Nonylphenol (NP) is a ubiquitous endocrine-disrupting chemical with confirmed adverse effects on multiple human physiological systems, posing urgent demands for its accurate detection in environmental and biological matrices. This review aims to systematically summarize the pretreatment methods and mainstream detection techniques for NP, with a critical synthesis of their analytical performance, applicable scenarios, advantages, and limitations. Core comparative findings are clarified: chromatography-mass spectrometry technologies (LC-MS/MS, GC-MS) are the gold standard for trace NP detection in complex matrices, with differentiated pretreatment requirements; HPLC has wide applicability but limited sensitivity for ultra-trace analysis; immunological assays are suitable for rapid on-site screening but with high detection limits. This work provides standardized guidance for NP detection method selection, directly supporting environmental monitoring and health risk assessment of NP.

Background: Environmental endocrine disruptors (EEDs), endocrine-interfering pollutants, attract attention for potentially affecting heart diseases via epigenetics. Nonylphenol (NP), a classical representative of endocrine-disrupting chemicals, has previously been demonstrated by our research group to induce myocardial fibrosis in rats. LncRNA, a gene regulator, mediates EED-induced heart cell damage and fibrosis. Objective: This study aimed to investigate the role of long noncoding RNA OIP5 antisense RNA 1 (lncRNA OIP5-AS1) knockdown in NP-induced myocardial fibrosis. Methods: Small interfering RNA (siRNA) transfection was used to interfere with the expression of lncRNA OIP5-AS1 in H9C2 cells. Lactate dehydrogenase (LDH), cell Counting Kit-8 (CCK-8), transwell, quantitative real time polymerase chain reaction (qRT-PCR), and Western blot assays were employed to detect cell membrane integrity, proliferation, migration ability, and the expression of fibrosis-related genes/proteins in H9C2 cells. This process was also validated in Sprague Dawley (SD) rats. Results: The expression of fibrosis-related factor mRNA and proteins in H9C2 cells increased, and the expression of lncRNA OIP5-AS1 was significantly upregulated after 24 h of exposure to 70 µmol/L NP. The knockdown of lncRNA OIP5-AS1 did not show differential changes in LDH activity across treatment groups. However, the knockdown of lncRNA OIP5-AS1 significantly attenuated NP-induced proliferation and migration abilities of H9C2 cells and inhibited the increase in the expression of fibrosis-related factor mRNA/proteins caused by NP. This suggested that the interference with lncRNA OIP5-AS1 expression inhibited the NP-induced myocardial fibrosis in H9C2 cells. In vivo results suggested that NP exposure and isoproterenol hydrochloride groups in rats showed accumulation of myocardial collagen fibers in the interstitial space, increased distribution and content of collagen fibers, and elevated expression of fibrosis-related proteins. The distribution range, content of collagen fibers, and expression of fibrosis-related proteins significantly reduced in rats with lncRNA OIP5-AS1 knockdown exposed to NP compared with those in the NP group. Conclusions: The expression of lncRNA OIP5-AS1 was upregulated in NP-treated H9C2 cells, rat hearts, and myocardial fibrosis model rats. Knockdown of lncRNA OIP5-AS1 was associated with attenuated NP-induced myocardial fibrosis and reduced collagen deposition.

Background: Competing endogenous RNAs (ceRNAs) represent a novel mechanism involving interactions among different RNAs, playing a crucial role in the gene regulatory networks throughout the life cycle. CeRNAs are implicated in cardiovascular diseases (CVDs) caused by environmental endocrine disruptors (EDCs); however, existing studies are not yet systematic, and the mechanisms underlying their effects remain unclear. Objective: This study aimed to systematically elucidate the role of ceRNAs in EDC-induced CVDs and provide valuable insights regarding disease mechanisms and developing new therapeutic strategies. Methods: Comprehensive searches for research related to EDC-induced cardiovascular diseases were conducted across PubMed, Web of Science, and ScienceDirect databases. Eligible studies were screened, and those containing information on the regulatory mechanisms of ceRNAs were extracted and analyzed. Results: Notably, ceRNA-mediated effects of EDC exposure on CVDs mainly occurred through four pathways. First, upon exposure to EDCs, micro RNAs, messenger RNAs (mRNAs), long-chain non-coding RNAs, circular RNAs are differentially regulated, activating signaling pathways such as nuclear factor erythroid 2-related factor 2 and p38 mitogen-activated protein kinase/nuclear factor-κB, which lead to atherosclerosis. Second, EDC exposure alters mRNAs and proteins involved in ceRNA networks, activating the PTEN-induced kinase 1/Parkin and transforming growth factor-β1/LIM domain kinase 1 signaling pathways, leading to cardiomyopathy. Third, EDCs increase ceRNA-related mRNA levels, thereby raising the risk of CVDs. Lastly, ceRNAs participate in EDC exposure to upregulate nitric oxide or reactive oxygen species, ultimately causing vascular diseases. Conclusion: Altogether, the findings of this study show that ceRNAs hold significant potential for identifying target genes and signaling pathways associated with CVDs, which may facilitate deeper studies into CVD management.

