHP groups. Based upon functional predictions, OF + DEHP treatment altered carbohydrate metabolism, while both OF and OF + DEHP affected biosynthesis of fatty acids and lipid metabolism. Co-occurrence network analysis revealed decreases in cluster size and a fracturing of the microbial community network into unconnected components and a loss of keystone species in the OF + DEHP treatment when compared to Control and OF treatments. Data suggest that the addition of DEHP in the diet may exacerbate microbial dysbiosis, a consequence that may explain in part its role as an obesogenic chemical.

The microbiome regulates endocrine systems and influences many aspects of hormone signaling. Using examples from different animal taxa, we highlight the state of the science in microbiome research as it relates to endocrinology and endocrine disruption research. Using a comparative approach discussing fish, birds, and mammals, we demonstrate the bidirectional interaction between microbiota and hormone systems, presenting concepts that include (1) gastrointestinal microbiome regulation of the neuroendocrine feeding axis; (2) stress hormones and microbial communities; (3) the role of site-specific microbiota in animal reproduction; (4) microbiome effects on the neuroendocrine systems and behavior; and (5) novel mechanisms of endocrine disruption through the microbiome. This mini-review demonstrates that hormones can directly affect the richness and diversity of microbiota and conversely, microbiota can influence hormone production and mediate their functions in animals. In addition, microbiota can influence the action of a diverse range of neurotransmitters and neuropeptides in the central nervous system, which can lead to behavioral disruptions. As many animals have species-specific reproductive behaviors, it is important to understand how shifts in the microbiota relate to these complex interactions between sexes. This is especially important for captive animals on specialized diets, and there are significant implications for microbiome research in conservation and reproductive biology. For example, microbial metabolites may modify motility of gametes or modulate hormone-receptor interactions in reproductive tissues. Thus, efforts to incorporate metabolomics into the science of microbiome-endocrine relationships, both those produced by the host and those generated from microbial metabolism, are increasingly needed. These concepts have fostered an exciting emerging era in comparative endocrinology.

Epidemiological evidence suggests that phthalate plasticizers may act as “obesogens”, which are chemicals that exacerbate obesity. The gastrointestinal (GI) system is the primary exposure route for phthalates, however, the relationship between phthalate-driven perturbations of GI system functions that can influence obesity has yet to be examined. To address this knowledge gap, we exposed Danio rerio (zebrafish) for 60 days to either (1) Control feeding (5 mg/fish/day), (2) Overfeeding (20 mg/fish/day) or (3) Overfeeding with diethyl-hexyl phthalate (DEHP) (20 mg/fish/day with 3 mg/kg DEHP). After 60 days, Overfed and Overfed + DEHP zebrafish had elevated body mass, and hepatosomatic and gonadosomatic indices. RNAseq analysis of the GI revealed enrichment of gene networks related to lipid metabolism in the Overfed + DEHP group. Many of the enriched networks were under transcriptional control of peroxisome proliferator activated receptor alpha (pparα), a known modulator of lipid metabolism, immune function, and GI function. Real-time PCR confirmed that pparα was overexpressed in the Overfed + DEHP zebrafish, further revealing a pathway by which DEHP may influence lipid metabolism via the GI. These data increase our understanding of phthalate-driven effects on GI function and lipid metabolism, identifying gut-specific gene networks that may drive phthalate-exacerbated obesity.

The microbiome plays an essential role in the health and onset of diseases in all animals, including humans. The microbiome has emerged as a central theme in environmental toxicology because microbes interact with the host immune system in addition to its role in chemical detoxification. Pathophysiological changes in the gastrointestinal tissue caused by ingested chemicals and metabolites generated from microbial biodegradation can lead to systemic adverse effects. The present critical review dissects what we know about the impacts of environmental contaminants on the microbiome of aquatic species, with special emphasis on the gut microbiome. We highlight some of the known major gut epithelium proteins in vertebrate hosts that are targets for chemical perturbation, proteins that also directly cross-talk with the microbiome. These proteins may act as molecular initiators for altered gut function, and we propose a general framework for an adverse outcome pathway that considers gut dysbiosis as a major contributing factor to adverse apical endpoints. We present 2 case studies, nanomaterials and hydrocarbons, with special emphasis on the Deepwater Horizon oil spill, to illustrate how investigations into the microbiome can improve understanding of adverse outcomes. Lastly, we present strategies to functionally relate chemical-induced gut dysbiosis with adverse outcomes because this is required to demonstrate cause-effect relationships. Further investigations into the toxicant-microbiome relationship may prove to be a major breakthrough for improving animal and human health. Environ Toxicol Chem 2018;37:2758-2775. © 2018 SETAC.

