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Perfluorooctanoic acid (PFOA), a perfluoroalkyl compound, is linked to congenital heart diseases, though its underlying mechanisms remain unclear. We hypothesized that PFOA induces cardiac defects through the inhibition of the Keap1/Nrf2 pathway, leading to oxidative damage in cardiomyocytes. In this study, zebrafish embryos exposed to PFOA showed significant cardiac malformations and dysfunction, characterized by excessive reactive oxygen species (ROS), malondialdehyde (MDA) production, decreased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities. Additionally, we observed dysregulation in the expression of key cardiac development genes (vmhc, gata4, nkx2.5, and sox9b). PFOA also reduced the expression of keap1, nrf2, and ho-1. After overexpression of Nrf2, levels of ROS and MDA decreased, while levels of SOD, CAT, and GSH-Px increased. Additionally, cardiomyocyte apoptosis and cardiac malformations were alleviated. These findings have suggested that PFOA induces oxidative stress through Keap1/Nrf2 pathway inhibition, ultimately leading to cardiac defects., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xing Liu reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS), two prominent per- and polyfluoroalkyl substances (PFASs), are potentially harmful to many human organs. However, there only exist limited methods to mitigate their health hazards. The aim of this study is to combine a bioinformatics analysis with in vitro experiments to discover small molecules that can alleviate liver damage caused by PFOA/PFOS. We identified 192 and 82 key genes related to hepatocytes exposed to PFOA and PFOS, respectively. The functional enrichment analysis of key genes suggested cellular senescence may be important in PFOA/PFOS-induced hepatotoxicity. The in vitro models revealed that PFOA/PFOS led to hepatocyte senescence by increasing the activity of SA-β-gal, inducing mitochondrial dysfunction, impacting cell cycle arrest, and elevating the expressions of p21, p53, IL-1β, and SASP-related cytokines. The drug-target gene set enrichment analysis method was employed to compare the transcriptome data from the Gene Expression Omnibus database (GEO), Comparative Toxicogenomics Database (CTD), and the high-throughput experiment- and reference-guided database (HERB), and 21 traditional Chinese medicines (TCMs) were identified that may alleviate PFOA/PFOS-induced liver aging. The experimental results of co-exposure to PFOA/PFOS and TCMs showed that sanguinarine has particular promise in alleviating cellular senescence caused by PFOA/PFOS. Further investigations revealed that the mTOR-p53 signaling pathway was involved in PFOA/PFOS-mediated hepatic senescence and can be blocked using sanguinarine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The spread of opportunistic pathogens (OPs) and antibiotic resistance genes (ARGs) through drinking water has already caused serious human health issues. There is also an urgent need to know the effects of perfluorooctanoic acid (PFOA) on OPs with different ARGs in drinking water. Our results suggested that PFOA accumulation and release from the pipelines induced its concentration in pipelines effluents increase from 0.03 ± 0.01 μg/L to 0.70 ± 0.01 μg/L after 6 months accumulation. The PFOA also promoted the growth of Hyphomicrobium, Microbacterium, and Bradyrhizobium. In addition, PFOA accumulation and release from the pipelines enhanced the metabolism and tricarboxylic acid (TCA) cycle processes, resulting in more extracellular polymeric substances (EPS) production. Due to EPS protection, Pseudomonas aeruginosa and Legionella pneumophila increased to (7.20 ± 0.09) × 10 4 gene copies/mL, and (8.85 ± 0.11) × 10 2 gene copies/mL, respectively. Moreover, PFOA also enhanced the transfer potential of different ARGs, including emrB, mdtB, mdtC, mexF, and macB. The main bacterial community composition and the main OPs positively correlated with the main ARGs and mobile genetic elements (MGE)-ARGs significantly. Therefore, PFOA promoted the propagation of OPs with different ARGs. These results are meaningful for controlling the microbial risk caused by the OPs with ARGs and MGE-ARGs in drinking water., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Perfluoroalkyl carboxylic acids (PFCAs) enter surface waters through wastewater discharge and atmospheric deposition, accumulating within aquatic ecosystems and organisms, causing dysfunction or mortality. This study investigates the migration, sources and ecological risks of six PFCAs in the coastal Wulong River basin and the estuary along the eastern coast of China. The six PFCAs detected in the Wulong River included, at concentrations ranging from 17.36 to 57.92 ng/L. The distribution of PFCAs concentrations throughout the estuary were as follows: Northeast China (414.07 ng/L) > North China (325.97 ng/L) > East China (249.53 ng/L) > South China (63.61 ng/L), with perfluorooctanoic acid (PFOA) being the dominant PFCA. Toxicity data was collected for all detected PFCAs and the species sensitivity distribution (SSD) method was used to derive the predicted no effect concentrations (PNECs) for all six PFCAs. The risk quotient (RQ) method showed that the risk posed to aquatic organisms in the river basin from all six PFCAs was relatively low (RQ < 1). However, joint probability curve (JPC) analysis revealed that the probability of perfluoropentanoic acid (PFPeA) causing harm to 5% of aquatic species reached 41.13%. Considering the frequency of occurrence and persistence of PFCAs in aquatic environments, these findings indicate they have the potential to induce serious toxic effects on aquatic organisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Due to the persistent nature and significant negative impacts of perfluorooctanoic acid (PFOA) on human health and other organisms, the emergence of new PFOA alternatives, such as perfluoro (2-methyl-3-oxhexanoic) acid (GenX) and perfluoro-3,6,9-trioxyundecanoic acid (PFO3TDA), have drawn significant attention. However, the toxic effects of PFOA and its substitutes on bones remain limited. In this study, we administered different concentrations of PFOA, GenX, and PFO3TDA via gavage to 3-week-old male BALB/C mice for four weeks. X-ray and micro-CT scans revealed shortening of the femur and tibia and significant reduction in bone density. Additionally, PFOA, GenX, and PFO3TDA promoted osteoblast senescence and impaired osteogenic capabilities. This was characterized by a decrease in the expression of osteogenesis-related genes (OCN, ALP, Runx2, etc.) and an increase in the expression of aging and inflammation-related factors (p16 INK4a , P21, MMP3, etc). Furthermore, RNA sequencing revealed activation of the ferroptosis pathway in PFOA-treated osteoblasts, characterized by notable lipid peroxidation and excessive iron accumulation. Finally, by inhibiting the ferroptosis pathway with ferrostatin-1 (Fer-1), we effectively alleviated the senescence of MC3T3-E1 cells treated with PFOA, GenX, and PFO3TDA, and improved their osteogenic capabilities. Therefore, our study provides a new therapeutic insight into the impact of PFOA and its substitutes on bone growth and development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hexafluoropropylene oxide dimer acid (HFPO-DA) and perfluoroethylcyclohexane sulfonate (PFECHS) are increasingly used as alternatives for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). However, their immunotoxicity and underlying molecular mechanisms remain poorly understood. Here, to assess immunotoxic effects, zebrafish embryos were exposed to environmentally relevant concentrations of PFOA, PFOS, HFPO-DA, and PFECHS for four days. Results revealed that all four per- and polyfluoroalkyl substances (PFAS) resulted in decreased heart rate and spontaneous movement, and induced oxidative stress in zebrafish larvae. Notably, HFPO-DA exhibited more severe oxidative stress than PFOA. Immune dysfunction was observed, characterized by elevated cytokine, complement factor, nitric oxide, and neutrophil content, along with a significant decrease in lysozyme content. Transcriptomic analysis revealed the activation of Toll-like receptor (TLR)/NOD-like receptor (NLR)/RIG-I-like receptor (RLR) and associated downstream genes, indicating their pivotal role in PFAS-induced immunomodulation. Molecular docking simulations demonstrated stable interactions between PFAS and key receptors (TLR2, NOD2 and RIG-I). Overall, HFPO-DA and PFECHS exhibited immunotoxic effects in zebrafish larvae similar to legacy PFAS, providing important information for understanding the toxic mode of action of these emerging alternatives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Contamination of per- and polyfluoroalkyl substances (PFAS) poses a significant threat to soil ecosystem health, yet there remains a lack of understanding regarding the responses of soil microbial communities to prolonged PFAS exposure in field conditions. This study involved a three-year field investigation to track changes in microbial communities and functions in soil subjected to the contamination of a primary PFAS, perfluorooctanoic acid (PFOA). Results showed that PFOA exposure altered soil bacterial and fungal communities in terms of diversity, composition, and structure. Notably, certain bacterial communities with a delayed reaction to PFOA contamination showed the most significant response after one year of exposure. Fungal communities were sensitive to PFOA in soil, exhibiting significant responses within just four months of exposure. After two years, the impact of PFOA on both bacterial and fungal communities was lessened, likely due to the long-term adaptation of microbial communities to PFOA. Moreover, PFOA exposure notably inhibited alkaline phosphatase activity and reduced certain phosphorus cycling-related functional genes after three years of exposure, suggesting potential disruptions in soil fertility. These new insights advance our understanding of the long-term effects of PFOA on soil microbial communities and functions at a field scale., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Although recent in vitro experimental results have raised the question of whether maternal exposure to per- and polyfluoroalkyl substances (PFAS) may be a potential environmental risk factor for chromosomal abnormalities, epidemiological studies investigating these associations are lacking., Objectives: This study examined whether prenatal PFAS exposure is associated with a higher prevalence of chromosomal abnormalities among offspring., Methods: We used data from the Japan Environment and Children's Study, a nationwide birth cohort study, and employed logistic regression models to examine the associations between maternal plasma PFAS concentrations in the first trimester and the diagnosis of chromosomal abnormalities in all births (artificial abortions, miscarriages, stillbirths, and live births) up to 2 years of age. In addition, we examined associations with mixtures of PFAS using multipollutant models., Results: The final sample consisted of 24,724 births with singleton pregnancies, of which 44 confirmed cases of chromosomal abnormalities were identified (prevalence: 17.8/10,000 births). When examined individually, exposure to perfluorononanoic acid (PFNA) and perfluorooctane sulfonic acid (PFOS) showed positive associations with any chromosomal abnormalities with age-adjusted odds ratios of 1.81 (95% CI: 1.26, 2.61) and 2.08 (95% CI: 1.41, 3.07) per doubling in concentration, respectively. These associations remained significant after Bonferroni correction, although they did not reach the adjusted significance threshold in certain sensitivity analyses. Furthermore, the doubling in all PFAS included as a mixture was associated with chromosomal abnormalities, indicating an age-adjusted odds ratio of 2.25 (95% CI: 1.34, 3.80), with PFOS as the predominant contributor, followed by PFNA, perfluoroundecanoic acid (PFUnA), and perfluorooctanoic acid (PFOA)., Discussion: The study findings suggested a potential association between maternal exposure to PFAS, particularly PFOS, and chromosomal abnormalities in offspring. However, the results should be interpreted cautiously, because selection bias arising from the recruitment of women in early pregnancy may explain the associations. https://doi.org/10.1289/EHP13617.