OBJECTIVE:To investigate the role of PINK1/Parkin-mediated mitophagy in regulating synaptic remodeling of neuronal cells in depression-like behaviors induced by nonylphenol (NP). METHODS:In vitro experiments: HT-22 neuronal cells were exposed to NP, and mitophagy and Parkin expression were inhibited using specific inhibitors. The cells were categorized into the following groups: (1) control (C) and low-dose NP group (L: 2.5 µM), medium-dose NP group (M: 50 µM), and high-dose NP groups (H: 100 µM); (2) control (C), NP (100 µM), Mdivi-1 (5 µM), and Mdivi-1 + NP (5 µM Mdivi-1 +100 µM NP) groups; (3) control (C), NP (100 µM), AC220 (2 nM), and AC220 + NP (2 nM AC220 +100 µM NP) groups. In vivo experiments: a total of 48 mice, including 24 C57BL/6 wild-type mice and 24 PKRK2 gene-knockout mice, were randomly assigned to the following four groups: control (C), NP (100 mg/kg/day), PKRK2-knockout (KO), and PKRK2-knockout + NP (100 mg/kg/day, KH) groups, with 12 mice in each group. RESULTS:In vitro: With increasing NP concentration, the ATP content reduced and the expressions of synaptic remodeling-related proteins (i.e., PSD-95, BDNF, SYN) decreased. In contrast, the expressions of mitophagy-related proteins and those involved in the PINK1/Parkin-signaling pathway (such as p62, Beclin1, PINK1, Parkin) increased (P < 0.05). Inhibition of mitophagy with Mdivi-1 alleviated the NP-induced changes in synaptic, mitophagy-related, and PINK1/Parkin pathway-related proteins. Similarly, the inhibition of Parkin with AC220 mitigated NP-induced effects on synaptic, mitophagy-related, and PINK1/Parkin-signaling pathway-related proteins and mRNA expression. In vivo: PKRK2 gene-knockout mice exhibited improved NP-induced depression-like behaviors and decreased NP-induced synaptic morphology and mitochondrial ultrastructure changes. Moreover, the gene knockout alleviated the downregulation of synaptic remodeling-related proteins and inhibited the PINK1/Parkin-signaling pathway-mediated mitophagy activated by NP. CONCLUSION:Mitophagy inhibition or PKRK2 knockout can alleviate NP-induced downregulation of synaptic remodeling-related proteins, protect synaptic morphology and ultrastructure, and improve NP-induced depression-like behaviors.

The aim of this work was to determine whether chronic exposure to nonylphenol (NP) at environmental concentration would have toxic effects on thyroid function and thyroid hyperplasia disease and whether zinc-selenium green tea has a protective effect on thyroid damage induced by NP in male rats. B-ultrasound revealed that there were thyroid nodules in both the zinc-selenium green tea group and the NP group. The group exposed to NP showed irregular follicle shapes, an increased number of small follicles, and increased follicular epithelial thickness. The epithelial thickness of the tea groups was significantly lower than that of the NP group (H = 38.85, P <= 0.001). Exposure to NP could induce the increased protein levels of ER alpha, ER(3, TR alpha, and TR(3 in thyroid tissues. The expression of ER alpha (F = 20.75, P <= 0.001), ER(3 (F = 32.32, P <= 0.001), TR alpha (F = 13.81, P <= 0.001), and TR(3 (F = 13.92, P <= 0.001) proteins in the zinc-selenium green tea group was decreased compared with that in the NP group. Chronic NP exposure could cause pathological damage to the thyroid tissue. Zinc selenium tea could provide protective effects for the thyroid damage caused by NP.

