Triclosan administration to humanized UDP-glucuronosyltransferase 1 neonatal mice induces UGT1A1 through a dependence on PPARα and ATF4.

Triclosan (TCS) is an antimicrobial toxicant found in a myriad of consumer products and has been detected in human tissues, including breastmilk. We have evaluated the impact of lactational TCS on UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and bilirubin metabolism in humanized UGT1 (hUGT1) neonatal mice. In hUGT1 mice, expression of the hepatic UGT1A1 gene is developmentally delayed resulting in elevated total serum bilirubin (TSB) levels. We found that newborn hUGT1 mice breastfed or orally treated with TCS presented lower TSB levels along with induction of hepatic UGT1A1. Lactational and oral treatment by gavage with TCS leads to the activation of hepatic nuclear receptors constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor alpha (PPARα), and stress sensor, activating transcription factor 4 (ATF4). When CAR-deficient hUGT1 mice (hUGT1/Car-/-) were treated with TCS, TSB levels were reduced with a robust induction of hepatic UGT1A1, leaving us to conclude that CAR is not tied to UGT1A1 induction. Alternatively, when PPARα-deficient hUGT1 mice (hUGT1/Pparα-/-) were treated with TCS, hepatic UGT1A1 was not induced. Additionally, we had previously demonstrated that TCS is a potent inducer of ATF4, a transcriptional factor linked to the integrated stress response. When ATF4 was deleted in liver of hUGT1 mice (hUGT1/Atf4ΔHep) and these mice treated with TCS, we observed superinduction of hepatic UGT1A1. Oxidative stress genes in livers of hUGT1/Atf4ΔHep treated with TCS were increased, suggesting that ATF4 protects liver from excessive oxidative stress. The increase oxidative stress may be associated with superinduction of UGT1A1. The expression of ATF4 in neonatal hUGT1 hepatic tissue may play a role in the developmental repression of UGT1A1.

Wastewater contaminants in a fractured bedrock aquifer and their potential use as enteric virus indicators.

Domestic wastewater is a source of persistent organic pollutants and pathogens to the aquatic environment, including groundwater aquifers. Wastewater contaminants include a variety of personal care products, pharmaceuticals, endocrine disrupters, bacteria, and viruses. Groundwater from 22 wells completed in a semi-confined to confined, fractured Silurian dolostone aquifer in southern Wellington County, Ontario, Canada, was analyzed for 14 organic wastewater contaminants (4 artificial sweeteners, 10 pharmaceuticals) as well as E. coli, total coliforms, and 6 human enteric viruses. Enteric viruses were detected in 8.6% of 116 samples, and at least one organic wastewater contaminant was detected in 82% of the wells (in order of decreasing detection frequency: acesulfame, ibuprofen, sulfamethoxazole, triclosan, carbamazepine, and saccharin). Virus indicator metrics [positive and negative predictive values (PPV, NPV), sensitivity, specificity] were calculated at the sample and well level for the organic wastewater compounds, E. coli, and total coliforms. Fecal bacteria were not good predictors of virus presence (PPV = 0%-8%). Of the potential chemical indicators, triclosan performed the best at the sample level (PPV = 50%, NPV = 100%), and ibuprofen performed the best at the well level (PPV = 60%, NPV = 67%); however, no samples had triclosan or ibuprofen concentrations above their practical quantification limits. Therefore, none of the compounds performed sufficiently well to be considered reliable for assessing the potential threat of enteric viruses in wastewater-impacted groundwater in this bedrock aquifer. Future studies need to evaluate the indicator potential of persistent organic wastewater contaminants in different types of aquifers, especially in fractured rock where heterogeneity is strong.IMPORTANCEAssessing the potential risk that human enteric viruses pose in groundwater aquifers used for potable water supply is complicated by several factors, including: (i) labor-intensive methods for the isolation and quantification of viruses in groundwater, (ii) the temporal variability of these viruses in domestic wastewater, and (iii) their potentially rapid transport in the subsurface, especially in fractured rock aquifers. Therefore, aquifer risk assessment would benefit from the identification of suitable proxy indicators of enteric viruses that are easier to analyze and less variable in wastewater sources. Traditional fecal indicators (e.g., E. coli and coliforms) are generally poor indicators of enteric viruses in groundwater. While many studies have examined the use of pharmaceutical and personal care products as tracers of domestic wastewater and fecal pollution in the environment, there is a paucity of data on the potential use of these chemical tracers as enteric virus indicators, especially in groundwater.