Perfluorooctanoic acid (PFOA), a persistent organic pollutant known for its chemical stability, is widely dispersed in the environment, posing significant health risks to mammals through various exposure routes such as ingestion, inhalation, and dermal contact. In this study, mice were exposed to PFOA (0, 0.2, 2 mg/L) through drinking water for 180 days to investigate its toxic effects on the colon. We identified differentially expressed genes through RNA sequencing and validated the impact of PFOA on the expression of these genes in colon tissue. Our findings revealed that long-term exposure to PFOA caused inflammatory bowel disease (IBD)-like damage to the mouse colon. We found PFOA could induce damage to the intestinal barrier. Inhibition of the Wnt signaling pathway following PFOA exposure results in impaired stem cell function in the colon of mice. Furthermore, PFOA activated the PPAR signaling pathway, disrupting cellular lipid metabolism in colon tissues. Additionally, PFOA induced inflammatory responses in colon tissue, facilitating NLR family, pyrin domain containing 3 (NLRP3) inflammasome activation and cell apoptosis. This study offers a thorough understanding of the mechanisms responsible for the damage to mouse colon tissue resulting from long-term exposure to PFOA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

6:2 fluorotelomer carboxylic acid (6:2 FTCA) is a perfluorooctanoic acid (PFOA) substitute, which is supposedly less accumulative and toxic than PFOA. However, 6:2 FTCA is structurally similar to PFOA, and there had already been reports about its toxicities comparable to PFOA. The aim of the current study is to assess potential effects of developmental exposure to 6:2 FTCA on the development of kidney in chicken embryo and to investigate underlying mechanism. Fertile chicken eggs were exposed to 1.25 mg/kg, 2.5 mg/kg or 5 mg/kg doses of 6:2 FTCA, or 2 mg/kg PFOA, then incubated to hatch. Serum and kidney of hatchling chickens were collected. Blood urea nitrogen (BUN) and creatinine (Cre) levels were measured with commercially available kits. Morphology of kidney was assessed with histopathology. To further reveal molecular mechanism of observed endpoints, IGF signaling molecules were assessed in the kidney samples with qRT-PCR, results indicated that IGFBP3 is a potentially crucial molecule. Lentiviruses overexpressing or silencing IGFBP3 were designed and applied to enhance/suppress the expression of IGFBP3 in developing chicken embryo for further verification of its role in the observed effects. Disrupted nephron formation, in the manifestation of decreased glomeruli number/area and increased serum BUN/Cre levels, was observed in the animals developmentally exposed to 6:2 FTCA. Correspondingly, IGF signaling molecules (IGF1, IGF1R and IGFBP3) were affected by 6:2 FTCA exposure. Meanwhile, overexpression of IGFBP3 effectively alleviated such changes, while silencing of IGFBP3 mimicked observed effects. In conclusion, developmental exposure to 6:2 FTCA is associated with disrupted chicken embryo renal development, in which IGFBP3 seems to be a remarkable contributor, suggesting potential health risks for human and other species. Further risk assessments and mechanistic works are necessary., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Qixiao Jiang reports financial support was provided by National Natural Science Foundation of China. Yuxu Zhong reports financial support was provided by Logistics Scientific Research Plan. Junhua Yuan reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many studies have reported that prenatal exposure to Per- and Polyfluoroalkyl Substances (PFASs) can disrupt immune function. However, little is known about the effects of PFASs on immune molecules. The study analyzed the association between prenatal exposure to mixed and single PFASs and plasma immune molecules in three-year-old children., Methods: Ten PFASs were measured in umbilical cord serum, while peripheral blood samples were collected at age three to measure immune molecules. Associations between exposure to individual and combined PFASs and immune molecules were analyzed using Generalized Linear Models and Weighted Quantile Sum (WQS) regression., Results: (1) Interleukin-4 (IL-4) increased by 23.85% (95% CI:2.99,48.94) with each doubling of Perfluorooctanoic Acid (PFOA), and Interleukin-6 (IL-6) increased by 39.07% (95%CI:4.06,85.86) with Perfluorotridecanoic Acid (PFTrDA). Elevated PFOA and Perfluorononanoic Acid (PFNA) were correlated with increases of 34.06% (95% CI: 6.41, 70.28) and 24.41% (95% CI: 0.99, 53.27) in Eotaxin-3, respectively. Additionally, the doubling of Perfluorohexane Sulfonic Acid (PFHxS) was associated with a 9.51% decrease in Periostin (95% CI: -17.84, -0.33). (2) The WQS analysis revealed that mixed PFASs were associated with increased IL-6 (β = 0.37, 95%CI:0.04,0.69), mainly driven by PFTrDA, PFNA, and 8:2 Chlorinated Perfluoroethyl Sulfonamide (8:2 Cl-PFESA). Moreover, mixed PFASs were linked to an increase in Eotaxin-3 (β = 0.32, 95% CI: 0.09,0.55), primarily influenced by PFOA, PFTrDA, and Perfluorododecanoic Acid (PFDoDA)., Conclusions: Prenatal PFASs exposure significantly alters the levels of immune molecules in three-year-old children, highlighting the importance of understanding environmental impacts on early immune development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite its widespread use as a stabilizer across various industries over the past several decades, the health effects of chronic exposure to PFOA are still unclear. We administered PFOA by oral gavage (0, 12.5, 50, and 200 μg/day/mouse, eight groups) to male and female mice for six months. Body weight gain decreased with dose accompanied by increased liver weight, and PFOA altered liver damage-related-blood biochemical indicators and induced pathological lesions, including hepatocellular hypertrophy, cholangiofibrosis, and centrilobular hepatocellular vacuolation. Loss of the Golgi apparatus, formation of lamellar body-like structures, and lipid accumulation were observed in the liver of PFOA-treated mice. We also cohabited five pairs of male and female mice for the last ten days of administration, dosed PFOA to dam up to 28 days after birth, and investigated effects on reproduction and development. The survival rate of pups and the sex ratio of surviving mice decreased significantly at the highest dose. PFOA tissue concentration increased with the dose in the parent mice's liver and the pups' blood and brain. Taken together, we suggest that PFOA primarily affects the liver and reproduction system and that disturbance in lipid metabolism and Golgi's structural stability may be involved in PFOA-induced toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

High-dose perfluorooctanoic acid (PFOA) impairs oocyte maturation and offspring quality. However, the physiological concentrations of PFOA in follicular fluids of patients with premature ovarian insufficiency (POI) were detected at lower levels, thus the relationship between physiological PFOA and reproductive disorders remains elusive. Here, we investigated whether physiological PFOA exposure affects gonad function in adult zebrafish. Physiological PFOA exposure resulted in POI-like phenotypes in adult females, which exhibited decreased spawning frequency, reduced number of ovulated eggs, abnormal gonadal index, and aberrant embryonic mortality. Meanwhile, oocytes from PFOA-exposed zebrafish showed mitochondrial disintegration and diminished mitochondrial membrane potential. Unlike the high-dose treated oocytes exhibiting high reactive oxygen species (ROS) levels and excessive apoptosis, physiological PFOA reduced the ROS levels and did not trigger apoptosis. Interestingly, physiological PFOA exposure would not affect testis function, indicating specific toxicity in females. Mechanistically, PFOA suppressed the NAD+ biosynthesis and impaired mitochondrial function in oocytes, thus disrupting oocyte maturation and ovarian fertility. Nicotinamide mononucleotide (NMN), a precursor for NAD+ biosynthesis, alleviated the PFOA-induced toxic effects in oocytes and improved the oocyte maturation and fertility upon PFOA exposure. Our findings discover new insights into PFOA-induced reproductive toxicity and provide NMN as a potential drug for POI therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Per- and polyfluoroalkyl substances (PFAS) such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) and perfluoro-2-methyl-3-oxahexanoic acid (GenX), the new replacement PFAS, are major environmental contaminants. In rodents, these PFAS induce several adverse effects on the liver, including increased proliferation, hepatomegaly, steatosis, hypercholesterolemia, nonalcoholic fatty liver disease and liver cancers. Activation of peroxisome proliferator receptor alpha by PFAS is considered the primary mechanism of action in rodent hepatocyte-induced proliferation. However, the human relevance of this mechanism is uncertain. We investigated human-relevant mechanisms of PFAS-induced adverse hepatic effects using FRG liver-chimeric humanized mice with livers repopulated with functional human hepatocytes. Male FRG humanized mice were treated with 0.067 mg/L of PFOA, 0.145 mg/L of PFOS, or 1 mg/L of GenX in drinking water for 28 days. PFOS caused a significant decrease in total serum cholesterol and LDL/VLDL, whereas GenX caused a significant elevation in LDL/VLDL with no change in total cholesterol and HDL. All three PFAS induced significant hepatocyte proliferation. RNA-sequencing with alignment to the human genome showed a total of 240, 162, and 619 differentially