Metabolic syndrome (MetS) is considered to be an important factor leading to an increased risk of chronic non-communicable diseases. Studies have found that exposure to environmental endocrine disruptors (EEDs) is associated with MetS, but the relationship between the two is unclear. In order to clarify the relationship between the two, a systematic review and meta-analysis were conducted to investigate their association. We searched Web of Science databases, Embase, and PubMed. We then utilized I2 statistics to assess the literature heterogeneity and pooled the data using both fixed-effects model (I2 < 50%) and the random effects model (I2 > 50%) in accordance with the PRISMA guidelines. The results showed that exposure to perfluoroalkyl substances (PFASs) was associated to specific components of MetS, such as PFNA and "high waist circumference" (OR = 1.23, 95% CI: 1.10-1.38), and PFOA and "elevated blood pressure" (OR = 1.05, 95% CI: 1.01-1.08). Exposure to phthalates (PAEs) increases the risk of MetS, with MECPP (OR = 1.16, 95% CI: 1.04-1.29) being an example. Moreover, polychlorinated biphenyls (PCBs) (OR = 1.47, 95% CI: 1.13-1.93) and organochlorine pesticides (OCPs) (OR = 1.97, 95% CI: 1.33-2.90) showed a positive association with the MetS. This study reveals that EEDs are a risk factor for MetS, which provides new evidence for the relationship between population EEDs exposure and MetS.

Objective: To provide a theoretical basis for investigating ADHD etiology in children, we aimed to investigate an association between environmental endocrine disruptors (EEDs) and attention deficit and hyperactivity disorder (ADHD) in children. Methods: Relevant studies on the relationship between EEDs and ADHD in children from January 2008 to December 2023 were collected. The fixed-effects model was used for studies with I2 < 50 %, whereas the random-effects model was used for studies with I2 > 50 % per the results of the literature heterogeneity test. A sensitivity analysis was performed to evaluate the stability of the combined results. Furthermore, Egger’s and Begg’s tests were used in combination with funnel plots to evaluate publication bias. Results: In total, 19 articles were included in the present meta-analysis. These results indicated that BPA and PAE exposure would increase the risk of ADHD. The results of the meta-analysis of sex subgroups showed that exposure to BPA, PAEs, PAHs increased the risk of ADHD in male children, whereas an inverse association was observed between exposure to PFAS and ADHD in female children. Conclusion: EEDs included in this study, such as BPA and PAEs, were associated with the increased risk of ADHD in children.

BACKGROUND:Liver fibrosis (LF) is a common pathological feature in several chronic liver diseases. Nonylphenol (NP) accumulates in the liver and impairs its function. The mechanism by which NP exposure induces LF remains to be elucidated. OBJECTIVE:This study aimed to determine whether NP activates Pink1/Parkin-mediated mitophagy to promote lipid droplet degradation in hepatic stellate cells, which then contributes to the development of LF. METHODS:Human hepatic stellate cells (LX-2) were categorized into six groups: control, Quizartinib (a Parkin inhibitor), NP, Quizartinib + NP, Mdivi-1 (a mitophagy inhibitor), and Mdivi-1 + NP. Sixty male C57BL/6 mice were randomly assigned to six groups of 10 mice each: control (corn oil), low-dose NP (25 mg/kg), medium-dose NP (50 mg/kg), high-dose NP (100 mg/kg), Parkin knockout (KO, corn oil), and Parkin KO + NP (100 mg/kg). An additional four mice were set aside as a LF model group (Model, received 10 % CCl₄ intraperitoneally at 5 mL/kg, three times per week). All treatments were administered for 35 days. RESULTS:In vitro, NP exposure caused LX-2 cells to lose their stellate morphology and become elongated. Furthermore, treatment with 40 μM NP decreased the expression of the lipid droplet-coating protein Perilipin 5 (Plin5) and enhanced the expression of fibrosis markers (alpha-smooth muscle actin [α-SMA], Collagen Ⅰ) and mitophagy-related proteins (Pink1, Parkin, Beclin1, LC3 Ⅱ) (P < 0.05). However, the inhibition of Parkin or mitophagy reversed NP-induced downregulation of Plin5 and upregulation of fibrosis markers and mitophagy-related proteins (P < 0.05). In vivo, NP exposure significantly increased the liver index and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in mice. However, Parkin KO reduced liver dysfunction (P < 0.05). As the NP dose increased, the Plin5 expression decreased in a dose-dependent manner, whereas fibrosis markers (α-SMA, Collagen Ⅰ) and mitophagy-related proteins (Pink1, Parkin, Beclin1, LC3 Ⅱ) increased. Nonetheless, Parkin KO mitigated the reduction of Plin5 and the elevation of fibrosis and mitophagy markers (P < 0.05). NP exposure considerably augmented hepatic collagen deposition in a dose-dependent manner, disrupted mitochondrial integrity, increased autophagosome numbers, and reduced the hepatic lipid droplet content. Nevertheless, Parkin KO reduced these pathological alterations (P < 0.05). CONCLUSION:NP induces LF by activating Pink1/Parkin-mediated mitophagy, which promotes lipid droplet degradation in hepatic stellate cells.