Citral and triclosan synergistically silence quorum sensing and potentiate antivirulence response in Pseudomonas aeruginosa.

Among the ESKAPE pathogens, Pseudomonas aeruginosa is an extensively notorious superbug that causes difficult-to-treat infections. Since quorum sensing (QS) directly promotes pseudomonal virulence, targeting QS circuits is a promising approach for disarming phenotypic virulence. Hence, this study scrutinizes the anti-QS, antivirulence, and anti-biofilm potential of citral (CiT; phytochemical) and triclosan (TcN; disinfectant), alone and in combination, against P. aeruginosa PAO1/PA14. The findings confirmed synergism between CiT and TcN and revealed their quorum quenching (QQ) potential. At sub-inhibitory levels, CiT-TcN combination significantly impeded pyocyanin, total bacterial protease, hemolysin, and pyochelin production alongside inhibiting biofilm formation in P. aeruginosa. Moreover, the QQ and antivirulence potential of CiT and TcN was positively correlated by molecular docking studies that predicted strong associations of the drugs with QS receptors of P. aeruginosa. Collectively, the study identifies CiT-TcN as an effective drug combination that harbors QQ, antivirulence, and anti-biofilm prospects against P. aeruginosa.

A Unique Monitoring Method for Fecal and Sewage-Derived Chemical Pollution Utilizing International Pellet Watch Approach.

This study established a unique approach to assess fecal contamination by measuring fecal sterols, especially coprostanol (5ß-cholestanol-3ß-ol, 5ß) and cholestanol (5α-cholestan-3ß-ol, 5α) and their ratio 5ß/(5ß + 5α) alongside triclosan (TCS) and methyl-triclosan (MTC) in beached plastic pellets across 40 countries. Coprostanol concentrations ranged from 3.6 to 8190 ng/g pellet with extremely high levels in densely populated areas in African countries. The 5ß/(5ß + 5α) ratio was not affected by the difference in residence time of pellets in aquatic environments, and their spatial pattern showed a positive correlation with that of sedimentary sterols, demonstrating its reliability as an indicator of fecal contamination. Pellets from populated areas of economically developing countries, i.e., Africa and Asia, with lower coverage of wastewater treatment exhibited higher 5ß/(5ß + 5α) ratios (∼0.7) corresponding to ∼1% sewage in seawater, while pellets from developed countries, i.e., the USA, Canada, Japan, and Europe, with higher coverage of modern wastewater treatment displayed lower ratios (∼0.5), corresponding to the first contact limit. Triclosan levels were higher in developing countries (0.4-1298 ng/g pellet), whereas developed countries showed higher methyl-triclosan levels (0.5-70 ng/g pellet) due to TCS conversion during secondary treatment. However, some samples from Japan and Europe displayed higher TCS levels, suggesting contributions from combined sewage overflow (CSO). Combination of 5ß/(5ß + 5α) and MTC/TCS ratios revealed extreme fecal contamination from direct input of raw sewage due to inadequate treatment facilities in some African and South and Southeast Asian countries.

Assessing silver nanoparticle and antimicrobial combinations for antibacterial activity and biofilm prevention on surgical sutures.

AIMS: To evaluate the effect of silver nanoparticles alone and in combination with Triclosan, and trans-cinnamaldehyde against Staphylococcus aureus and Escherichia coli biofilms on sutures to improve patients' outcomes. METHODS AND RESULTS: Silver nanoparticles were prepared by chemical method and characterized by UV-visible spectrophotometer and dynamic light scattering. The minimum inhibitory concentration was assessed by the Microdilution assay. The antibiofilm activity was determined using crystal violet assay. A checkerboard assay using the fractional inhibitory concentration index and time-kill curve was used to investigate the synergistic effect of silver nanoparticle combinations. The hemolytic activity was determined using an erythrocyte hemolytic assay. Our results revealed that silver nanoparticles, Triclosan, and trans-cinnamaldehyde (TCA) inhibited S.aureus and E.coli biofilms. Silver nanoparticles with TCA showed a synergistic effect (FICI values 0.35 and 0.45 against S. aureus and E. coli biofilms, respectively), and silver nanoparticles with Triclosan showed complete inhibition of S. aureus biofilm. The hemolytic activity was <2.50% for the combinations.