expressed genes after PFOA, PFOS, and GenX exposure, respectively. Upstream regulator analysis revealed that all three PFAS induced activation of p53 and inhibition of androgen receptor and NR1D1, a transcriptional repressor important in circadian rhythm. Further biochemical studies confirmed NR1D1 inhibition and in silico modeling indicated potential interaction of all three PFAS with the DNA-binding domain of NR1D1. In conclusion, our studies using FRG humanized mice have revealed new human-relevant molecular mechanisms of PFAS including their previously unknown effect on circadian rhythm., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Early brain development depends on adequate transport of thyroid hormones (THs) from the maternal circulation to the fetus. To reach the fetal brain, THs have to cross several physiological barriers, including the placenta, blood-brain-barrier and blood-cerebrospinal fluid-barrier. Transport across these barriers is facilitated by thyroid hormone transmembrane transporters (THTMTs). Some endocrine disrupting chemicals (EDCs) can interfere with the transport of THs by THTMTs. To screen chemicals for their capacity to disrupt THTMT facilitated TH transport, in vitro screening assays are required. In this study, we developed assays for two THTMTs, organic anion transporter polypeptide 1C1 (OATP1C1) and organic anion transporter 4 (OAT4), both known to play a role in the transport of THs across barriers. We used overexpressing cell models for both OATP1C1 and OAT4, which showed an increased uptake of radiolabeled T4 compared to control cell lines. Using these models, we screened various reference and environmental chemicals for their ability to inhibit T4 uptake by OATP1C1 and OAT4. Tetrabromobisphenol A (TBBPA) was identified as an OATP1C1 inhibitor, more potent than any of the reference chemicals tested. Additionally perfluorooctanesulfonic acid (PFOS), perfluoroctanic acid (PFOA), pentachlorophenol and quercetin were identified as OATP1C1 inhibitors in a similar range of potency to the reference chemicals tested. Bromosulfophthalein, TBBPA, PFOA and PFOS were identified as potent OAT4 inhibitors. These results demonstrate that EDCs commonly found in our environment can disrupt TH transport by THTMTs, and contribute to the identification of molecular mechanisms underlying TH system disruption chemicals., (© 2024. The Author(s).)

Exposed to ubiquitously perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) has been associated with non-alcoholic fatty liver disease (NAFLD), yet the underlying molecular mechanism remains elusive. The extrapolation of empirical studies correlating per- and polyfluoroalkyl substance (PFAS) exposure with NAFLD occurrence to real-life exposure was hindered by the limited availability of mechanistic data at environmentally relevant concentrations. Herein, a novel pathway mediating hepatocyte lipid accumulation by PFOA and PFOS at human-relevant dose (<10 μM) was identified by integrating CRISPR-Cas9 genome screening, concentration-dependent transcriptional assay in HepG2 cell and epidemiological data mining. 1) At genetic level, nudt7 showed the highest enriched potency among 569 NAFLD-related genes, and the transcription of nudt7 was significantly downregulated by PFOA and PFOS exposure (<7 μM). 2) At molecular pathway, upon exposure to ≤10 -4  μM PFOA and PFOS, the downregulation of nudt7 transcriptional expression triggered the reduction of Ace-CoA hydrolase activity. 3) At cellular level, increased lipids were measured in HepG2 cells with PFOA and PFOS (<2 μM). Overall, we identified a novel mechanism mediated by transcriptional downregulation of nudt7 gene in hepatocellular lipid increase treated with PFOA and PFOS, which could potentially explain the NAFLD occurrence associated with exposure to PFASs in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The coexistence of multiple emerging contaminants imposes a substantial burden on the ecophysiological functions in organisms. The combined toxicity and underlying mechanism requires in-depth understanding. Here, marine blue mussel (Mytilus galloprovincialis L.) was selected and exposed to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and perfluorooctanoic acid (PFOA) individually and in combination at environmental related concentrations to elucidate differences in stress responses and potential toxicological mechanisms. Characterization and comparison of accumulation, biomarkers, histopathology, transcriptomics and metabolomics were performed. Co-exposure resulted in differential accumulation patterns, exacerbated histopathological alterations, and different responses in oxidative stress and biomarkers for xenobiotic transportation. Moreover, the identified differentially expressed genes (DEGs) and differential metabolites (DEMs) in mussels were found to be annotated to different metabolic pathways. Correlation analyses further indicated that DEGs and DEMs were significantly correlated with the above biomarkers. BDE-47 and PFOA altered the genes and metabolites related to amino acid metabolism, energy and purine metabolism, ABC transporters, and glutathione metabolism to varying degrees, subsequently inducing accumulation differences and combined toxicity. Furthermore, the present work highlighted the pivotal role of Nrf2-keap1 detoxification pathway in the acclimation of M. galloprovincialis to reactive oxygen species (ROS) stress induced by BDE-47 and PFOA. This study enabled more comprehensive understanding of combined toxic mechanism of multi emerging contaminants pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

PFOA is a legacy Per- and Polyfluorinated Substances (PFAS), a group of chemicals widely used in various industrial applications and consumer products. Although there has been a voluntary phase out of PFOA since 2005, it is still widely detected in various water supplies. A growing body of evidence suggests an association between PFOA exposure, particularly during developmental stages, with increased risks of neurodegenerative diseases (NDs). The neurotoxic mechanism of developmental PFOA exposure, however, remains poorly understood. Utilizing human induced-pluripotent stem cell (hiPSC)-derived cortical neurons, we investigated the effect of PFOA exposure prior to differentiation and assessed changes in neuronal characteristics, transcriptome, and neurodegeneration markers mimicking a Developmental Origin of Health and Disease (DoHAD) paradigm. Exposure to PFOA before neuron differentiation resulted in persistent alterations in nuclear morphology, neuronal network, and calcium activity. RNA sequencing analysis further revealed transcriptomic changes aligning with Alzheimer's Disease (AD) after PFOA exposure. These observations were further corroborated by alterations in tau phosphorylation markers, the presence of fibrillar tau, an increase in liquid droplets, and a decrease in RNA translational efficiency characterized using a battery of biochemical assays. Taken together, our results revealed persistent deficits of key neuronal characteristics induced by pre-differentiation PFOA exposure, suggesting impairments in several AD-related pathways that can together contribute to the elevation of AD risk after pre-differentiation PFOA exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

With the restricted use of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), a number of alternatives to PFOS and PFOA have attracted great interest. Most of the alternatives are still characterized by persistence, bioaccumulation, and a variety of toxicity. Due to the production and use of these substances, they can be detected in the atmosphere, soil and water body. They affect human health through several exposure pathways and especially enter the gut by drinking water and eating food, which results in gut toxicity. In this review, we summarized the effects of PFOS, PFOA and 9 alternatives on pathological changes in the gut, the disruption of physical, chemical, biological and immune barriers of the intestine, and the gut-organ axis. This review provides a valuable understanding of the gut toxicity of PFOS, PFOA and their alternatives as well as the human health risks of emerging contaminants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Perfluorooctanoic acid (PFOA), a member of per- and polyfluoroalkyl substances (PFASs), has been widely used in manufacturing for decades. Currently, PFOA is strictly regulated, but due to its high stability and persistence, it is detected in both environmental as well as in human matrices. To elucidate mechanisms of PFOA toxicity in humans, we determined the genome-wide transcriptomic changes of peripheral blood mononuclear cells (PBMC) responding to PFOA exposure in a sex-stratified analysis. This work employed samples from 145 female and 143 male participants of the CELSPAC: YA study to characterize PFOA-associated transcripts in a broader context using computational analysis. PFOA-associated gene expression differed significantly between men and women, as only 2 % of mapped genes were expressed in both sexes. Disease-specific enrichment analysis revealed cancer and immune-related disease terms as those most enriched in male and female populations. Patterns of enriched terms within the gene set enrichment analysis indicated three main targets of PFOA toxicity: i) lipid metabolism for women; ii) cell cycle regulation for men; and iii) immune system response for both sexes. In summary, our genome-wide transcriptomics analysis described sex-specific differences in PFOA-associated gene expression and provided evidence about biological pathways