Environmental endocrine disruptors (EEDs) are exogenous chemicals that impair physiological health by disrupting endocrine function. The gut-brain axis represents a complex bidirectional communication network integrating the gut microbiome, immune system, neural signaling, and endocrine pathways to maintain systemic homeostasis. Within this interconnected system, gut microbiota influence mood regulation, immune activity modulates neural processes, and neural signaling governs circadian and sleep cycles. This review explores the multi-system impacts of EEDs across four key physiological domains: (1) gut microbial ecology, (2) immune function, (3) neuroendocrine regulation, and (4) developmental processes. Evidence indicates that EED exposure disrupts intestinal microbial composition, leading to dysbiosis marked by the depletion of beneficial taxa and the expansion of pathogenic species. Concurrently, EEDs impair gut-associated immune cell populations (T cells, B cells, and macrophages), undermining mucosal immunity and increasing susceptibility to inflammatory bowel disease, autoimmune conditions, and gastrointestinal malignancies. At the endocrine level, EEDs interfere with the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, contributing to hormonal imbalances and impaired reproductive development. Neurochemically, they disrupt the synthesis, release, and degradation of key neurotransmitters, including norepinephrine, dopamine, and serotonin, while exerting direct neurotoxic effects such as cerebrovascular abnormalities and delayed cerebellar myelination. In summary, this review delineates the mechanistic pathways through which EEDs perturb gut-brain axis homeostasis. These insights provide a scientific basis for designing targeted therapeutic interventions and shaping evidence-based public health policies.

Environmental endocrine disruptors (EDCs) affect the immune system and influence the development of autoimmune diseases (ADs). However, a comprehensive summary of the relationship between EDCs and ADs has not been developed. Consequently, we conducted a systematic review and meta-analysis of previous observational studies examining the association between exposure to EDCs and AD outcomes. We searched relevant literature published from January 2008 to the present, which ultimately included 19 studies. The synthesis of evidence demonstrated a positive association between AD risk and exposure to major EDC classes such as bisphenols (strongest association: OR = 2.38, 95% CI: 1.27-4.45), organochlorine pesticides, phthalates, and polycyclic aromatic hydrocarbons. This trend was not observed for polychlorinated biphenyls. These findings position EDC exposure as a potential risk factor for ADs, yet the mechanistic pathways require elucidation. Future high-quality longitudinal and experimental studies are essential to confirm these relationships and explore the underlying biology.