The first-in-class pyrazole-based dual InhA-VEGFR inhibitors towards integrated antitubercular host-directed therapy.

Several facets of the host response to tuberculosis have been tapped for clinical investigation, especially targeting angiogenesis mediated by VEGF signaling from infected macrophages. Herein, we rationalized combining the antiangiogenic effects of VEGFR-2 blockade with direct antitubercular InhA inhibition in single hybrid dual inhibitors as advantageous alternatives to the multidrug regimens. Inspired by expanded triclosans, the ether ligation of triclosan was replaced by rationalized linkers to assemble the VEGFR-2 inhibitors thematic scaffold. Accordingly, new series of 3-(p-chlorophenyl)-1-phenylpyrazole derivatives tethered to substituted ureas and their isosteres were synthesized, evaluated against Mycobacterium tuberculosis virulent cell line H37Rv, and assessed for their InhA inhibitory activities. The urea derivatives 8d and 8g exhibited the most promising antitubercular activity (MIC = 6.25 µg/mL) surpassing triclosan (MIC = 20 µg/mL) with potential InhA inhibition, thus identified as the study hits. Interestingly, both compounds inhibited VEGFR-2 at nanomolar IC50 (15.27 and 24.12 nM, respectively). Docking and molecular dynamics simulations presumed that 8d and 8g could bind to their molecular targets InhA and VEGFR-2 posing essential stable interactions shared by the reference inhibitors triclosan and sorafenib. Finally, practical LogP, Lipinski's parameters and in silico ADMET calculations highlighted their drug-likeness as novel leads in the arsenal against TB.

Efficient removal of triclosan from water through activated carbon adsorption and photodegradation processes.

This study investigated the application of adsorption with activated carbons (ACs) and photodegradation to reduce the concentration of triclosan (TCS) in aqueous solutions. Concerning adsorption, ACs (Darco, Norit, and F400) were characterised and batch experiments were performed to elucidate the effect of pH on equilibrium. The results showed that at pH = 7, the maximum adsorption capacity of TCS onto the ACs was 18.5 mg g-1 for Darco, 16.0 mg g-1 for Norit, and 15.5 mg g-1 for F400. The diffusional kinetic model allowed an adequate interpretation of the experimental data. The effective diffusivity varied and increased with the amount of TCS adsorbed, from 1.06 to 1.68 × 10-8 cm2 s-1. In the case of photodegradation, it was possible to ensure that the triclosan molecule was sensitive to UV light of 254 nm because the removal was over 80 % using UV light. The removal of TCS increased in the presence of sulfate radicals. It was possible to identify 2,4-dichlorophenol as one of the photolytic degradation products of triclosan, which does not represent an environmental hazard at low concentrations of triclosan in water. These results confirm that the use of AC Darco, Norit, and F400 and that photodegradation processes with UV light and persulfate radicals are effective in removing TCS from water, reaching concentration levels that do not constitute a risk to human health or environmental hazard. Both methods effectively eliminate pollutants with relatively easy techniques to implement.

Triclosan disturbs nitrogen removal in constructed wetlands: Responses of microbial structure and functions.

