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This study investigates factors affecting reproduction in fish exposed to pulp and paper mill effluents by comparing effluents from countries with varying levels of documented effects. To explore the hypothesis of wood as a common source of endocrine disrupting compounds, feedstocks from each country were analyzed. Analyses included in vitro assays for androgenic activity (binding to goldfish testis androgen receptors), estrogenic activity (yeast estrogen screen), and neurotransmitter enzyme inhibition (monoamine oxidase and glutamic acid decarboxylase). Chemical analyses included conventional extractives, known androgens, and gas chromatograph index (GCI) profiles. All effluents and wood contained androgenic activity, particularly in nonpolar fractions, although known androgens were undetected. Effluents with low suspended solids, having undergone conventional biotreatment had lower androgenic activities. Estrogenic activity was only associated with Brazilian effluents and undetected in wood. All effluents and wood inhibited neurotransmitter enzymes, predominantly in polar fractions. Kraft elemental chlorine free mills were associated with the greatest neurotransmitter inhibition. Effluent and wood GCI profiles were correlated with androgenic activity and neurotransmitter enzyme inhibition. Differences in feedstock bioactivities were not reflected in effluents, implying mill factors mitigate bioactive wood components. No differences in bioactivities could be discerned on the basis of country of origin, thus we predict effluents in regions lacking monitoring would affect fish reproduction and therefore recommend implementing such programs.

Bisphenol A (BPA) is an endocrine disruptor frequently detected in human biofluids. Dermal absorption of BPA from thermal paper receipts occurs but BPA pharmacokinetics following dermal exposure is not understood. To compare the pharmacokinetics of dermal and dietary BPA exposure, six male participants handled simulated receipts containing relevant levels of BPA (isotope-labeled BPA-d 16 ) for 5 min, followed by hand-washing 2 h later. Urine (0-48 h) and serum (0-7.5 h) were monitored for free and total BPA-d 16 . One week later, participants returned for a dietary administration with monitoring as above. One participant repeated the dermal administration with extended monitoring of urine (9 days) and serum (2 days). After dietary exposure, urine total BPA-d 16 peaked within 5 h and quickly cleared within 24 h. After dermal exposure, cumulative excretion increased linearly for 2 days, and half the participants still had detectable urinary total BPA-d 16 after 1 week. The participant repeating the dermal exposure had detectable BPA-d 16 in urine for 9 days, showed linear cumulative excretion over 5 days, and had detectable free BPA-d 16 in serum. Proportions of free BPA-d 16 in urine following dermal exposure (0.71%-8.3% of total BPA-d 16 ) were generally higher than following the dietary exposure (0.29%-1.4%). Compared to dietary BPA exposure, dermal absorption of BPA leads to prolonged exposure and may lead to higher proportions of unconjugated BPA in systemic circulation.

Bisphenol A (BPA) is used in a variety of consumer products, including some paper products, particularly thermal receipt papers, for which it is used as a color developer. Nevertheless, little is known about the magnitude of BPA contamination or human exposure to BPA as a result of contact with paper and paper products. In this study, concentrations of BPA were determined in 15 types of paper products (n = 202), including thermal receipts, flyers, magazines, tickets, mailing envelopes, newspapers, food contact papers, food cartons, airplane boarding passes, luggage tags, printing papers, business cards, napkins, paper towels, and toilet paper, collected from several cities in the USA. Thermal receipt papers also were collected from Japan, Korea, and Vietnam. BPA was found in 94% of thermal receipt papers (n = 103) at concentrations ranging from below the limit of quantitation (LOQ, 1 ng/g) to 13.9 mg/g (geometric mean: 0.211 mg/g). The majority (81%) of other paper products (n = 99) contained BPA at concentrations ranging from below the LOQ to 14.4 μg/g (geometric mean: 0.016 μg/g). Whereas thermal receipt papers contained the highest concentrations of BPA (milligram-per-gram), some paper products, including napkins and toilet paper, made from recycled papers contained microgram-per-gram concentrations of BPA. Contamination during the paper recycling process is a source of BPA in paper products. Daily intake (DI) of BPA through dermal absorption was estimated based on the measured BPA concentrations and handling frequency of paper products. The daily intake of BPA (calculated from median concentrations) through dermal absorption from handling of papers was 17.5 and 1300 ng/day for the general population and occupationally exposed individuals, respectively; these values are minor compared with exposure through diet. Among paper products, thermal receipt papers contributed to the majority (>98%) of the exposures. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a common endocrine disruptor widely used in the production of electronic, sports, and medical equipment, as well as consumer products like milk bottles, dental sealants, and thermal paper. Despite its widespread use, current assessments of BPA exposure risks remain limited due to the lack of comprehensive cross-species comparative analyses. To address this gap, we conducted a study aimed at identifying genes and fundamental molecular processes consistently affected by BPA in various species and tissues, employing an effective data integration method and bioinformatic analyses. Our findings revealed that exposure to BPA led to significant changes in processes like lipid metabolism, proliferation, and apoptosis in the tissues/cells of mammals, fish, and nematodes. These processes were found to be commonly affected in adipose, liver, mammary, uterus, testes, and ovary tissues. Additionally, through an in-depth analysis of signaling pathways influenced by BPA in different species and tissues, we observed that the JUN/FOS, EGFR, ER, PPARG, and P53 pathways, along with their downstream key transcription factors and kinases, were all impacted by BPA. Our study provides compelling evidence that BPA indeed induces similar toxic effects across different species and tissues. Furthermore, our investigation sheds light on the underlying molecular mechanisms responsible for these toxic effects. By uncovering these mechanisms, we gain valuable insights into the potential health implications associated with BPA exposure, highlighting the importance of comprehensive assessments and awareness of this widespread endocrine disruptor.