Background Numerous toxicological studies have focused on injury caused by exposure to single types of nanoparticles, but few have investigated how such exposures impact a host’s immune response to pathogen challenge. Few studies have shown that nanoparticles can alter a host’s response to pathogens (chiefly bacteria) but there is even less knowledge of the impact of such particles on viral infections. In this study, we performed experiments to investigate if exposure of mice to single-walled carbon nanotubes (SWCNT) alters immune mechanisms and viral titers following subsequent influenza A virus (IAV) infection. Methods Male C57BL/6 mice were exposed to 20 μg of SWCNT or control vehicle by intratracheal instillation followed by intranasal exposure to 3.2 × 104 TCID50 IAV or PBS after 3 days. On day 7 mice were euthanized and near-infrared fluorescence (NIRF) imaging was used to track SWCNT in lung tissues. Viral titers, histopathology, and mRNA expression of antiviral and inflammatory genes were measured in lung tissue. Differential cell counts and cytokine levels were quantified in bronchoalveolar lavage fluid (BALF). Results Viral titers showed a 63-fold increase in IAV in SWCNT + IAV exposed lungs compared to the IAV only exposure. Quantitation of immune cells in BALF indicated an increase of neutrophils in the IAV group and a mixed profile of lymphocytes and neutrophils in SWCNT + IAV treated mice. NIRF indicated SWCNT remained in the lung throughout the experiment and localized in the junctions of terminal bronchioles, alveolar ducts, and surrounding alveoli. The dual exposure exacerbated pulmonary inflammation and tissue lesions compared to SWCNT or IAV single exposures. IAV exposure increased several cytokine and chemokine levels in BALF, but greater levels of IL-4, IL-12 (P70), IP-10, MIP-1, MIP-1α, MIP-1β, and RANTES were evident in the SWCNT + IAV group. The expression of tlr3, ifnβ1, rantes, ifit2, ifit3, and il8 was induced by IAV alone but several anti-viral targets showed a repressed trend (ifits) with pre-exposure to SWCNT. Conclusions These findings reveal a pronounced effect of SWCNT on IAV infection in vivo as evidenced by exacerbated lung injury, increased viral titers and several cytokines/chemokines levels, and reduction of anti-viral gene expression. These results imply that SWCNT can increase susceptibility to respiratory viral infections as a novel mechanism of toxicity. Electronic supplementary material The online version of this article (10.1186/s12985-017-0909-z) contains supplementary material, which is available to authorized users.

Nanomaterial science and design have shifted from generating single passive nanoparticles to more complex and adaptive multi-component nanohybrids. These adaptive nanohybrids (ANHs) are designed to simultaneously perform multiple functions, while actively responding to the surrounding environment. ANHs are engineered for use as drug delivery carriers, in tissue-engineered templates and scaffolds, adaptive clothing, smart surface coatings, electrical switches and in platforms for diversified functional applications. Such ANHs are composed of carbonaceous, metallic or polymeric materials with stimuli-responsive soft-layer coatings that enable them to perform such switchable functions. Since ANHs are engineered to dynamically transform under different exposure environments, evaluating their environmental behavior will likely require new approaches. Literature on polymer science has established a knowledge core on stimuli-responsive materials. However, translation of such knowledge to environmental health and safety (EHS) of these ANHs has not yet been realized. It is critical to investigate and categorize the potential hazards of ANHs, because exposure in an unintended or shifting environment could present uncertainty in EHS. This article presents a perspective on EHS evaluation of ANHs, proposes a principle to facilitate their identification for environmental evaluation, outlines a stimuli-based classification for ANHs and discusses emerging properties and dynamic aspects for systematic EHS evaluation.

The number of potential applications for manufactured nanomaterials (NMs) is growing exponentially around the world as is concomitant research into the possible consequences of inadvertent or purposeful releases into the environment. Fish and other aquatic organisms reside in bodies of water where many NMs may potentially be deposited, as these environments act as terminal sinks for many contaminants. A growing body of evidence suggests that some NMs, depending on their composition, size, and/or surface functionalization, can affect fish health by adversely interacting with gill function or by entering circulation through the digestive tract. The goal of this study was to investigate the role surface functionalization plays on oral bioavailability of NMs, using quantum dots (QDs) as a model. Three different surface functional groups, amino, carboxyl, and PEG were investigated. Additionally, two different exposure scenarios, a single dose or 5 sequential doses over 2 weeks, were used to determine which tissues were the sites of greatest accumulation over time. Results show QDs are able to enter the blood stream after ingestion, and accumulate in the intestine, liver, gonads, and other organs in female and male fathead minnows. Data from a repeated dosing experiment indicated that QDs were retained and accumulated in most tissues in a surface functionalization and sex specific manner. The carboxyl and amino QDs were found to be most readily taken up and the carboxyl QDs were found to be in the greatest concentration in the most number of tissues including the gonad, spleen and kidneys in both males and females.