This study investigated the influence of wetland types (vertical and tidal flow constructed wetlands [CWs] [VFCW and TFCW, respectively]) and concentrations of triclosan (TCS) on the removal of pollutants (TCS and nitrogen) and microbial characteristics. The efficiency of TCS removal was significantly higher with 5 µg/L TCS (Phase B) than with 30 µg/L (Phase C) in the two CWs. The efficiencies of removal of NH4+-N and NO3--N were significantly inhibited in Phase C. Compared with the VFCW, the TFCW removed more NH4+-N at the same concentration of TCS, whereas less NO3--N was removed, and it even accumulated. Saccharimondales, an important functional genus with the highest abundance and more node connections with other genera, had a sharp decrease in relative abundance as the increasing concentrations of TCS of the two CWs conformed with its relative abundance and significantly negatively correlated with the concentration of TCS. Differentiated Roseobacter_Clade_CHAB-I-5_Lineage and Sphaerotilus were enriched in the VFCW and TFCW, respectively. The abundance of enzymes that catalyzed nitritation was significantly inhibited by TCS, whereas nitrate reductase (EC 1.7.99.4) catalyzed both denitrification and dissimilatory nitrate reduction to ammonium (DNRA), and nitrite reductase (NADH) (EC 1.7.1.15) that catalyzed DNRA comprised a larger proportion in the two CWs. Simultaneously, the abundances of two enzymes were higher in the TFCW than in the VFCW. The network analysis indicated that the main genera were promoted more by TCS in the VFCW, while inhibited in the TFCW. Moreover, the concentrations of nitrogen (NH4+-N, NO3--N, and TN) significantly positively correlated with TCS-resistant bacteria, and negatively correlated with most nitrogen-transforming bacteria with species that varied between the VFCW and TFCW. The results of this study provide a reference for the molecular biological mechanism of the simultaneous removal of nitrogen and TCS in the CWs.

Current state of knowledge of triclosan (TCS)-dependent reactive oxygen species (ROS) production.

Triclosan (TCS) is widely used in a number of industrial and personal care products. This molecule can induce reactive oxygen species (ROS) production in various cell types, which results in diverse types of cell responses. Therefore, the aim of the present study was to summarize the current state of knowledge of TCS-dependent ROS production and the influence of TCS on antioxidant enzymes and pathways. To date, the TCS mechanism of action has been widely investigated in non-mammalian organisms that may be exposed to contaminated water and soil, but there are also in vivo and in vitro studies on plants, algae, mammalians, and humans. This literature review has revealed that mammalian organisms are more resistant to TCS than non-mammalian organisms and, to obtain a toxic effect, the effective TCS dose must be significantly higher. The TCS-dependent increase in the ROS level causes damage to DNA, protein, and lipids, which together with general oxidative stress leads to cell apoptosis or necrosis and, in the case of cancer cells, faster oncogenesis and even initiation of oncogenic transformation in normal human cells. The review presents the direct and indirect TCS action through different receptor pathways.

Two-year dermal carcinogenicity bioassay of triclosan in B6C3F1 mice.

Triclosan is a widely used antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Due to its extensive use, there is potential for humans in all age groups to receive lifetime exposures to triclosan, yet data on the chronic dermal toxicity/carcinogenicity of triclosan are still lacking. We evaluated the toxicity/carcinogenicity of triclosan administered dermally to B6C3F1 mice for 104 weeks. Groups of 48 male and 48 female B6C3F1 mice received dermal applications of 0, 1.25, 2.7, 5.8, or 12.5 mg triclosan/kg body weight (bw)/day in 95% ethanol, 7 days/week for 104 weeks. Vehicle control animals received 95% ethanol only; untreated, naïve control mice did not receive any treatment. There were no significant differences in survival among the groups. The highest dose of triclosan significantly decreased the body weight of mice in both sexes, but the decrease was ≤ 9%. Minimal-to-mild epidermal hyperplasia, suppurative inflammation (males only), and ulceration (males only) were observed at the application site in the treated groups, with the highest incidence occurring in the 12.5 mg triclosan/kg bw/day group. No tumors were identified at the application site. Female mice had a positive trend in the incidence of pancreatic islet adenoma. In male mice, there were positive trends in the incidences of hepatocellular carcinoma and hepatocellular adenoma or carcinoma (combined), with the increase of carcinoma being significant in the 5.8 and 12.5 mg/kg/day groups and the increase in hepatocellular adenoma or carcinoma (combined) being significant in the 2.7, 5.8, and 12.5 mg/kg/day groups.