underlying PFOA toxicity in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Per- and polyfluoroalkyl substances (PFAS) exposure is a potential risk factor for thyroid cancer and may be a contributor to the increasing thyroid cancer incidence rates. A systematic review and meta-analysis was performed to summarize all human studies to date investigating the association between PFAS exposure and thyroid cancer. A search of the National Library of Medicine and National Institutes of Health PubMed and Scopus databases was done to identify relevant articles published in English through January 2024. Studies reporting the association between PFAS exposure and thyroid cancer using odds ratios (OR) were included in the meta-analysis with summary estimate calculated using a random effects model (n=5). Perfluorooctanoic acid (PFOA) was the most investigated PFAS. Results of the included studies varied, ranging from significant positive to significant negative associations with thyroid cancer incidence for different PFAS. Meta-analyses of PFOA, Perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexanesulfonic acid (PFHxS) were not significant. This comprehensive review of the current literature highlights the limited knowledge and inconsistent results of this association. Large longitudinal cohort studies with varying time between sample collection and thyroid cancer diagnosis are needed to better understand the role of PFAS exposure on thyroid carcinogenesis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maaike van Gerwen reports financial support was provided by National Institutes of Health. Lauren Petrick reports financial support was provided by National Institutes of Health. Angela Leung reports a relationship with United States Environmental Protection Agency that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As perfluorooctanoic acid (PFOA) alternatives, hexafluoropropylene oxide dimeric acid (HFPO-DA) and hexafluoropropylene oxide trimeric acid (HFPO-TA) have been increasingly used and caused considerable water pollution. However, their toxicities to aquatic organisms are still not well known. Therefore, in this study, zebrafish embryos were exposed to PFOA (0, 1.5, 3 and 6 mg/L), HFPO-DA (0, 3, 6 and 12 mg/L) and HFPO-TA (0, 1, 2 and 4 mg/L) to comparatively investigate their thyroid disrupting effects and the developmental toxicity. Results demonstrated that waterborne exposure to PFOA and its two alternatives decreased T4 contents, the heart rate and swirl-escape rate of zebrafish embryos/larvae. The transcription levels of genes related to thyroid hormone regulation (crh), biosynthesis (tpo and tg), function (trα and trβ), transport (transthyretin, ttr), and metabolism (dio1, dio2 and ugt1ab), were differently altered after the exposures, which induced the thyroid disrupting effects and decreased the heart rate. In addition, the transcription levels of some genes related to the nervous system development were also significantly affected, which was associated with the thyroid disrupting effects and consequently affected the locomotor activity of zebrafish. Therefore, HFPO-DA and HFPO-TA could not be safe alternatives to PFOA. Further studies to uncover the underlying mechanisms of these adverse effects are warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

As alternatives of perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimeric acid (HFPO-DA) and trimeric acid (HFPO-TA) have been detected increasingly in environmental media and even humans. They have been shown to exhibit reproductive toxicity to model species, but their effects on human remain unclear due to the knowledge gap in their mode of action. Herein, (anti-)androgenic effects of the two HFPOs and PFOA were investigated and underlying toxicological mechanism was explored by combining zebrafish test, cell assay and molecular docking simulation. Exposure of juvenile zebrafish to the chemicals during sex differentiation promoted feminization, with HFPO-TA acting at an environmental concentration of 1 μg/L. The chemicals inhibited proliferation of human prostate cells and transcriptional activity of human and zebrafish androgen receptors (AR), with HFPO-TA displaying the strongest potency. Molecular docking revealed that the chemicals bind to AR in a conformation similar to a known AR antagonist. Combined in vivo, in vitro and in silico results demonstrated that the chemicals disrupted sex differentiation likely by antagonizing AR-mediated pathways, and provided more evidence that HFPO-TA is not a safe alternative to PFOA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Perfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that have attracted considerable attention due to their widespread utilization, resilient characteristics, adverse health implications, and regulatory scrutiny. Despite documented toxicity in living organisms, the precise molecular mechanisms governing the induced adverse effects remain unclear. This study aims to elucidate mechanisms of toxic action by collecting empirical data sets along oxidative stress and metabolic disruption pathways. We investigated the impact of long-chain PFAS (perfluorooctanoic acid (PFOA)) and its short-chain analog (perfluorobutanoic acid (PFBA)) on human neuronal cells (SH-SY5Y). The functionalities of enzymes associated with oxidative stress (catalase and glutathione reductase) and cellular metabolism (lactate dehydrogenase and pyruvate dehydrogenase) were also characterized. Our results reveal that a 24-hour exposure to PFOA and PFBA generated significant levels of reactive oxygen species. Correspondingly, there was a notable decline in catalase and glutathione reductase activities, with PFBA demonstrating a more pronounced effect. High concentrations of PFOA and PFBA reduced metabolic activity. Lactate dehydrogenase activity was only impacted by a high concentration of PFBA, while pyruvate dehydrogenase activity was decreased with PFBA exposure and increased with PFOA exposure. The findings from this study contribute to the knowledge of PFAS and cell interactions and reveal the potential underlying mechanisms of PFAS-induced toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cardiovascular diseases (CVDs) are one of the major causes of death globally. In addition to traditional risk factors such as unhealthy lifestyles (smoking, obesity, sedentary) and genetics, common environmental exposures, including persistent environmental contaminants, may also influence CVD risk. Per- and polyfluoroalkyl substances (PFASs) are a class of highly fluorinated chemicals used in household consumer and industrial products known to persist in our environment for years, causing health concerns that are now linked to endocrine disruptions and related outcomes in women, including interference of the cardiovascular and reproductive systems. In postmenopausal women, higher levels of PFAS are observed than in premenopausal women due to the cessation of menstruation, which is crucial for PFAS excretion. Because of these findings, we explored the association between perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorobutanesulfonic acid in postmenopausal women from our previously established CVD study. We used liquid chromatography with tandem mass spectrometry, supported by machine learning approaches, and the detection and quantification of serum metabolites and proteins. Here, we show that PFOS can be a good predictor of coronary artery disease, whereas PFOA can be an intermediate predictor of coronary microvascular disease. We also found that the PFAS levels in our study are significantly associated with inflammation-related proteins. Our findings may provide new insight into the potential mechanisms underlying the PFAS-induced risk of CVDs in this population. This study shows that exposure to PFOA and PFOS is associated with an increased risk of cardiovascular disease in postmenopausal women. PFOS and PFOA levels correlate with amino acids and proteins related to inflammation. These circulating biomarkers contribute to the etiology of CVD and potentially implicate a mechanistic relationship between PFAS exposure and increased risk of cardiovascular events in this population., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Per- and polyfluoroalkyl substances (PFAS) are anthropogenic organofluorine compounds that persist indefinitely in the environment and bioaccumulate throughout all trophic levels. Biomonitoring efforts have detected multiple PFAS in the serum of most people. Immune suppression has been among the most consistent effects of exposure to PFAS. PFAS often co-occur as mixtures in the environment, however, few studies have examined immunosuppression of PFAS mixtures or determined whether PFAS exposure affects immune function in the context of infection. In this study, mixtures containing two or four different PFAS and a mouse model of infection with influenza A virus (IAV) were used to assess immunotoxicity of PFAS mixtures. PFAS were administered via the drinking water as either a binary mixture of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) or quaternary mixture of PFOS, PFOA, perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA). The results indicated that the binary mixture affected the T-cell response, while the quaternary mixture affected the B-cell response to infection. These findings indicate that the immunomodulatory effects of PFAS mixtures are not simply additive, and that the sensitivity of immune responses to PFAS varies by cell type and mixture. The study also demonstrates the importance of studying adverse health effects of PFAS mixtures.