Lab animals such as mice and rats are widely used in toxicity research of food additive and pharmaceutics, despite the well-recognized research limitation such as the inability to simulate human neurological diseases, faster absorption of chemicals, big variations among species, and high cost when using a large number of animals. The Society of Toxicology's guidance now focuses on minimizing discomfort and distress of lab animals, finding alternative ways to reduce animal number, replacing animals with in vitro models, and complying to the animal welfare policies. The chicken embryonic model can be a better alternative to mice and rats because of its abundant availability and cost-effectiveness. It can be studied in both laboratory and natural environment, with easy manipulation in ovo or in vivo . The objective of this review paper is to evaluate the use of chicken embryonic model in toxicity evaluation for endocrine-disrupting chemicals (EDCs) and nanoparticles (NPs) by different end points to determine more comprehensive toxic responses. The end points include chicken embryonic mortality and hatchability, developmental malformation analysis, hormonal imbalance, physiological changes in endocrine organs, and antiangiogenesis. Major research methodologies using chicken embryos are also summarized to demonstrate their versatile practice and valuable application in modern toxicity evaluation of EDCs and NPs.

The classification of bisphenol A (BPA) as an industrial endocrine disruptor has led to a ban of this ubiquitous critical starting material from food and medical applications. Thus, scientists worldwide are researching to develop non-ER binding starting compounds to fulfill unmet market needs. In line with this trending research topic, the current paper highlights the development of tetrazole derivatives bearing a bisphenol structure (TbB) as a novel weak binder or potential inactive to the estrogen receptor (ER) and androgen receptor (AR). The structure and ligand-based approach supported by binding affinity analysis, electrostatic complementarity, ADMET prediction, and in silico studies identified TbBs as privileged substitutes for BPA. Five TbB ligands were successfully synthesized and subjected to biological testing comprising radioligand competitive binding and functional cellular assays. The measured IC 50 value for BPA was found to be 0.24 μM, whereas all the inhibitions were less than 15% for the two TbB ligands, 223-2 and 223-3. As these TbB ligands did not meet the established acceptance criteria of 50% inhibition, they are considered as extremely weak binders to ERα. Steric clashes, the desolvation effect, and the increased total polar surface area (TPSA) of TbB ligands in the hydrophobic binding site are hypothesized to be possible reasons for low binding. Modeling studies complemented by bioassays highlight TbB compounds as privileged prospective BPA replacements. However, more research on TbB ligand toxicity is needed to understand and substantiate that the adverse effects on the hormonal system, for example, via metabolic activation, are not elicited.

Endocrine-disrupting chemicals (EDCs) can inadvertently interact with 12 classic nuclear receptors (NRs) that disrupt the endocrine system and cause adverse effects. There is no widely accepted understanding about what structural features make thousands of EDCs able to activate different NRs as well as how these structural features exert their functions and induce different outcomes at the cellular level. This paper applies the hierarchical characteristic fragment methodology and high-throughput screening molecular docking to comprehensively explore the structural and functional features of EDCs for the 12 NRs based on more than 7000 chemicals from curated datasets. EDCs share three levels of key fragments. The primary and secondary fragments are associated with the binding of EDCs to four groups of receptors: steroidal nuclear receptors (SNRs, including androgen, estrogen, glucocorticoid, mineralocorticoid, and progesterone), retinoic acid receptors, thyroid hormone receptors, and vitamin D receptors. The tertiary fragments determine the activity type by interacting with two key locations in the ligand-binding domains of NRs (N-H5-H3-C and N-H7-H11-C for SNRs and N-H5-H5'-H2'-H3-C and N-H6'-H11-C for non-SNRs). The resulting compiled structural fragments of EDCs together with elucidated compound NR binding modes provide a framework for understanding the interactions between EDCs and NRs, facilitating faster and more accurate screening of EDCs for multiple NRs in the future.