Studies have shown that mercury (Hg) exposure during pregnancy is associated with adverse birth outcomes (ABO) in infants, but the association between the two has not been systematically summarized. Therefore, we conducted a systematic review and meta-analysis of existing observational studies on the association between maternal Hg exposure (MHE) during pregnancy and ABO in infants to evaluate the association between them. We comprehensively searched all relevant literature published in three electronic databases (Web of Science, PubMed, Embase) from 2004 to June 2024. According to the heterogeneity, fixed effect model (I2 ≤ 50 %) or random effect model (I2 > 50 %) was used to pool the associated effect values. The results showed a positive association between MHE and low birth weight (LBW) (OR = 1.079, 95 % CI: 1.032–1.128) and no statistically significant association between and preterm birth (PTB) (OR = 1.044, 95 % CI: 0.956–1.140) and small-for-gestational-age (SGA) (OR = 1.006, 95 % CI: 0.983–1.030). In addition, each 10-fold increase in MHE during pregnancy was associated with abnormal Birth Anthropometrics. These findings suggest that MHE is a risk factor for LBW and is associated with abnormal anthropometric measurements at birth. However, there is insufficient evidence for Hg exposure and SGA, PTB. Further population-based studies are warranted to investigate these associations.

Thyroid cancer (TC) is one of the most common endocrine malignancies worldwide, yet the association between pesticide exposure and TC has not been systematically summarized. This study aimed to elucidate the relationship between pesticide exposure and TC, focusing on insecticides, herbicides, and fungicides. Considering exposure to different pesticide types, we employed fixed- or random-effects meta-analysis to calculate odds ratios (ORs) and their corresponding 95 % confidence intervals (CIs) based on the degree of heterogeneity. The results indicated a positive association between exposure to insecticides (OR = 1.07, 95 % CI: 1.02-1.12), herbicides (OR = 1.10, 95 % CI: 1.04-1.17), and fungicides (OR = 1.21, 95 % CI: 1.13-1.29) and TC. Furthermore, sex-based analysis revealed that the risk of TC due to pesticide exposure was higher in females (OR = 1.52, 95 % CI: 1.26-1.84) than males (OR = 0.95, 95 % CI: 0.87-1.03). Specifically, insecticide exposure was positively associated with TC in females (OR = 1.46, 95 % CI: 1.18-1.80), while in males, herbicide exposure was negatively associated with TC (OR = 0.85, 95 % CI: 0.75-0.96), whereas fungicide exposure was positively associated (OR = 1.38, 95 % CI: 1.04-1.84). Pesticide exposure is a risk factor for TC, with females exhibiting a higher risk than males.

BACKGROUND:Exposure to nonylphenol (NP) has been linked to depressive-like behaviors, while tea consumption is associated with a reduced risk of depression. This study investigates and compares the effects of tea polyphenols (TPs) and tea polysaccharides (TPSs) in alleviating NP-induced depressive-like behaviors, focusing on neuronal apoptosis and disrupted monoamine neurotransmitter secretion. METHODS:Thirty-two specific-pathogen-free male, Sprague-Dawley rats (age: 4 weeks) were randomly assigned to four groups: control (5 mL/kg corn oil), NP (40 mg/kg NP), NP+TPS (25 mg/kg TPS), and NP+TP (50 mg/kg TP) groups. RESULTS:The NP+TP group exhibited a shorter latency period in the feeding test than the NP group. Both NP+TP and NP+TPS groups showed reduced immobility time in the tail suspension and forced swimming tests. NP accumulation in the midbrain and cortical tissues was lower in these two groups. Additionally, these groups showed an increased number of "pear-shaped" neurons and higher serum neurotransmitter levels. The NP+TP and NP+TPS groups also demonstrated increased expression of estrogen receptor β (ERβ), tryptophan hydroxylase (TPH1), tryptophan hydroxylase-2 (TPH2), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) at both protein and gene levels. These two groups also showed a progressive increase in neuron counts, a more organized arrangement, and reduced nuclear staining intensity compared with the NP group. Moreover, their IL-1β and IL-18 levels were lower, along with a reduction in Iba-1-positive microglia. The neuronal apoptosis rate, number of apoptotic cells, and expression of apoptosis-related inflammatory proteins (NLRP3, GSDMD, and Caspase-1) were also decreased in the NP+TP and NP+TPS groups. CONCLUSION:TP and TPS mitigate NP-induced depressive-like behaviors by significantly reducing neuronal apoptosis, normalizing monoamine neurotransmitter secretion, and alleviating neuroinflammation. These findings highlight the potential of these tea components as neuroprotective agents against environmental endocrine disruptor-induced depression.