Per- and poly-fluoroalkyl substances (PFAS) are an emerging class of persistent organic pollutants that are widespread in aquatic ecosystems and pose a serious threat to aquatic organisms. It is thus crucial to explore the toxicity mechanisms of PFAS to submerged macrophytes and biofilms. In this study, Vallisneria natans (V. natans) was exposed to environmentally relevant concentrations of perfluorooctanoic acid (PFOA) and perfluorooctane sulphonate (PFOS). Results showed that PFAS induced the excessive production of reactive oxygen species, triggering antioxidant responses. V. natans exhibited an improved stress tolerance by altering the biosynthesis of several plant secondary metabolites and the histidine, arginine, proline pathways in response to PFAS exposure. Moreover, PIP1-1, PIP2-2, SLAH1 and SLAH2 genes were upregulated, indicating the activation of aquaporins and slow-type anion channels. The uptake of PFOA and PFOS by V. natans was 41.74 % and 52.31 %, respectively. Notably, PFAS bound to functional proteins (GSTF10), promoting the detoxification of plants. Exposure to PFAS also altered the structure of biofilms by inducing the synthesis of large amounts of polysaccharides and proteins. The diversity and richness of the microbial community within periphytic biofilms changed significantly. These results provide a comprehensive description of the responses of aquatic plants and periphytic biofilms to PFAS and the removal mechanism of PFAS, contributing to the environmental risk assessments and removal of PFAS in aquatic ecosystems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The disruption of per- and polyfluoroalkyl substances (PFASs) on bile acid (BA) homeostasis has raised public concerns, making the evaluation of their effects and underlying mechanisms a high priority. Although the use of perfluorooctanoic acid (PFOA) has been restricted, it remains a widespread legacy PFAS in the environment. Concurrently, the use of its prevalent short-chain alternative, perfluorobutanoic acid (PFBA), is increasing, yet the toxicity assessment of PFBA remains inadequate. In this study, C57BL/6N mice were exposed to PFOA and PFBA (0.4 or 10 mg/kg body weight) by gavage for 28 days. The results showed that both PFOA and PFBA significantly increased hepatic weight, although PFBA exhibited lower bioaccumulation than PFOA in the liver. Targeted metabolomics revealed that PFOA significantly decreased total BA levels and altered their composition. Conversely, PFBA, without significantly altering total BA levels, notably changed their composition, such as increasing the proportion of cholic acid. Further investigations using in vivo and in vitro assays suggested that PFOA inhibited the expression of Cyp7A1, a key BA synthetase, potentially via PPARα activation, thereby reducing BA levels. In contrast, PFBA enhanced Cyp7A1 expression, associated with the inhibition of intestinal Farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) pathway. This study evaluated the differences in the BA-interfering effects of PFOA and PFBA and shed light on the potential mechanisms, which will provide new insights into the health risks of legacy PFASs and their alternatives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Perfluorooctanoic acid (PFOA), an emerging pollutant, has been frequently detected in organic solid waste. It becomes a major concern for compost application, but studies on its toxic effects during composting are rare. This study evaluated the impact of PFOA presence at the environmentally relevant level on the humification process and microbiology during composting. The results showed that the PFOA presence (15.5 μg/kg dry) caused 45.5 % and 40.5 % decreases in the total organic carbon and humic acid-like substances, respectively. PFOA negatively affected microbial activity during the thermophilic period, as evidenced by the increases in reactive oxygen species and lactate dehydrogenase concentration. It altered the microbial community with an enrichment of Bacteroidota, conducive to resisting press. Unexpectedly, the PFOA presence induced hormesis at the maturity period, consistent with stimulated carbon metabolism (i.e., glycolysis and oxidative phosphorylation). The modulated microbial metabolism stimulated the catabolic metabolism of small-molecule humus precursors and reduced intracellular quinone availability. Furthermore, the secretion of auxiliary activities for crude fiber degradation was suppressed, which decreased the generation of extracellular quinone, and thereby impeded the humification process. These findings deciphered the metabolic response of composting to PFOA presence and highlighted the potential carbon loss of PFOA-containing composting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Minimizing the detrimental impacts of perfluorooctanoic acid (PFOA) on human health is a daunting task. Here, we aimed to propose effective strategies for reducing PFOA-induced mitochondrial toxicity in human liver and intestinal cells. PFOA could occupy the fatty acid-binding pockets of human peroxisome proliferator-activated receptor alpha (hPPARα). PFOA not only could structurally interact with hPPARα, but also substantially upregulated the expression levels of PPARα and its downstream gene (i.e., pyruvate dehydrogenase kinase (PDK4)). The increased expression of PDK4 was associated with the mitochondrial toxicity of PFOA, and inhibition of PDK4 or knock-down of PDK4 could effectively attenuate the mitochondrial toxicity of PFOA. Moreover, modification of carboxyl group via an esterification of PFOA into methyl perfluorooctanoate (MePFOA) decreased the affinity to hPPARα, resulting in the loss of upregulated expressions of PPARα and PDK4. Lower mitochondrial toxicity and cytotoxicity were found in the MePFOA-treated cells compared to PFOA exposure. Our study supported that the carboxyl group of PFOA (as functional head group) was required for inducing its mitochondrial toxicity. Two strategies, including modification of functional head group and inhibition of toxic target of PFOA, are feasible to ameliorate mitochondrial toxicity of PFOA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The increasing use of industrial chemicals has raised concerns regarding exposure to endocrine-disrupting chemicals (EDCs), which interfere with developmental, reproductive and metabolic processes. Of particular concern is their interaction with adipose tissue, a vital component of the endocrine system regulating metabolic and hormonal functions. The SGBS (Simpson Golabi Behmel Syndrome) cell line, a well-established human-relevant model for adipocyte research, closely mimics native adipocytes' properties. It responds to hormonal stimuli, undergoes adipogenesis and has been successfully used to study the impact of EDCs on adipose biology. In this study, we screened human exposure-relevant doses of various EDCs on the SGBS cell line to investigate their effects on viability, lipid accumulation and adipogenesis-related protein expression. Submicromolar doses were generally well tolerated; however, at higher doses, EDCs compromised cell viability, with cadmium chloride (CdCl 2 ) showing the most pronounced effects. Intracellular lipid levels remained unaffected by EDCs, except for tributyltin (TBT), used as a positive control, which induced a significant increase. Analysis of adipogenesis-related protein expression revealed several effects, including downregulation of fatty acid-binding protein 4 (FABP4) by dibutyl phthalate, upregulation by CdCl 2 and downregulation of perilipin 1 and FABP4 by perfluorooctanoic acid. Additionally, TBT induced dose-dependent upregulation of C/EBPα, perilipin 1 and FABP4 protein expression. These findings underscore the importance of employing appropriate models to study EDC-adipocyte interactions. Conclusions from this research could guide strategies to reduce the negative impacts of EDC exposure on adipose tissue., (© 2024 The Author(s). Journal of Applied Toxicology published by John Wiley & Sons Ltd.)