Antidepressants that enter receiving waters through final treated wastewater effluent have exhibited relatively low acute toxicity in traditional fish tests at currently measured concentrations. However, the psychotropic mode of action of these compounds warrants examination of the behavioral effects these chemicals may have on aquatic organisms. Previous research has demonstrated that exposure to the antidepressant fluoxetine causes decreased brain serotonin levels in fish and results in a decreased ability to capture prey. Another antidepressant, venlafaxine, has been found at low μg/L concentrations in final treated wastewater effluent. The objective of this study was to quantify the effects of venlafaxine on fish predation behavior and determine if this effect was correlated with changes in brain neurotransmitter concentrations. The predator prey bioassay used hybrid striped bass (Morone saxatilis x Morone chrysops) as the predator and fathead minnows (Pimephales promelas) as prey. Bass were exposed to venlafaxine (0-500 μg/L) for a period of 6 days and then allowed to recover for 6 days. During both exposure and recovery, bass were fed four minnows every third day. The time to capture the minnows was quantified and compared among treatments to determine if there was an effect on predation behavior. Brain tissue was analyzed for serotonin, norepinephrine, and dopamine, to determine the relationship between exposure concentration, brain monoamine levels, and predation behavior. Results indicated that venlafaxine exposures increased time to capture prey 1 and 2 by day 6 for the 250 and 500 μg/L treatments. Time to capture prey 3 was increased for all venlafaxine treatments by day 6. Venlafaxine caused a statistically significant decrease in brain serotonin concentrations that initially decreased in a dose dependent manner before reaching a steady state by the end of exposures for all treatments. No significant, dose-dependent changes in dopamine or norepinephrine were seen. Brain serotonin alone did not adequately explain behavioral results. Serotonin response in other tissues as well as peripheral effects may have accounted for additional behavioral responses after brain serotonin reached a depressed steady state.

Detection of SWCNTs in complex matrices presents a unique challenge as common techniques lack spatial resolution and specificity. Near infrared fluorescence (NIRF) has emerged as a valuable tool for detecting and quantifying SWCNTs in environmental samples by exploiting their innate fluorescent properties. The objective of this study was to optimize NIRF-based imaging and quantitation methods for tracking and quantifying SWCNTs in an aquatic vertebrate model in conjunction with assessing toxicological end points. Fathead minnows (Pimephales promelas) were exposed by single gavage to SWCNTs and their distribution was tracked using a custom NIRF imaging system for 7 days. No overt toxicity was observed in any of the SWCNT treated fish; however, histopathology observations from gastrointestinal (GI) tissue revealed edema within the submucosa and altered mucous cell morphology. NIRF images showed strong SWCNT-derived fluorescence signals in whole fish and excised intestinal tissues. Fluorescence was not detected in other tissues examined, indicating that no appreciable intestinal absorption occurred. SWCNTs were quantified in intestinal tissues using a NIRF spectroscopic method revealing values that were consistent with the pattern of fluorescence observed with NIRF imaging. Results of this work demonstrate the utility of NIRF imaging as a valuable tool for examining uptake and distribution of SWCNTs in aquatic vertebrates.