Interleukin 1ß and interleukin 6 production in human immune cells is stimulated by the antibacterial compound Triclosan.

Triclosan (TCS) is an antimicrobial compound widely used in personal hygiene products such as mouthwash and toothpaste; and has been found in human blood, breast milk, and urine. Interleukin (IL)-6 and IL-1 beta (IL-1ß) are pro-inflammatory cytokines regulating cell growth, tissue repair, and immune function; increased levels of each have been associated with many diseases, including cancer. Previous studies showed that TCS at concentrations between 0.05 and 5 µM consistently increased the secretion of IL-1ß and IL-6 from human immune cells within 24 h of exposure. The current study demonstrates that this increase in secretion was not due simply to release of existing stores but was due to an increase in cellular production/levels (both secreted and intracellular levels) of each of these cytokines. Production of IL-1ß and IL-6 was increased by exposure to one or more concentration of TCS at each length of exposure (10 min, 30 min, 6 h, and 24 h). TCS-induced stimulation of cytokine production was shown to be dependent on the mitogen-activated protein kinase (MAPK) p44/42 (ERK 1/2). It was also shown that these TCS-induced increases in IL-1ß and IL6 production were accompanied by increased mRNA for IL-1ß and IL-6. The ability of TCS to increase production indicates that rather than activating a self-limiting process of depleting cells of already existing stores of IL-1ß or IL-6, TCS can stimulate a process that has the capacity to provide sustained production of these cytokines and thus may lead to chronic inflammation and its pathological consequences.

Cholesterol mediates the effects of single and multiple environmental phenols in urine on obesity.

BACKGROUND: Overweight and obesity are among the leading chronic diseases worldwide. Environmental phenols have been renowned as endocrine disruptors that contribute to weight changes; however, the effects of exposure to mixed phenols on obesity are not well established. METHODS: Using data from adults in National Health and Nutrition Examination Survey, this study examined the individual and combined effects of four phenols on obesity. A combination of traditional logistic regression and two mixed models (weighted quantile sum (WQS) regression and Bayesian kernel-machine regression (BKMR)) were used together to assess the role of phenols in the development of obesity. The potential mediation of cholesterol on these effects was analyzed through a parallel mediation model. RESULTS: The results demonstrated that solitary phenols except triclosan were inversely associated with obesity (P-value < 0.05). The WQS index was also negatively correlated with general obesity (ß: 0.770, 95% CI: 0.644-0.919, P-value = 0.004) and abdominal obesity (ß: 0.781, 95% CI: 0.658-0.928, P-value = 0.004). Consistently, the BKMR model demonstrated the significant joint negative effects of phenols on obesity. The parallel mediation analysis revealed that high-density lipoprotein mediated the effects of all four single phenols on obesity, whereas low-density lipoprotein only mediated the association between benzophenol-3 and obesity. Moreover, Cholesterol acts as a mediator of the association between mixed phenols and obesity. Exposure to single and mixed phenols significantly and negatively correlated with obesity. Cholesterol mediated the association of single and mixed environmental phenols with obesity. CONCLUSIONS: Assessing the potential public health risks of mixed phenols helps to incorporate this information into practical health advice and guidance.

Ecotoxicological and human health risk assessment of triclosan antibacterial agent from municipal wastewater treatment plants.

In this study, the occurrence and environmental risks related to triclosan (TCS) in the two wastewater treatment plants (WWTPs) were investigated in Isfahan, Iran. Influent and effluent samples were collected and analyzed by dispersive liquid-liquid microextraction (DLLME)-GC-MS method with derivatization. Moreover, the risk of TCS exposure was conducted for aquatic organisms (algae, crustaceans, and fishes) and humans (males and females). TCS mean concentrations in influent and effluent of WWTPs were in the range of 3.70-52.99 and 0.83-1.09 µg/L, respectively. There were also no differences in the quantity of TCS and physicochemical parameters among the two WWTPs. The mean risk quotient (RQ) for TCS was higher than 1 (in algae) with dilution factors (DFs) equal to 1 in WWTP1. Moreover, the RQ value was higher than 1 for humans based on the reference dose of MDH (RFDMDH) in WWTP1. Furthermore, TCS concentration in wastewater effluent was the influential factor in varying the risk of TCS exposure. The results of the present study showed the risk of TCS exposure from the discharge of effluent of WWTP1 was higher than WWTP2. Moreover, the results of this study may be suitable for promoting WWTP processes to completely remove micropollutants.