The increasing interfacial impacts of polystyrene nanoplastics (PS) and per- and polyfluoroalkyl substances (PFAS) complex aquatic environments are becoming more evident, drawing attention to the potential risks to aquatic animal health and human seafood safety. This study aims to investigate the relative impacts following exposure (7 days) of Crassostrea hongkongensis oysters to the traditional PFAS congener, perfluorooctanoic acid (PFOA) at 50 μg/L, and its novel alternative, hexafluoropropylene oxide dimer acid (HFPO-DA), also known as GenX at 50 μg/L, in conjunction with fluorescent polystyrene nanoplastics (PS, 80 nm) at 1 mg/L. The research focuses on assessing the effects of combined exposure on oxidative stress responses and gut microbiota in the C. hongkongensis. Comparing the final results of PS + GenX (PG) and PS + PFOA (PF) groups, we observed bioaccumulation of PS in both groups, with the former causing more pronounced histopathological damage to the gills and intestines. Furthermore, the content of antioxidant enzymes induced by PG was higher than that of PF, including Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Reductase (GR) and Glutathione Peroxidase (GSH). Additionally, in both PG and PF groups, the expression levels of several immune-related genes were significantly upregulated, including tnfα, cat, stat, tlr-4, sod, and β-gbp, with no significant difference between these two groups (p > 0.05). Combined exposure induced significant changes in the gut microbiota of C. hongkongensis at its genus level, with a significant increase in Legionella and a notable decrease in Endozoicomonas and Lactococcus caused by PG. These shifts led to beneficial bacteria declining and pathogenic microbes increasing. Consequently, the microbial community structure might be disrupted. In summary, our findings contribute to a deeper understanding of the comparative toxicities of marine bivalves under combined exposure of traditional and alternative PFAS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

As part of the US Environmental Protection Agency's perfluoroalkyl and polyfluoroalkyl substances (PFAS) Action Plan, the agency is committed to increasing our understanding of the potential ecological effects of PFAS. The objective of these studies was to examine the developmental toxicity of PFAS using the laboratory model amphibian species Xenopus laevis. We had two primary aims: (1) to understand the developmental toxicity of a structurally diverse set of PFAS compounds in developing embryos and (2) to characterize the potential impacts of perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), and hexafluoropropylene oxide-dimer acid (HFPO-DA a.k.a. GenX), on growth and thyroid hormone-controlled metamorphosis. We employed a combination of static renewal and flow-through exposure designs. Embryos were exposed to 17 structurally diverse PFAS starting at the midblastula stage through the completion of organogenesis (96 h). To investigate impacts on PFOS, PFOA, PFHxS, and HFPO-DA on development and metamorphosis, larvae were exposed from premetamorphosis (Nieuwkoop Faber stage 51 or 54) through pro metamorphosis. Of the PFAS tested in embryos, only 1H,1H,10H,10H-perfluorodecane-1,10-diol (FC10-diol) and perfluorohexanesulfonamide (FHxSA) exposure resulted in clear concentration-dependent developmental toxicity. For both of these PFAS, a significant increase in mortality was observed at 2.5 and 5 mg/L. For FC10-diol, 100% of the surviving embryos were malformed at 1.25 and 2.5 mg/L, while for FHxSA, a significant increase in malformations (100%) was observed at 2.5 and 5 mg/L. Developmental stage achieved was the most sensitive endpoint with significant effects observed at 1.25 and 0.625 mg/L for FC10-diol and FHxSA, respectively. In larval studies, we observed impacts on growth following exposure to PFHxS and PFOS at concentrations of 100 and 2.5 mg/L, respectively, while no impacts were observed in larvae when exposed to PFOA and HFPO-DA at concentration of 100 mg/L. Further, we did not observe impacts on thyroid endpoints in exposed larvae. These experiments have broadened our understanding of the impact of PFAS on anuran development., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals that are resistant to biodegradation and are environmentally persistent. PFAS are found in many consumer products and are a major source of water and soil contamination. This study investigated the effects of an environmentally relevant PFAS mixture (perfluorooctanoic acid [PFOA], perfluorooctanesulfonic acid [PFOS], perfluorohexanesulfonic acid [PFHxS]) on the transcriptome and function of human granulosa cells (hGCs). Primary hGCs were harvested from follicular aspirates of healthy, reproductive-age women who were undergoing oocyte retrieval for in vitro fertilization. Liquid Chromatography with tandem mass spectrometry (LC/MS-MS) was performed to identify PFAS compounds in pure follicular fluid. Cells were cultured with vehicle control or a PFAS mixture (2 nM PFHxS, 7 nM PFOA, 10 nM PFOS) for 96 h. Analyses of cell proliferation/apoptosis, steroidogenesis, and gene expression were measured via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays/immunofluorescence, ELISA/western blotting, and RNA sequencing/bioinformatics, respectively. PFOA, PFOS, and PFHxS were detected in 100% of follicle fluid samples. Increased cell proliferation was observed in hGCs treated with the PFAS mixture with no impacts on cellular apoptosis. The PFAS mixture also altered steroid hormone synthesis, increasing both follicle-stimulating hormone-stimulated and basal progesterone secretion and concomitant upregulation of STAR protein. RNA sequencing revealed inherent differences in transcriptomic profiles in hGCs after PFAS exposure. This study demonstrates functional and transcriptomic changes in hGCs after exposure to a PFAS mixture, improving our knowledge about the impacts of PFAS exposures and female reproductive health. These findings suggest that PFAS compounds can disrupt normal granulosa cell function with possible long-term consequences on overall reproductive health., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Physiologically based kinetic (PBK) models are widely used in pharmacology and toxicology for predicting the internal disposition of substances upon exposure, voluntarily or not. Due to their complexity, a large number of model parameters need to be estimated, either through in silico tools, in vitro experiments, or by fitting the model to in vivo data. In the latter case, fitting complex structural models on in vivo data can result in overparameterization and produce unrealistic parameter estimates. To address these issues, we propose a novel parameter grouping approach, which reduces the parametric space by co-estimating groups of parameters across compartments. Grouping of parameters is performed using genetic algorithms and is fully automated, based on a novel goodness-of-fit metric. To illustrate the practical application of the proposed methodology, two case studies were conducted. The first case study demonstrates the development of a new PBK model, while the second focuses on model refinement. In the first case study, a PBK model was developed to elucidate the biodistribution of titanium dioxide (TiO2) nanoparticles in rats following intravenous injection. A variety of parameter estimation schemes were employed. Comparative analysis based on goodness-of-fit metrics demonstrated that the proposed methodology yields models that outperform standard estimation approaches, while utilizing a reduced number of parameters. In the second case study, an existing PBK model for perfluorooctanoic acid (PFOA) in rats was extended to incorporate additional tissues, providing a more comprehensive portrayal of PFOA biodistribution. Both models were validated through independent in vivo studies to ensure their reliability., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology.)