This paper aims to identify structural motifs within a molecule that contribute the most toward a chemical being an endocrine disruptor. We have developed a deep neural network-based toolkit toward this aim. The trained model can virtually assess a synthetic chemical's potential to be an endocrine disruptor using machine-readable molecular representation, simplified molecular input line entry system (SMILES). Our proposed toolkit is a multilabel or multioutput classification model that combines both convolution and long short-term memory (LSTM) architectures. The toolkit leverages the advantages of an active learning-based framework that combines multiple sources of data. Class activation maps (CAMs) generated from the feature-extraction layers can identify the structural alerts and the chemical environment that determines the specificity of the structural alerts.

The nuclear androgen receptor (AR) is one of the most relevant biological targets of Endocrine Disrupting Chemicals (EDCs), which produce adverse effects by interfering with hormonal regulation and endocrine system functioning. This paper describes novel in silico models to identify organic AR modulators in the context of the Collaborative Modeling Project of Androgen Receptor Activity (CoMPARA), coordinated by the National Center of Computational Toxicology (U.S. Environmental Protection Agency). The collaborative project involved 35 international research groups to prioritize the experimental tests of approximatively 40k compounds, based on the predictions provided by each participant. In this paper, we describe our machine learning approach to predict the binding to AR, which is based on a consensus of a multivariate Bernoulli Naive Bayes, a Random Forest, and N-Nearest Neighbor classification models. The approach was developed in compliance with the Organization of Economic Cooperation and Development (OECD) principles, trained on 1687 ToxCast molecules classified according to 11 in vitro assays, and further validated on a set of 3,882 external compounds. The models provided robust and reliable predictions and were used to gather novel data-driven insights on the structural features related to AR binding, agonism, and antagonism.

The compound 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP), a derivative of bisphenol S (BPS), has been detected in thermal paper and human urine samples; however, its potential effects on the endocrine system are largely unknown. The present study was conducted to determine the adverse effects of BPSIP on egg production, relative organ weights, plasma levels of sex hormones, and transcription of genes related to the hypothalamus-pituitary-gonad (HPG) axis in zebrafish (Danio rerio). In male fish, the gonadosomatic index was significantly decreased at concentrations of 5 and 50 μg/L BPSIP. The estrogenic (increase in the 17β-estradiol/testosterone [E2/T] ratio) and antiandrogenic (decrease in T) effects were observed in fish exposed to BPSIP and males were more sensitive to the adverse effects than females. The changes in sex hormones were supported by the regulation of genes along the HPG axis, such as cyp19, 17βhsd, and cyp17 transcripts. Although the effective concentration for endocrine disruption was greater than that of BPS, the actions of BPSIP on the steroidogenic pathway were similar to the effects of BPS exposure.

Because of their large and widespread application, phthalates or phthalic acid esters (PAEs) are ubiquitous in all the environmental compartements. They have been widely detected throughout the worldwide environment. Indoor air where people spend 65-90% of their time is also highly contaminated by various PAEs released from plastics, consumer products as well as ambient suspended particulate matter. Because of their widespread application, PAEs are the most common chemicals that humans are in contact with daily. Based on various exposure mechanisms, including the ingestion of food, drinking water, dust/soil, air inhalation and dermal exposure the daily intake of PAEs may reach values as high as 70 μg/kg/day. PAEs are involved in endocrine disrupting effects, namely, upon reproductive physiology in different species of fish and mammals. They also present a variety of additional toxic effects for many other species including terrestrial and aquatic fauna and flora. Therefore, their presence in the environment has attracted considerable attention due to their potential impacts on ecosystem functioning and on public health. This paper is a synthesis of the extensive literature data on behavior, transport, fate and ecotoxicological state of PAEs in environmental matrices: air, water, sediment, sludge, wastewater, soil, and biota. First, the origins and physicochemical properties of PAEs that control the behavior, transport and fate in the environment are reviewed. Second, the compilation of data on transport and fate, adverse environmental and human health effects, legislation, restrictions, and ecotoxicological state of the environment based on PAEs is presented.