We report here the first studies addressing fate and transport of single walled carbon nanotubes (SWNTs) in aquatic mesocosms. The experimental design was structured to study the impact of nanomaterials within a tightly controlled and highly instrumented wetland ecosystems (aka mesocosm) and to address questions including fate and transport, effect on community structure, effects on biogeochemical function, and effects on productivity of the ecosystem. We added well-dispersed CoMoCat SWNTs (cSWNT,0 = 2.5 mg L−1) to the water column of a wetland mesocosm and examined the resulting phase distribution over time. Rapid settling of SWNTs from the water column was observed within a period of 2 days (Cw,t/Cw,0 < 0.01) after spiking. Samples from all mesocosm compartments (e.g. aquatic/semi aquatic plants, biofilm, mosquitofish and sediment) were analyzed to evaluate the transport and fate of SWNTs in the ecosystem. SWNTs were quantified in organism and sediment extracts using near-infrared fluorescence spectroscopy (NIRF). This technique can be used to quantitatively detect SWNTs in sediment and biotic matrices at environmentally relevant concentrations (MDLwater 5 μg L−1 MDLsediment 0.5 μg g−1 MDLbiota 5 μg g−1 wet weight) and qualitatively characterize SWNT samples before and after the studies. Results indicated that rapid aggregation and settling of SWNT resulted in accumulation of SWNT in surficial sediment. Sediment concentrations were spatially variable across the mesocosm, and thus estimates of SWNT mass balance within the mesocosm ranged from 7–48%. No bioaccumulation of SWNT in aquatic plants or vertebrates was observed over the 10 month incubation. However, NIRF imaging analysis suggested that mosquitofish ingested SWNT-laden particles but that burdens of SWNTs were confined to gut contents and may have been rapidly eliminated.

Recent evidence suggests that, because of their sorptive nature, if single-walled carbon nanotubes (SWCNTs) make their way into aquatic environments, they may reduce the toxicity of other waterborne contaminants. However, few studies have examined whether contaminants remain adsorbed following ingestion by aquatic organisms. The objective of this study was to examine the bioavailability and bioactivity of ethinyl estradiol (EE2) sorbed onto SWCNTs in a fish gastrointestinal (GI) tract. Sorption experiments indicated that SWCNTs effectively adsorbed EE2, but the chemical was still able to bind and activate soluble estrogen receptors (ERs) in vitro. However, centrifugation to remove SWCNTs and adsorbed EE2 significantly reduced ER activity compared to that of EE2 alone. Additionally, the presence of SWCNTs did not reduce the extent of EE2-driven induction of vitellogenin 1 in vivo compared to the levels in organisms exposed to EE2 alone. These results suggest that while SWCNTs adsorb EE2 from aqueous solutions, under biological conditions EE2 can desorb and retain bioactivity. Additional results indicate that interactions with gastrointestinal proteins may decrease the level of adsorption of estrogen to SWCNTs by 5%. This study presents valuable data for elucidating how SWCNTs interact with chemicals that are already present in our aquatic environments, which is essential for determining their potential health risk.

Nano-titanium dioxide (TiO

The diverse biological effects of xenoestrogens may be explained by their ability to differentially recruit co-regulatory proteins to the estrogen receptor (ER). We employed high-throughput receptor affinity binding and co-regulatory protein recruitment screening assays based on fluorescence polarization and time resolved florescence resonance energy transfer (TR-FRET), respectively, to assess xenoestrogen-specific binding and co-regulatory protein recruitment to the ER. Then we used a functional proteomic assay based on co-immunoprecipitation of ER-bound proteins to isolate and identify intact co-regulatory proteins recruited to a ligand-activated ER. Through these approaches, we revealed differential binding affinity of bisphenol-A (BPA) and genistein (GEN) to the human ERα (ESR1) and ligand-dependent recruitment of SRC-1 and SRC-3 peptides. Recruitment profiles were variable for each ligand and in some cases were distinct compared to 17β-estradiol (E2). For example, E2 and GEN recruited both SRC-1 and -3 peptides whereas BPA recruited only SRC-1 peptides. Results of the functional proteomic assay showed differential recruitment between ligands where E2 recruited the greatest number of proteins followed by BPA then GEN. A number of proteins share previously identified relationships with ESR1 as determined by STRING analysis. Although there was limited overlap in proteins identified between treatments, all ligands recruited proteins involved in cell growth as determined by subnetwork enrichment analysis (p < 0.05). A comparative, in silico analysis revealed that fewer interactions exist between zebrafish (Danio rerio) esr1 and zebrafish orthologs of proteins identified in our functional proteomic analysis. Taken together these results identify recruitment of known and previously unknown co-regulatory proteins to ESR1 and highlight new methods to assay recruitment of low abundant and intact, endogenous co-regulatory proteins to ESR1 or other nuclear receptors, in both human and aquatic species.