We conducted a meta-analysis to evaluate relevant literature published between January 2003 and December 2023 in order to provide updated epidemiological evidence on the relationship between endocrine-disrupting chemicals (EDCs) and neurodegenerative diseases (NDs). A systematic search of related studies was conducted in PubMed, Web of Science, and Embase. A total of 21 studies were included, with 286,610 subjects for meta-analysis. Analysis revealed that exposure to polychlorinated biphenyls (odds ratio [OR] = 1.08, 95% confidence interval [CI]: 1.03-1.14) posed a risk for NDs, while organochlorine pesticide (OR = 1.11, 95% CI: 1.05-1.17) exposure exhibited a positive correlation with ND risk. Subgroup analysis by disease indicated a positive association between EDC exposure and Alzheimer's disease (OR = 1.03, 95% CI: 1.00-1.07) and amyotrophic lateral sclerosis (OR = 1.02, 95% CI: 1.01-1.03) risk. Our meta-analysis indicates that human exposure to EDCs has adverse effects on NDs.

The mechanisms underlying environmental endocrine disruptors (EEDs)-induced cardiovascular diseases (CVDs) are not well understood. Specifically, it is unclear whether nonylphenol (NP) exposure regulates myocardial fibrosis (MF) by activating myosin light chain (MLC) through the Ras homolog gene family member A (RhoA)/Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) pathway. To confirm that NP induced MF and explore the underlying mechanism via the RhoA/ROCK1/MLC-signaling pathway. Male Sprague-Dawley (SD) rats were used in the in vitro experiments. Primary cardiac fibroblasts (CFs) were extracted and treated with recombinant human transforming growth factor-beta 1 (TGF-β1) for 24 h to establish a fibrosis model. The first phase of the experiment comprised three groups: control, NP-exposure (30 µmol/L NP), and model (10 ng/mL TGF-β1). The second phase involved five groups: control, ROCK1-inhibitor (50 µmol/L, Fas), NP+ROCK1-inhibitor (30 µmol/L NP+50 µmol/L Fas), NP-exposure (30 µmol/L NP), and model (10 ng/mL TGF-β1). For the in vivo experiment, the animal experiments included 60 male SD rats who were categorized into five groups of 12 rats each, as follows: control (corn oil), ROCK1-inhibitor (10 mg/kg/day Fas), NP+ROCK1-inhibitor (50 mg/kg/day NP+10 mg/kg/day Fas), NP-exposure (50 mg/kg/day NP), and model (isoprenaline hydrochloride). NP was administered for 90 days via gavage. Fas was injected intraperitoneally for 30 days, and isoprenaline hydrochloride (ISO) was injected subcutaneously on the back for 10 days. In vitro, when compared with the control group, the protein expression of MF markers (i.e., collagen I, collagen III, and α-SMA) and RhoA/ROCK1/MLC-signaling pathway markers (i.e., TGF-β1, RhoA, ROCK1, MLC, and p-MLC) increased in the NF-exposed CFs. Following intervention with the inhibitor, in comparison to the NP group, the protein and fluorescence expression of TGF-β1, RhoA, ROCK1, MLC, and p-MLC were alleviated in the NP+ROCK1-inhibitor group. In vivo, the NP group exhibited mitochondrial damage, disorganized myocardial fibers, abnormal collagen deposition, and increased collagen fibers, whereas the Fas+NP group exhibited an alleviation in these pathological changes. As opposed to the control group, both systolic and diastolic blood pressure levels were elevated in the NP exposure and model groups, reduced in the Fas group, and alleviated in the NP+Fas group. The protein expression of MF markers (i.e., collagen I, collagen III, and α-smooth muscle actin [α-SMA]) increased in the NP-exposure group, which was alleviated in the NP+inhibitor group. In comparison with the NP group, TGF-β1, RhoA, ROCK1, and MLC mRNA expression, whereas the TGF-β1, RhoA, ROCK1, MLC, and p-MLC protein expression were alleviated in the NP+ROCK1-inhibitor group. NP exposure may induce MF by activating the RhoA/ROCK1/MLC-signaling pathway.