In vitro cytocompatibility of triclosan coated Polyglactin910 sutures.

Bioabsorbable sutures can improve the medical functions of existing non-absorbable sutures, and may produce new medical effects, and are expected to become a new generation of medical degradable materials. In this study, the cytocompatibility of triclosan coated polyglactin910 sutures (CTS-PLGA910) was analyzed and different concentrations of sutures were prepared. The effects of sutures on the cytotoxicity and cell proliferation of HUVEC were studied by CCK-8 assay. The hemolysis, total antioxidant capacity (T-AOC) activity and nitric oxide (NO) content were investigated to improve the blood compatibility of sutures. The results showed that the hemolysis rate of CTS-PLGA910 was less than 5%. After treatment on HUVEC cells for 48 and 72 h, there was no significant change in NO content in CTS-PLGA910 groups compared with the control group, while T-AOC activity and antioxidant capacity were significantly increased in medium and high dose groups. In summary, the blood compatibility and cell compatibility were significantly improved, which provided a basis for the clinical application of sutures in the future.

Effects of chronic triclosan exposure on nephrotoxicity and gut microbiota dysbiosis in adult mice.

Triclosan (TCS), a broad-spectrum, lipophilic, and antibacterial agent, has been commonly used in cosmetics, medical devices, and household products. The toxicity of TCS has recently become a research hotspot. Emerging evidence has shown that TCS can easily migrate to humans and animals and cause adverse effects on various target organs. However, the effects of TCS exposure on nephrotoxicity and underlying mechanisms remain unknown. The aim of the present study was to explore TCS-induced nephrotoxicity. Therefore, we establish a mouse model based on adult male mice to explore the effects of 10-week TCS exposure (50 mg/kg) on kidney. After mice were sacrificed, their blood, feces, and renal tissues were harvested for further analysis. We found that TCS treatment dramatically caused kidney structural damage, and increased blood urea nitrogen (BUN) and creatinine (Cr) expression levels, which indicated renal dysfunction. In addition, TCS exposure increased the malondialdehyde (MDA) and decreased superoxide dismutase (SOD) and total cholesterol (TCHO) expression levels, which indicated oxidative stress and lipid metabolism changes. The RNA sequencing (RNA-seq) of kidney tissue identified 221 differentially expressed genes (DEGs) enriched in 50 pathways, including drug metabolism-other enzymes, oxidative phosphorylation, glutathione metabolism, and inflammatory mediator regulation of TRP channels signaling pathways. The full-length 16S rRNA gene sequencing results showed that TCS exposure altered the community of gut microbiota, which was closely related to renal function damage. The above findings provide new insights into the mechanism of TCS-induced nephrotoxicity.

Co-exposure to polystyrene nanoplastics and triclosan induces synergistic cytotoxicity in human KGN granulosa cells by promoting reactive oxygen species accumulation.

In recent years, nanoplastics (NPs) and triclosan (TCS, a pharmaceutical and personal care product) have emerged as environmental pollution issues, and their combined presence has raised widespread concern regarding potential risks to organisms. However, the combined toxicity and mechanisms of NPs and TCS remain unclear. In this study, we investigated the toxic effects of polystyrene NPs and TCS and their mechanisms on KGN cells, a human ovarian granulosa cell line. We exposed KGN cells to NPs (150 µg/mL) and TCS (15 µM) alone or together for 24 hours. Co-exposure significantly reduced cell viability. Compared with exposure to NPs or TCS alone, co-exposure increased reactive oxygen species (ROS) production. Interestingly, co-exposure to NPs and TCS produced synergistic effects. We examined the activity of superoxide dismutase (SOD) and catalase (CAT), two antioxidant enzymes; it was significantly decreased after co-exposure. We also noted an increase in the lipid oxidation product malondialdehyde (MDA) after co-exposure. Furthermore, co-exposure to NPs and TCS had a more detrimental effect on mitochondrial function than the individual treatments. Co-exposure activated the NRF2-KEAP1-HO-1 antioxidant stress pathway. Surprisingly, the expression of SESTRIN2, an antioxidant protein, was inhibited by co-exposure treatments. Co-exposure to NPs and TCS significantly increased the autophagy-related proteins LC3B-II and LC3B-Ⅰ and decreased P62. Moreover, co-exposure enhanced CASPASE-3 expression and inhibited the BCL-2/BAX ratio. In summary, our study revealed the synergistic toxic effects of NPs and TCS in vitro exposure. Our findings provide insight into the toxic mechanisms associated with co-exposure to NPs and TCS to KGN cells by inducing oxidative stress, activations of the NRF2-KEAP1-HO-1 pathway, autophagy, and apoptosis.