Previous studies indicate that exposure of fish to pristine single-walled carbon nanotubes (SWCNTs) by oral gavage, causes no overt toxicity, and no appreciable absorption has been observed. However, in the environment, SWCNTs are likely to be present in dietary sources, which may result in differential impacts on uptake and biological effects. Additionally, the potential of these materials to sorb nutrients (proteins, carbohydrates, and lipids) while present in the gastrointestinal (GI) tract may lead to nutrient depletion conditions that impact processes such as growth and reproduction. To test this phenomenon, fathead minnows were fed a commercial diet either with or without SWCNTs for 96 h. Tracking and quantification of SWCNTs using near-infrared fluorescence (NIRF) imaging during feeding studies showed the presence of food does not facilitate transport of SWCNTs across the intestinal epithelia. Targeting genes shown to be responsive to nutrient depletion (peptide transporters, peptide hormones, and lipases) indicated that pept2, a peptide transporter, and cck, a peptide hormone, showed differential mRNA expression by 96 h, a response that may be indicative of nutrient limitation. The results of the current study increase our understanding of the movement of SWCNTs through the GI tract, while the changes in nutrient processing genes highlight a novel mechanism of sublethal toxicity in aquatic organisms.

Increased use of antidepressants has led to an increase in their detection in final treated wastewater effluents and receiving streams. Antidepressants are intended to modify human behavior by altering brain chemistry, and because of the high functional conservation of antidepressant target receptors in vertebrates, aquatic organisms may be at risk. The antidepressant bupropion is designed to alter brain norepinephrine and dopamine concentrations in humans. The objective of the present study was to understand if alteration of dopaminergic neurotransmitter concentrations in the hybrid striped bass (Morone saxatilis × Morone chrysops) brain by bupropion would alter this predator's ability to capture prey. The authors exposed hybrid striped bass to bupropion in a static system for 6 d, followed by a 6-d recovery period. During the present study's 12-d experiment, each hybrid striped bass was fed 4 unexposed fathead minnows every 3 d, and the time it took the hybrid striped bass to consume each of those 4 fathead minnows was quantified. After each feeding event, hybrid striped bass brains were harvested and analyzed for changes in several brain neurotransmitter concentrations, including serotonin, norepinephrine, dopamine, and many of their metabolites. Although bupropion altered the concentration of dopamine and many of the dopaminergic neurotransmitter metabolite concentrations in the brains on day 3 of the exposure, it did not alter the time to capture prey. This suggests that alteration of dopaminergic neurotransmitter concentrations in the hybrid striped bass brain does not alter a predator's ability to capture prey. Environ Toxicol Chem 2016;35:2058-2065. © 2016 SETAC.

Antidepressants have been found in measurable concentrations in final treated wastewater effluent and receiving waters throughout the world. Studies have shown that these concentrations are typically not overtly toxic, but the psychotropic mode of action of these chemicals warrants examination of their behavioral effects. Exposure of hybrid striped bass to the antidepressants fluoxetine or venlafaxine alone has been shown to cause decreased brain serotonin levels and increased time to capture prey at concentrations typically 1 to 2 orders of magnitude higher than environmentally relevant concentrations. In the present study, equally effective doses of fluoxetine and venlafaxine were used to perform a mixture study, using a toxic unit approach to determine whether these antidepressants may act in an additive manner at lower concentrations. The results indicated that mixtures of these antidepressants caused decreased brain serotonin and increased time to capture prey at concentrations lower than reported in previous studies. Low concentration mixtures caused an additive effect on brain serotonin levels and time to capture prey, whereas higher concentrations were less than additive. The results were consistent with the dose addition concept, with higher concentration mixtures potentially saturating the effects on serotonin in the brain. Results from the present study indicate that antidepressants have the potential to be additive on the biochemical and individual scale, which necessitates more robust analysis of antidepressant mixtures and their potential to act together in low concentration scenarios.

A number of studies have used functional neuroimaging to examine the neural mechanisms of sentence comprehension; however, few fMRI studies have examined activation patterns associated with sentence comprehension after accounting for activation attributable to single-word-level tasks important for sentence comprehension. To investigate the patterns of activation associated with sentence comprehension after controlling for single word reading and maintaining single words in memory, 20 unimpaired adult readers completed a block design paradigm which included sentence comprehension, single word reading, and short-term memory (for words) tasks. Results indicated that, regardless of the aspect of sentence comprehension being controlled for, activation was observed in bilateral temporal lobes (left > right) as well as bilateral occipital lobes and middle frontal gyri. Additional findings showed that bilateral superior parietal lobe activation was greatest for short-term memory for words, while left anterior inferior frontal gyri activation (centered around Brodmann's area 47) was greatest for single word reading. Results suggest that temporal cortex (left > right) is a core region important for sentence comprehension beyond the short-term memory and semantic requirements inherent in processing sentences.