The urban-water cycle modifies natural stream hydrology, and domestic and commercial activities increase the burden of endocrine-disrupting chemicals, such as steroidal hormones and 4-nonylphenol, that can disrupt endocrine system function in aquatic organisms. This paper presents a series of integrated chemical and biological investigations into the occurrence, fate, and effects of endocrine-disrupting chemicals in the City of Boulder Colorado's WWTF and Boulder Creek, the receiving stream. Results are presented showing the effects of a full-scale upgrade of the WWTF (that treats 0.6 m(3) s(-1) of sewage) from a trickling filter/solids contact process to an activated sludge process on the removal of endocrine-disrupting compounds and other contaminants (including nutrients, boron, bismuth, gadolinium, and ethylenediaminetetraacetic acid) through each major treatment unit. Corresponding impacts of pre- and postupgrade effluent chemistry on fish reproductive end points were evaluated using on-site, continuous-flow experiments, in which male fathead minnows (Pimephales promelas) were exposed for 28 days to upstream Boulder Creek water and WWTF effluent under controlled conditions. The upgrade of the WWTF resulted in improved removal efficiency for many endocrine-disrupting chemicals, particularly 17β-estradiol and estrone, and fish exposed to the postupgrade effluent indicated reduction in endocrine disruption relative to preupgrade conditions.

The adsorption of two representative PhACs (naproxen and carbamazepine) and one EDC (nonylphenol) were evaluated on two granular activated carbons (GAC). The primary objective was to investigate preloading effects by natural organic matter (NOM) on adsorption capacity and kinetics under conditions and concentrations (i.e., ng/L) relevantfor drinking water treatment Isotherms demonstrated that all compounds were significantly negatively impacted by NOM fouling. Adsorption capacity reduction was most severe for the acidic naproxen, followed by the neutral carbamazepine and then the more hydrophobic nonylphenol. The GAC with the wider pore size distribution had considerably greater NOM loading, resulting in lower adsorption capacity. Different patterns forthe change in Freundlich K(F) and 1/n with time revealed different competitive mechanisms for the different compounds. Mass transport coefficients determined by short fixed-bed (SFB) tests with virgin and preloaded GAC demonstrated thatfilm diffusion primarily controls mass transfer on virgin and preloaded carbon. Naproxen suffered the greatest deteriorative effect on kinetic parameters due to preloading, followed by carbamazepine, and then nonylphenol. A type of surface NOM/biofilm, which appeared to add an additional masstransfer resistance layer and thus reduce film diffusion, was observed. In addition, electrostatic interactions between NOM/biofilm and the investigated compounds are proposed to contribute to the reduction of film diffusion. A companion paper building on this work describes treatability studies in pilot-scale GAC adsorbers and the effectiveness of a selected fixed-bed model.

Graphical systems models are powerful tools that can help facilitate hypothesis-driven ecotoxicogenomic research and aid in mechanistic interpretation of results. This paper describes a novel graphical model of the teleost brain-pituitary-gonadal (BPG) axis designed for ecotoxicogenomics research on endocrine-disrupting chemicals using small fish models. The model incorporates six compartments representing the major organs involved in the fish reproductive axis and depicts the interactions of over 105 proteins and 40 simple molecules, transcriptional regulation of 25 genes, and over 300 different reactions/ processes. Application of the model is illustrated in the context of a study examining effects of the competitive aromatase inhibitor, fadrozole, on gene expression in gonad, brain, and liver tissue of fathead minnows. Changes in mRNA transcript abundance were measured using a fathead minnow oligonucleotide microarray and quantitative real-time polymerase chain reaction. Gene expression changes observed in the ovaries of females exposed to 6.3 microg fadrozole/L for7 d were functionally consistent with fadrozole's mechanism of action, and expected compensatory responses of the BPG axis to fadrozole's effects. Furthermore, microarray results helped identify additional elements (genes/ proteins) that could be included in the model to potentially increase its predictive capacity. With proper recognition of

In the past 10 years, many thousands of research papers covering the many different aspects of endocrine disruption in the environment have been published. What has been learned from all this research? We have tried to reduce this very large volume of research into a relatively small number of "lessons". Hence, this paper is not a typical review, but instead it summarizes our personal opinions on what we consider are the major messages to have come from all this research. We realize that what has been a lesson to us may have been obvious from the outset to someone more knowledgeable on that particular aspect of the burgeoning field of endocrine disruption. In addition, it is inevitable that others will consider that we have "missed" some lessons that they would have expected to find included in our list. If so, we encourage them to submit them as responses to our paper. Our own lessons range widely, from the design and interpretation of data from fieldwork studies, through some key messages to come out of the very many laboratory studies that have been conducted, to issues around the sources and fates in the environment of endocrine-disrupting chemicals, and finally to the key role of sewage treatment in controlling the concentrations of these chemicals in the aquatic environment. Having (hopefully) learned our lessons, we have then applied them to the difficult issue of how best to approach future concerns about the potential impacts of other new and emerging contaminants (e.g., pharmaceuticals) on wildlife.