Triclosan induces earlier puberty onset in female mice via interfering with L-type calcium channels and activating Pik3cd.

Triclosan (TCS) is a broad-spectrum antibacterial chemical widely presents in people's daily lives. Epidemiological studies have revealed that TCS exposure may affect female puberty development. However, the developmental toxicity after low-dose TCS continuous exposure remains to be confirmed. In our study, 8-week-old ICR female mice were continuously exposed to TCS (30, 300, 3000 µg/kg/day) or vehicle (corn oil) from 2 weeks before mating to postnatal day 21 (PND 21) of F1 female mice, while F1 female mice were treated with TCS intragastric administration from PND 22 until PND 56. Vaginal opening (VO) observation, hypothalamic-pituitary-ovarian (HPO) axis related hormones and genes detection, and ovarian transcriptome analysis were carried out to investigate the effects of TCS exposure on puberty onset. Meanwhile, human granulosa-like tumor cell lines (KGN cells) were exposed to TCS to further explore the biological mechanism of the ovary in vitro. The results showed that long-term exposure to low-dose TCS led to approximately a 3-day earlier puberty onset in F1 female mice. Moreover, TCS up-regulated the secretion of estradiol (E2) and the expression of ovarian steroidogenesis genes. Notably, ovarian transcriptomes analysis as well as bidirectional validation in KGN cells suggested that L-type calcium channels and Pik3cd were involved in TCS-induced up-regulation of ovarian-related hormones and genes. In conclusion, our study demonstrated that TCS interfered with L-type calcium channels and activated Pik3cd to up-regulate the expression of ovarian steroidogenesis and related genes, thereby inducing the earlier puberty onset in F1 female mice.

Analysis of key circRNA events in the AOP framework of TCS acting on zebrafish based on the data-driven.

Triclosan (TCS) is a broad-spectrum antibiotic widely used in various personal care products. Research has found that exposure to TCS can cause toxic effects on organisms including neurotoxicity, cardiotoxicity, disorders of lipid metabolism, and abnormal vascular development, and the corresponding toxic mechanisms are gradually delving into the level of abnormal expression of miRNA regulating gene expression. Although the downstream mechanism of TCS targeting miRNA abnormal expression to induce toxicity is gradually improving, its upstream mechanism is still in a fog. Starting from the abnormal expression data of circRNA in zebrafish larvae induced by TCS, this study conducted a hierarchical analysis of the expression levels of all circRNAs, differential circRNAs, and trend circRNAs, and identified 29 key circRNA events regulating miRNA abnormal expression. In combination with GO and KEGG, the effects of TCS exposure were analyzed from the function and signaling pathway of the corresponding circRNA host gene. Furthermore, based on existing literature evidence about the biological toxicity induced by TCS targeting miRNA as data support, a competing endogenous RNAs (ceRNA) network characterizing the regulatory relationship between circRNA and miRNA was constructed and optimized. Finally, a comprehensive Adverse Outcome Pathway (AOP) framework of multiple levels of events including circRNA, miRNA, mRNA, pathway, and toxicity endpoints was established to systematically elucidate the toxic mechanism of TCS. Moreover, the rationality of the AOP framework was verified from the expression level of miRNA and adverse outcomes such as neurotoxicity, cardiotoxicity, oxidative stress, and inflammatory response by knockdown of circRNA48. This paper not only provides the key circRNA events for exploring the upstream mechanism of miRNA regulating gene expression but also provides an AOP framework for comprehensively demonstrating the toxicity mechanism of TCS on zebrafish, which is a theoretical basis for subsequent hazard assessment and prevention and control of TCS.