Objective: We here explored whether perinatal nonylphenol (NP) exposure causes myocardial fibrosis (MF) during adulthood in offspring rats and determined the role of the TGF-β1/LIMK1 signaling pathway in NP-induced fibrosis in cardiac fibroblasts (CFs). Methods and results: Histopathology revealed increased collagen deposition and altered fiber arrangement in the NP and isoproterenol hydrochloride (ISO) groups compared with the blank group. Systolic and diastolic functions were impaired. Western blotting and qRT-PCR demonstrated that the expression of central myofibrosis-related proteins (collagens Ι and ΙΙΙ, MMP2, MMP9, TGF-β1, α-SMA, IL-1β, and TGF-β1) and genes (Collagen Ι, Collagen ΙΙΙ, TGF-β1, and α-SMA mRNA) was upregulated in the NP and ISO groups compared with the blank group. The mRNA-seq analysis indicated differential expression of TGF-β1 signaling pathway-associated genes and proteins. Fibrosis-related protein and gene expression increased in the CFs stimulated with the recombinant human TGF-β1 and NP, which was consistent with the results of animal experiments. According to the immunofluorescence analysis and western blotting, NP exposure activated the TGF-β1/LIMK1 signaling pathway whose action mechanism in NP-induced CFs was further validated using the LIMK1 inhibitor (BMS-5). The inhibitor modulated the TGF-β1/LIMK1 signaling pathway and suppressed the NP-induced increase in fibrosis-related protein expression in the CFs. Thus, the aforementioned pathway is involved in NP-induced fibrosis. Conclusion: We here provide the first evidence that perinatal NP exposure causes myocardial fibrosis in growing male rat pups and reveal the molecular mechanism and functional role of the TGF-β1/LIMK1 signaling pathway in this process.

Thyroid disease has been rapidly increasing, but its causes remain unclear. At present, many studies have focused on the relationship between environmental endocrine disruptors (EEDs) and the pathogenesis of thyroid disease. Herein, we summarize such studies exploring the effects of exposure to common EEDs on thyrotoxicosis, finding that EEDs appear to contribute to the pathogenesis of thyroid-related diseases such as thyroid cancer, goiter, thyroiditis, hyperthyroidism, and hypothyroidism. To explore this causative effect in detail, we have analyzed the following three aspects of how EEDs are believed to exert their impacts on the occurrence and development of thyroid disease: (1) damage to the thyroid tissue structure, including disrupted mitochondria and the stratification of thyroid follicular epithelial cells; (2) disruption of thyroid hormone signaling, including thyroid hormone synthesis and secretion disorders, destruction of normal function of the hypothalamus-pituitary-thyroid axis, disturbed estrogen signaling in the body, alterations to the level of thyroid-stimulating hormone, inhibition of the release of thyroglobulin from thyroid cells, and reductions in the levels of sodium iodide co-transporters, thyroid peroxidase, deiodinase, and transthyretin; and (3) molecular mechanisms underlying the disruption of thyroid function, including competitive binding to T3 and T4 receptors, disturbance of the hypothalamic-pituitary-thyroid axis, activation of the ERK and Akt pathways, oxidative stress, regulation of the expression of the proto-oncogene k-Ras, tumor suppressor gene PTEN, and thyroid TSHR gene, and induction of autophagy in thyroid cells. Overall, this article reviews how EEDs can affect the occurrence and development of thyroid disease via multiple routes, thus providing new ideas to intervene for the prevention, diagnosis, treatment, and prognosis of thyroid disease.