The compound 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP), a derivative of bisphenol S (BPS), has been detected in thermal paper and human urine samples; however, its potential effects on the endocrine system are largely unknown. The present study was conducted to determine the adverse effects of BPSIP on egg production, relative organ weights, plasma levels of sex hormones, and transcription of genes related to the hypothalamus-pituitary-gonad (HPG) axis in zebrafish (Danio rerio). In male fish, the gonadosomatic index was significantly decreased at concentrations of 5 and 50 μg/L BPSIP. The estrogenic (increase in the 17β-estradiol/testosterone [E2/T] ratio) and antiandrogenic (decrease in T) effects were observed in fish exposed to BPSIP and males were more sensitive to the adverse effects than females. The changes in sex hormones were supported by the regulation of genes along the HPG axis, such as cyp19, 17βhsd, and cyp17 transcripts. Although the effective concentration for endocrine disruption was greater than that of BPS, the actions of BPSIP on the steroidogenic pathway were similar to the effects of BPS exposure. [ABSTRACT FROM AUTHOR]

Host cell proteins (HCPs) are process-related impurities of biopharmaceuticals that remain at trace levels despite multiple stages of downstream purification. Currently, there is interest in implementing LC-MS in biopharmaceutical HCP profiling alongside conventional ELISA, because individual species can be identified and quantitated. Conventional data dependent LC-MS is hampered by the low concentration of HCP-derived peptides, which are 5-6 orders of magnitude less abundant than the biopharmaceutical-derived peptides. In this paper, we present a novel data independent acquisition (DIA)-MS workflow to identify HCP peptides using automatically combined targeted and untargeted data processing, followed by verification and quantitation using parallel reaction monitoring (PRM). Untargeted data processing with DIA-Umpire provided a means of identifying HCPs not represented in the assay library used for targeted, peptide-centric, data analysis. An IgG1 monoclonal antibody (mAb) purified by Protein A column elution, cation exchange chromatography, and ultrafiltration was analyzed using the workflow with 1D-LC. Five protein standards added at 0.5 to 100 ppm concentrations were detected in the background of the purified mAb, demonstrating sensitivity to low ppm levels. A calibration curve was constructed on the basis of the summed peak areas of the three highest intensity fragment ions from the highest intensity peptide of each protein standard. Sixteen HCPs were identified and quantitated on the basis of the calibration curve over the range of low ppm to over 100 ppm in the purified mAb sample. The developed approach achieves rapid HCP profiling using 1D-LC and specific identification exploiting the high mass accuracy and resolution of the mass spectrometer. [ABSTRACT FROM AUTHOR]

The adsorption of two representative PhACs (naproxen and carbamazepine) and one EDC (nonylphenol) were evaluated on two granular activated carbons (GAC). The primary objective was to investigate preloading effects by natural organic matter (NOM) on adsorption capacity and kinetics under conditions and concentrations (i.e., ng/L) relevant for drinking water treatment. Isotherms demonstrated that all compounds were significantly negatively impacted by NOM fouling. Adsorption capacity reduction was most severe for the acidic naproxen, followed by the neutral carbamazepine and then the more hydrophobic nonylphenol. The GAC with the wider pore size distribution had considerably greater NOM loading, resulting in lower adsorption capacity. Different patterns for the change in Freundlich Kf and 1/n with time revealed different competitive mechanisms for the different compounds. Mass transport coefficients determined by short fixed-bed (SFB) tests with virgin and preloaded GAC demonstrated that film diffusion primarily controls mass transfer an virgin and preloaded carbon. Naproxen suffered the greatest deteriorative effect on kinetic parameters due to preloading, followed by carbamazepine, and then nonylphenol. A type of surface NOM/biofilm, which appeared to add an additional mass transfer resistance layer and thus reduce film diffusion, was observed. In addition, electrostatic interactions between NOM/biofilm and the investigated compounds are proposed to contribute to the reduction of film diffusion, A companion paper building on this work describes treatability studies in pilot-scale GAC adsorbers and the effectiveness of a selected fixed-bed model. [ABSTRACT FROM AUTHOR]