As a widely used alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been detected in the environment and humans; however, little is known regarding its male reproductive toxicity. To compare the effects of HFPO-TA on steroid hormone synthesis with PFOA, we exposed Leydig cells (MLTC-1) to non-lethal doses (0.1, 1, and 10 μM) of PFOA and HFPO-TA for 48 h. It was found that the levels of steroid hormones, 17α-hydroxyprogesterone (OHP), androstenedione (ASD), and testosterone (T) were significantly increased in 1 and 10 μM of PFOA and HFPO-TA groups, with greater elevation being observed in the HFPO-TA groups than in the PFOA groups at 10 μM. We further showed that the two rate-limiting steroidogenic genes (Star and Cyp11a1) were up-regulated, while Hsd3b, Cyp17a1, and Hsd17b were down-regulated or unchanged after PFOA/HFPO-TA exposure. Moreover, PFOA exposure significantly up-regulated histone H3K4me1/3 and H3K9me1, while down-regulated H3K4me2 and H3K9me2/3 levels. By contrast, H3K4me2/3 and H3K9me2/3 were enhanced, while H3K4me1 and H3K9me1 were repressed after HFPO-TA treatment. It was further confirmed that H3K4me1/3 were increased and H3K9me2 was decreased in Star and Cyp11a1 promoters by PFOA, while HFPO-TA increased H3K4me2/3 and decreased H3K9me1 in the two gene promoters. Therefore, we propose that low levels of PFOA/HFPO-TA enhance the expression of Star and Cyp11a1 by regulating H3K4 and H3K9 methylation, thus stimulating the production of steroid hormones in MLTC-1 cells. Collectively, HFPO-TA exhibits stronger effects on steroidogenesis compared to PFOA, which may be ascribed to the distinct regulation of histone modifications. These data suggest that HFPO-TA does not appear to be a safer alternative to PFOA on the aspect of male reproductive toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Perfluorooctanoic acid (PFOA), which widely presents in marine environment, may produce some adverse effects to aquatic organism. Mytilus edulis are popular due to their high protein and low fat content in China. However, few studies have investigated the effects of PFOA on the quality of aquatic products. Here, PFOA effects on basic nutritional indices in M. edulis were measured, and possible mechanisms were explored. PFOA caused clear variation in physiological and biochemical indices of M. edulis. The contents of some important proteins, nutrients, and amino acids etc. dropped. Integrating metabolomics data, we speculate PFOA exposure triggered inflammation and oxidative stress in mussels, interfered with the metabolic pathways related to the quality and the transport and absorption pathways of metal ions, and affected the levels of some important elements and metabolites, thus decreasing the nutritional quality of M. edulis. The study provides new insights into PFOA adverse effects to marine organism, and may offer some references for some researchers to assess food quality and ecological risk to pollutants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Perfluorooctanoic acid (PFOA) and atrazine are two endocrine disruptors that are widely found in waters. Negative effects of PFOA and atrazine have been studied individually, but few data have focused on their combined effects. Here, zebrafish embryos were used as model to investigate the combined toxicity of PFOA and atrazine. The acute toxicity of atrazine (11.9 mg/L) to zebrafish embryos was much higher than that of perfluorooctanoic acid (224.6 mg/L) as shown by the 120h-LC 50 value. Developmental effects, including delayed yolk sac absorption, spinal curvature, and liver abnormalities, were observed in both one- and two-component exposures. Notably, the rate of embryonic malformations in the co-exposure group was more than twice as high as that of single component exposure in the concentration range of 1/8-1/2 EC 50 , which indicated a synergistic effect of the binary mixture. The synergistic effect of PFOA-atrazine was further validated by combinatorial index (CI) modeling. In addition, changes of amino acid metabolites, reactive oxygen species and superoxide dismutase indicated that oxidative stress might be the main pathway for enhanced toxicity under co-exposure condition. Overall, co-exposure of PFOA and atrazine resulted in stronger developmental effects and more complicated amino acid metabolic response toward zebrafish, compared with single component exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10 -8 M to 4 × 10 -7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Per- and polyfluoroalkyl substances (PFAS) have already drawn a lot of attention for their accumulation and reproductive toxicity in organisms. Perfluorooctanoic acid (PFOA) and perfluorooctanoic sulfonate (PFOS), two representative PFAS, are toxic to humans and animals. Due to their widespread use in environmental media with multiple toxicities, PFOA and PFOS have been banned in numerous countries, and many substitutes have been produced to meet market requirements. Unfortunately, most alternatives to PFOA and PFOS have proven to be cumulative and highly toxic. Of the reported multiple organ toxicities, reproductive toxicity deserves special attention. It has been confirmed through epidemiological studies that PFOS and PFOA are not only associated with reduced testosterone levels in humans, but also with an association with damage to the integrity of the blood testicular barrier. In addition, for women, PFOA and PFOS are correlated with abnormal sex hormone levels, and increase the risk of infertility and abnormal menstrual cycle. Nevertheless, there is controversial evidence on the epidemiological relationship that exists between PFOA and PFOS as well as sperm quality and reproductive hormones, while the evidence from animal studies is relatively consistent. Based on the published papers, the potential toxicity mechanisms for PFOA, PFOS and their substitutes were reviewed. For males, PFOA and PFOS may produce reproductive toxicity in the following five ways: (1) Apoptosis and autophagy in spermatogenic cells; (2) Apoptosis and differentiation disorders of Leydig cells; (3) Oxidative stress in sperm and disturbance of Ca 2+ channels in sperm membrane; (4) Degradation of delicate intercellular junctions between Sertoli cells; (5) Activation of brain nuclei and shift of hypothalamic metabolome. For females, PFOA and PFOS may produce reproductive toxicity in the following five ways: (1) Damage to oocytes through oxidative stress; (2) Inhibition of corpus luteum function; (3) Inhibition of steroid hormone synthesis; (4) Damage to follicles by affecting gap junction intercellular communication (GJIC); (5) Inhibition of placental function. Besides, PFAS substitutes show similar reproductive toxicity with PFOA and PFOS, and are even more toxic to the placenta. Finally, based on the existing knowledge, future developments and direction of efforts in this field are suggested., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Perfluorooctanoate (PFOA) is widely used as a surfactant and has metabolic, immunologic, developmental, and genetic toxicity on marine organisms. However, the effects of PFOA on individual defense functions in mussels in the presence of titanium dioxide nanoparticles (nano-TiO 2 ) are poorly understood. To investigate the defense strategies and regulatory mechanisms of mussels under combined stressors, the thick-shell mussels Mytilus coruscus were exposed to different PFOA concentrations (0, 2 and 200 μg/L) and nano-TiO 2 (0 and 0.1 mg /L, size: 25 nm) for 14 days. The results showed that, compared to the control group, PFOA and nano-TiO 2 significantly reduced the number of byssal threads (NBT), byssal threads length (BTL), diameter of proximal threads (DPB), diameter of middle threads (DMB), diameter of distal byssal threads (DDB), adhesive plaque area (BPA), and breaking force of byssal threads (N). Under the influence of PFOA and nano-TiO 2 , the morphological surface smoothness of the fractured byssal threads surface increased, concurrently inducing an increased surface roughness in the adhesive plaques. Additionally, under the presence of PFOA and nano-TiO 2 , the foot displayed dispersed tissue organization and damaged villi, accompanied by an increased incidence of cellular apoptosis and an upregulation of the apoptosis gene caspase-8. Expression of the adhesion gene mfp-3 and byssal threads strength genes (preCOL-D, preCOL-NG) was upregulated. An interactive effect on the performance of byssal threads is observed under the combined influence of PFOA and nano-TiO 2 . Under co-exposure to PFOA and nano-TiO 2 , the performance of the byssal threads deteriorates, the foot structure is impaired, and the genes mRNA expression of byssal thread secretory proteins have compensated for the adhesion and byssal threads strength by up-regulation. Within marine ecosystems, organic and particulate contaminants exert a pronounced effect on the essential life processes of individual organisms, thereby jeopardizing their ecological niche within community assemblages and perturbing the dynamic equilibrium of the overarching ecosystem. ENVIRONMENTAL IMPLICATION: Perfluorooctanoic acid (PFOA) is prone to accumulate in marine organisms. TiO 2 nanoparticles (nano-TiO 2 ) are emerging environmental pollutants frequently found in marine environment. The effects of PFOA and nano-TiO 2 on marine mussels are not well understood, and their toxic mechanisms remain largely unknown. We investigated the impacts of PFOA and nano-TiO 2 on mussel byssus defense mechanisms. By assessing byssus performance indicators, morphological structures of the byssus, subcellular localization, and changes in byssal secretion-related genes, we revealed the combined effects and mechanisms through which these two types of pollutants may affect the functional capabilities and survival of mussels in the complex marine ecosystem., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Poly- and perfluoroalkyl substances (PFAS) are a group of compounds with uses in industry and many consumer products. Concerns about the potential health effects of these compounds resulted in regulation by the Stockholm Convention on the use of three of the most common PFAS, including perfluorooctanoic acid (PFOA). Thousands of PFAS remain in production that are unregulated and for which their toxicity is unknown. Our group recently identified a new class of PFAS, fluorotelomer ethoxylates (FTEOs), in indoor dust and industrial wastewater. In this study, we investigated the effect of PFAS on placental metabolism by exposing healthy, pregnant CD-1 mice to PFOA or FTEOs at one of three concentrations (0 ng/L (controls), 5 ng/L, 100 ng/L) (n = 7-8/group). While PFOA is banned and PFOA concentrations in human blood are decreasing, we hypothesize that FTEOs will cause adverse pregnancy outcomes similar to PFOA, the compounds they were meant to replace. Placental tissue samples were collected at embryonic day 17.5 and 1 H solid-state magic angle spinning nuclear magnetic resonance spectroscopy was used to determine the relative