Background: This study aimed to investigate the spatial learning/memory and motor abilities of rats and the alteration of miR-542-3p and pyroptosis in the midbrain nigrostriatal area in vivo after nonylphenol (NP) gavage and to explore the mechanism of miR-542-3p regulation of Toll-like receptor 4 (TLR4) in NP-induced pyroptosis in BV2 microglia in vitro. Methods: In vivo: Thirty-six specific-pathogen-free-grade Sprague-Dawley rats were divided into three equal groups: blank control group (treated with pure corn oil), NP group (treated with NP, 80 mg/kg body weight per day for 90 days), and positive control group [treated with lipopolysaccharide (LPS), 2 mg/kg body weight for 7 days]. In vitro: The first part of the experiment was divided into blank group (control, saline), LPS group [1 mu g/ ml + 1 mM adenosine triphosphate (ATP)], and NP group (40 mu mol/L). The second part was divided into mimics NC (negative control) group, miR-542-3p mimics group, mimics NC + NP group, and miR-542-3p mimics + NP group. Results: In vivo: Behaviorally, the spatial learning/memory and motor abilities of rats after NP exposure declined, as detected via Y-maze, open field, and rotarod tests. Some microglia in the substantia nigra of the NP-treated rats were activated. The downregulation of miR-542-3p was observed in rat brain tissue after NP exposure. The mRNA/protein expression of pyroptosis-related indicators (TLR4), NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), gasdermin-D (GSDMD), cysteinyl aspartate-specific proteinase-1 (caspase-1), and interleukin-18 (IL-18) in the substantia nigra of the midbrain increased after NP exposure. In vitro: ASC fluorescence intensity increased in BV2 cells after NP exposure. The mRNA and/or protein expression of pyroptosis-related indicators (TLR4, NLRP3, GSDMD, caspase-1, and IL-18) in BV2 cells was upregulated after NP exposure. The transfection of miR-542-3p mimics inhibited NP-induced ASC expression in BV2 cells. The overexpression of miR-542-3p, followed by NP exposure, significantly reduced TLR4, NLRP3, ASC, caspase-1, and IL-18 gene and/or protein expression. Conclusions: This study suggested that NP exposure caused a decline in spatial learning memory and whole-body motor ability in rats. Our study was novel in reporting that the upregulation of miR-542-3p targeting and regulating TLR4 could inhibit NLRP3 inflammatory activation and alleviate NP-induced microglia pyroptosis.

The aim of this study is to investigate the role of estrogen receptor β (ERβ) in nonylphenol (NP) - induced depression - like behavior in rats and its impact on the regulation of the TPH2/5-HT pathway. In the in vitro experiment, rat basophilic leukaemia cells (RBL-2H3) cells were divided into the four groups: blank group, NP group (20 μM), ERβ agonist group (0.01 μM), and NP＋ERβ agonist group (20 μM＋0.01 μM). For the in vivo experiment, 72 adult male Sprague-Dawley rats were randomly divided into following six groups: the Control, NP (40 mg/kg) group, ERβ agonist (2 mg/kg, Diarylpropionitrile (DPN)) group, ERβ inhibitor (0.1 mg/kg, 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl) phenol (PHTPP)) group, NP+ERβ agonist (40 mg/kg NP ＋ 2 mg/kg DPN) group, and NP+ERβ inhibitor (40 mg/kg NP + 0.1 mg/kg PHTPP) group, with 12 rats in each group. Each rat in drug group were given NP by gavage and/or received a single intraperitoneal injection of DPN 2 mg/kg or PHTPP 0.1 mg/kg. Both in vivo and in vitro, NP group showed a decrease in the expression levels of ERβ, tryptophan hydroxylase (TPH1), and tryptophan hydroxylase-2 (TPH2) genes and proteins, and reduced levels of DA, NE, and 5-hydroxytryptophan (5-HT) neurotransmitters. RBL-2H3 cells showed signs of cell shrinkage, with rounded cells, increased suspension and more loosely arranged cells. The effectiveness of the ERβ agonist stimulation exhibited an increase exceeding 60% in RBL-2H3 cells. The application of ERβ agonist resulted in an alleviation the aforementioned alterations. ERβ agonist activated the TPH2/5-HT signaling pathways. Compared to the control group, the NP content in the brain tissue of the NP group was significantly increased. The latency to eat for the rats was longer and the amount of food consumed was lower, and the rats had prolonged immobility time in the behavioral experiment of rats. The expression levels of ERβ, TPH1, TPH2, 5-HT and 5-HITT proteins were decreased in the NP group, suggesting NP-induced depression-like behaviours as well as disturbances in the secretion of serum hormones and monoamine neurotransmitters. In the NP group, the midline raphe nucleus showed an elongated nucleus with a dark purplish-blue colour, nuclear atrophy, displacement and pale cytoplasm. ERβ might ameliorate NP-induced depression-like behaviors, and secretion disorders of serum hormones and monoamine neurotransmitters via activating TPH2/5-HT signaling pathways.