Exposure to biocides and its association with atopic dermatitis among children and adolescents: A population-based cross-sectional study in South Korea.

BACKGROUND: Biocides have emerged as a contributor to the rising cases of atopic dermatitis among children and adolescents. Previous animal studies suggested that phenols, parabens, and pyrethroid insecticides present in these products might play a role in atopic dermatitis. However, there's limited epidemiological evidence confirming the individual or combined effects of exposure to these chemicals on atopic dermatitis in young populations. This study aimed to investigate the association between phenol, paraben, and pyrethroid metabolite levels in urine and atopic dermatitis among Korean children and adolescents METHODS: We analyzed 556 preschool children (3-5 years), 701 schoolchildren (6-11 years), and 731 adolescents (12-17 years) enrolled in the 4th Korean National Environmental Health Survey (KoNEHS) (2018-2020). We used logistic regression and Bayesian kernel machine regression to evaluate the association between atopic dermatitis and individual or mixed exposure to urinary triclosan (TCS), parabens (methylparaben, ethylparaben, propylparaben, and butylparaben), and 3-phenoxybenzoic acid (3-PBA) levels. RESULTS: Urinary TCS levels were positively associated with atopic dermatitis in schoolchildren. When stratified by sex, male schoolchildren exhibited an increasing prevalence of atopic dermatitis as their urinary TCS and 3-PBA levels increased. The combined effect of biocide mixtures on atopic dermatitis was also significantly increased in male schoolchildren, with TCS as the main contributor. CONCLUSIONS: These study findings suggest that biocides at levels found in Korean children and adolescents affect atopic dermatitis.

Triclosan induces liver injury in long-life exposed mice via activation of TLR4/NF-κB/NLRP3 pathway.

Triclosan (TCS) is a widely used synthetic, with broad-spectrum antibacterial properties found in both pharmaceuticals and personal care products. More specifically, it is hepatotoxic in rodents and exhibits differential effects in mice and humans. However, the mechanisms underlying TCS-induced liver toxicity have not been elucidated. This study examined the role of the toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB)/ nod-like receptor protein 3 (NLRP3) pathway in TCS-exposed liver toxicity by established a long-life TCS-exposed mice liver injury model. The 24 C57BL/6 pregnant mice exposed to TCS (0, 50 and 100 mg/kg) every day during the gestation and nursing period. After weaning, the male mice were left to continue administrate with TCS until 8 weeks of age. Then, mice in each group were sacrificed for investigation. Long-life exposure to TCS resulted in a reduction of body weight in growth mice. TCS exposure caused the increase of serum ALT, AST and ALP. The situation of inflammatory cell infiltration, macrophage recruitment and collagen fiber deposition in TCS-exposed mice liver tissues were performed by histological analysis including hematoxylin-eosin, Masson, Sirius red, and immunohistochemistry staining. Protein expression levels in TLR4/NF-κB/NLRP3 pathway was measured through Western blot, and the NLRP3 inflammasome activation was measured using real-time quantitative PCR (RT-qPCR). The results showed that exposure to TCS elevated TLR4, myeloid differentiation factor 88 (Myd88), TNF receptor associated factor 6 (TRAF6), enhanced NF-κB activation, and affected NLRP3 inflammasome activation in mice liver. Collectively, these findings indicate that long-life exposure to TCS-induced mice by upregulating the TLR4-Myd88-TRAF6 pathway, activating the NF-κB signaling cascade, initiating the NLRP3 inflammasome pathway, and ultimately leading to liver injury, including inflammation, hepatocyte pyroptosis and hepatofibrosis. Henceforth, the TLR4/NF-κB/NLRP3 pathway may now provide a theoretical basis and valuable therapeutic targets for overcoming TCS-induced liver toxicity.