concentration of placental metabolites (n = 18-20/group). At the highest concentration, the relative concentrations of glucose and threonine were increased and the relative concentration of creatine was decreased in the PFOA-exposed placentas compared to controls (p < 0.05). In contrast, the relative concentrations of asparagine and lysine were decreased and the relative concentration of creatine was increased in the FTEOs-exposed placentas compared to controls (p < 0.05). Partial least squares - discriminant analysis showed the FTEOs-exposed and control groups were significantly separated (p < 0.005) and pathway analysis found four biochemical pathways were perturbed following PFOA exposure, while one pathway was altered following FTEOs exposure. Maternal exposure to PFOA and FTEOs had a significant impact on the placental metabolome, with the effect depending on the pollutant. This work motivates further studies to determine exposure levels and evaluate associations with adverse outcomes in human pregnancies., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Exposure to environmental pollutants is suspected to be one of the potential causes accounting for the increase in thyroid cancer (TC) incidence worldwide. Among the ubiquitous pollutants, per-polyfluoroalkyl substances (PFASs), were demonstrated to exert thyroid disrupting effects. Perfluoroalkyl carboxylates (PFCAs) represent a subgroup of PFAS and include perfluoro carboxylic acids (PFOA and PFHxA) and perfluoropolyether carboxylic acid (C6O4). The potential relationship between exposure to PFCAs and TC was not yet fully elucidated. This in vitro study investigated whether certain PFCAs (C6O4, PFOA, and PFHxA) can influence the composition of TC microenvironment., Methods: Two models of normal thyroid cells in primary cultures: Adherent (A-NHT) and Spheroids (S-NHT) were employed. A-NHT and S-NHT were exposed to C6O4, PFOA or PFHxA (0; 0.01; 0.1, 1; 10; 100; 1000 ng/mL) to assess viability (WST-1 and AV/PI assay), evaluate spherification index (SI) and volume specifically in S-NHT. CXCL8 and CCL2 (mRNA and protein), and EMT-related genes were assessed in both models after exposure to PFCAs., Results: PFHxA reduced the viability of both A-NHT and S-NHT. None of the PFCAs interfered with the volume or spherification process in S-NHT. CXCL8 and CCL2 mRNA and protein levels were differently up-regulated by each PFCAs, being PFOA and PFHxA the stronger inducers. Moreover, among the tested PFCAs, PFHxA induced a more consistent increase in the mRNA levels of EMT-related genes., Conclusions: This is the first evaluation of the effects of exposure to PFCAs on factors potentially involved in establishing the TC microenvironment. PFHxA modulated the TC microenvironment at three levels: cell viability, pro-tumorigenic chemokines, and EMT-genes. The results provide further evidence of the pro-tumorigenic effect of PFOA. On the other hand, a marginal effect was observed for C6O4 on pro-tumorigenic chemokines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This research was supported by Solvay Specialty Polymers Italy S.p.A. The commissioning partly funded the consumables and personnel used in this study. The funder had no role in planning or executing the research, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Exposing marine organisms to contemporary contaminants, such as perfluorooctanoic acid (PFOA) and nano-titanium dioxide (nano-TiO 2 ), can induce multifaceted physiological consequences. Our investigation centered on the responses of the mussel, Mytilus coruscus, to these agents. We discerned pronounced disruptions in gill filament connections, pivotal structures for aquatic respiration, suggesting compromised oxygen uptake capabilities. Concurrently, the respiratory rate exhibited a marked decline, indicating a respiratory distress. Furthermore, the mussels' clearance rate, a metric of their filtration efficacy, diminished, suggesting the potential for bioaccumulation of deleterious substances. Notably, the co-exposure of PFOA and nano-TiO 2 exhibits interactive effects on the physiological performance of the mussels. The mussels' digestive performance waned in the face of heightened PFOA and nano-TiO 2 concentrations, possibly hampering nutrient assimilation and energy accrual. This was mirrored in the noticeable contraction of their energy budget, suggesting long-term growth repercussions. Additionally, the dysregulation of the gut microbiota and the reduction in its diversity further confirm alterations in intestinal homeostasis, subsequently impacting its physiological functions and health. Collectively, these findings underscore the perils posed by escalated PFOA and nano-TiO 2 levels to marine mussels, accentuating the need for a deeper understanding of nanoparticle-pollutant synergies in marine ecosystems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Poly- and perfluoroalkyl substances (PFAS) are frequently detected in the environment and are linked to adverse reproductive health outcomes in humans. Although legacy PFAS have been phased out due to their toxicity, alternative PFAS are increasingly used despite the fact that information on their toxic effects on reproductive traits is particularly scarce. Here, we exposed male guppies (Poecilia reticulata) for a short period (21 days) to an environmentally realistic concentration (1 ppb) of PFOA, a legacy PFAS, and its replacement compound, GenX, to assess their impact on reproductive traits and gene expression. Exposure to PFAS did not impair survival but instead caused sublethal effects. Overall, PFAS exposure caused changes in male sexual behaviour and had detrimental effects on sperm motility. Sublethal variations were also seen at the transcriptional level, with the modulation of genes involved in immune regulation, spermatogenesis, and oxidative stress. We also observed bioaccumulation of PFAS, which was higher for PFOA than for GenX. Our results offer a comprehensive comparison of these two PFAS and shed light on the toxicity of a newly emerging alternative to legacy PFAS. It is therefore evident that even at low concentrations and with short exposure, PFAS can have subtle yet significant effects on behaviour, fertility, and immunity. These findings underscore the potential ramifications of pollution under natural conditions and their impact on fish populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Considering that the PFOA and PFOS are widely spread chemicals with harmful effects in human and environmental health as well as the increasing interest of the scientific community in the implications that might present especially when they co-exist, this study aims to assess their harmful impacts, both individually and as a mixture on human lymphocytes and aquatic microorganisms. The cytokinesis-block micronucleus (CBMN) assay was used to examine their potential for cytotoxicity and genotoxicity towards human cells, and Microtox assay using Aliivibrio fischeri assay was used to estimate the environmental risk. Regarding the human lymphocytes, the tested concentrations ranged between 250 and 1000 μg L -1 , for all cases. PFOA increased slightly the frequency of micronuclei (MN) but without statistical significance. In the case of PFOS, our results showed a dose-dependent increase in the frequency of micronuclei which showed a statistically significant difference (p < 0.001) at 1000 μg L -1 , which is the highest studied concentration. Regarding the CBPI index, statistically significant (p < 0.05, p < 0.01, and p < 0.001 respectively) differences were observed at all studied concentrations of PFOS, compared to the control. The mixture was found to be more cytotoxic and genotoxic than the individual tested compounds, causing a higher decrease at the CBPI index even in lower concentrations and increase at the MN frequencies. Aliivibrio fischeri was exposed to various concentrations in the range of 0.5 μg L -1 - 20 mg L -1 , for 5 and 15 min and significant increase in the inhibition percentage at the highest tested concentration of their mixture after 15 min was observed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background : Exposure to environmental pollutants such as metals and Per- and Polyfluoroalkyl Substances (PFAS) has become common and increasingly associated with a decrease in the estimated Glomerular Filtration Rate (eGFR), which is a marker often used to measure chronic kidney disease (CKD). However, there are limited studies involving the use of both eGFR and the urine albumin creatinine ratio (uACR), which are more comprehensive markers to determine the presence of CKD and the complexity of pollutant exposures and response interactions, especially for combined metals and PFAS, which has not been comprehensively elucidated. Objective : This study aims to assess the individual and combined effects of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), Cadmium (Cd), Mercury (Hg), and Lead (Pb) exposure on CKD using data from the National Health and Nutritional Examination Survey (NHANES) 2017-2018. Methods : We employed the use of bivariate logistic regression and Bayesian Kernel Machine Regression (BKMR) in our analysis of the data. Results : Logistic regression results revealed a positive association between PFOA and CKD. Our BKMR analysis revealed a non-linear and bi-phasic relationship between the metal exposures and CKD. In our univariate exposure-response function plot, Cd and Hg exhibited a U and N-shaped interaction, which indicated a non-linear and non-additive relationship with both low and high exposures associated with CKD. In addition, the bivariate exposure-response function between two exposures in a mixture revealed that Cd had a U-shaped relationship with CKD at different quantiles of Pb, Hg, PFOA, and PFOS, indicating that both low and high levels of Cd is associated with CKD, implying a non-linear and complex biological interaction. Hg's interaction plot demonstrated a N-shaped association across all quantiles of Cd, with the 75th quantile of Pb and the 50th and 75th quantiles of PFOA and PFOS. Furthermore, the PIP results underscored Cd's consistent association with CKD (PIP = 1.000) followed by Hg's (PIP = 0.9984), then PFOA and PFOS with a closely related PIP of 0.7880 and 0.7604, respectively, and finally Pb (PIP = 0.6940), contributing the least among the five environmental pollutants on CKD, though significant. Conclusions : Our findings revealed that exposure to environmental pollutants, particularly Hg and Cd, are associated with CKD. These findings highlight the need for public health interventions and strategies to mitigate the cumulative effect of PFAS and metal exposure and elucidate the significance of utilizing advanced statistical methods and tools to understand the impact of environmental pollutants on human health. Further research is needed to understand the mechanistic pathways of PFAS and metal-induced kidney injury and CKD, and longitudinal studies are required to ascertain the long-term impact of these environmental exposures.