Transcriptomics-based analysis of sex-differentiated mechanisms of hepatotoxicity in zebrafish after long-term exposure to bisphenol AF.

Bisphenol AF (BPAF) is an emerging endocrine-disrupting chemical (EDC) prevalent in the environment as one of the main substitutes for bisphenol A. Sex-specific effects of EDCs have been commonly reported and closely linked to sexually dimorphic patterns of hormone metabolism and related gene expression during different exposure windows, but our understanding of these mechanisms is still limited. Here, following 28-day exposure of adult zebrafish to an environmentally relevant concentration of BPAF at 10 µg/L, the global transcriptional networks applying RNA sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) were respectively investigated in the male and female fish liver, connecting the sex-dependent toxicity of the long-term exposure of BPAF to molecular responses. As a result, more differentially expressed genes (DEGs) were detected in males (811) than in females (195), and spermatogenesis was the most enriched Gene Ontology (GO) functional classification in males, while circadian regulation of gene expression was the most enriched GO term in females. The expression levels of selected DEGs were routinely verified using qRT-PCR, which showed consistent alterations with the transcriptional changes in RNA-seq data. The causal network analysis by IPA suggested that the adverse outcomes of BPAF in males including liver damage, apoptosis, inflammation of organ, and liver carcinoma, associated with the regulation of several key DEGs detected in RNA-seq, could be linked to the activation of upstream regulatory molecules ifnα, yap1, and ptger2; while, the inhibition of upstream regulators hif1α, ifng, and igf1, leading to the down-regulated expression of several key DEGs, might be involved in BPAF's effects in females. Furthermore, BPAF exposure altered hepatic histological structure and inhibited antioxidant capability in both male and female livers. Overall, this study revealed different regulation networks involved in the sex-dependent effects of BPAF on the fish liver, and these detected DEGs upon BPAF exposure might be used as potential biomarkers for further assessing sex-specific hepatotoxicity following environmental EDC exposure.

Decreased modular segregation of the frontal-parietal network in major depressive disorder.

Major depressive disorder (MDD) is a common psychiatric condition associated with aberrant large-scale distributed brain networks. However, it is unclear how the network dysfunction in MDD patients is characterized by imbalance or derangement of network modular segregation. Fifty-one MDD patients and forty-three matched healthy controls (HC) were recruited in the present study. We analyzed intrinsic brain activity derived from resting-state functional magnetic resonance imaging (R-fMRI) and then examined brain network segregation by computing the participation coefficient (PC). Further intra- and inter-modular connections analysis were preformed to explain atypical PC. Besides, we explored the potential relationship between the above graph theory measures and symptom severity in MDD. Lower modular segregation of the frontal-parietal network (FPN) was found in MDD compared with the HC group. The MDD group exhibited increased inter-module connections between the FPN and cingulo-opercular network (CON), between the FPN and cerebellum (Cere), between the CON and Cere. At the nodal level, the PC of the anterior prefrontal cortex, anterior cingulate cortex, inferior parietal lobule (IPL), and intraparietal sulcus showed larger in MDD. Additionally, the inter-module connections between the FPN and CON and the PC values of the IPL were negatively correlated with depression symptom in the MDD group. These findings might give evidence about abnormal FPN in MDD from the perspective of modular segregation in brain networks.

Charting the dorsal-medial functional gradient of the default mode network in major depressive disorder.

Major depressive disorder (MDD) is a common and disabling psychiatric condition associated with aberrant functional activity of the default mode network (DMN). However, it is unclear how the DMN dysfunction in MDD patients is characterized by functional connectivity diversity or gradient and whether antidepressant therapy causes the abnormal functional gradient of the DMN to change toward normalization. In current work, we estimated the functional gradient of the DMN derived from resting state functional magnetic resonance imaging in MDD patients (n = 70) and matching healthy controls (n = 43) and identified MDD-related functional connectivity diversity of the DMN. The longitudinal changes of the DMN functional gradient in 36 MDD patients were assessed before and after 12-week antidepressant treatment. Compared to the healthy controls, the functional gradient of the DMN exhibited relatively relative compression along the dorsal-medial axis in MDD patients at baseline and antidepressant treatment could normalize these DMN gradient abnormalities. A regularized least-squares regression model based on DMN gradient features at baseline significantly predicted the change of Hamilton Depression Rating (HAMD) Scale scores after antidepressant treatment. The medial prefrontal cortex gradient had a more contribution to prediction of antidepressant efficacy. Our findings provided a novel insight into the neurobiological mechanism underlying MDD from the perspective of the DMN functional gradient.

Treatment Response Prediction for Major Depressive Disorder Patients via Multivariate Pattern Analysis of Thalamic Features.

Antidepressant treatment, as an important method in clinical practice, is not suitable for all major depressive disorder (MDD) patients. Although magnetic resonance imaging (MRI) studies have found thalamic abnormalities in MDD patients, it is not clear whether the features of the thalamus are suitable to serve as predictive aids for treatment responses at the individual level. Here, we tested the predictive value of gray matter density (GMD), gray matter volume (GMV), amplitude of low-frequency fluctuations (ALFF), and fractional ALFF (fALFF) of the thalamus using multivariate pattern analysis (MVPA). A total of 74 MDD patients and 44 healthy control (HC) subjects were recruited. Thirty-nine MDD patients and 35 HC subjects underwent scanning twice. Between the two scanning sessions, patients in the MDD group received selective serotonin reuptake inhibitor (SSRI) treatment for 3-month, and HC group did not receive any treatment. Gaussian process regression (GPR) was trained to predict the percentage decrease in the Hamilton Depression Scale (HAMD) score after treatment. The percentage decrease in HAMD score after SSRI treatment was predicted by building GPRs trained with baseline thalamic data. The results showed significant correlations between the true percentage of HAMD score decreases and predictions (p < 0.01, r 2 = 0.11) in GPRs trained with GMD. We did not find significant correlations between the true percentage of HAMD score decreases and predictions in GMV (p = 0.16, r 2 = 0.00), ALFF (p = 0.125, r 2 = 0.00), and fALFF (p = 0.485, r 2 = 0.10). Our results suggest that GMD of the thalamus has good potential as an aid in individualized treatment response predictions of MDD patients.

Occurrence, Distribution, and Risk of Organophosphate Flame Retardants in Sediments from Jiulong River Estuary and Adjacent Western Taiwan Strait, China.

Organophosphate ester flame retardants (OPFRs) are widely prevalent in the environment and are of significant concern because of their potential toxicity to human health and wildlife. In this study, the concentration, frequency, spatial distribution, potential sources, and ecological risks of OPFRs in sediments from the Jiulong River estuary and the adjacent western Taiwan Strait were investigated. Concentrations of four of the five studied OPFRs were between

Intergenerational toxic effects of parental exposure to bisphenol AF on offspring and epigenetic modulations in zebrafish.

Bisphenol AF (BPAF), an endocrine-disrupting chemical, has been detected in various environmental media because of its wide industrial applications. Meanwhile, substances that are known to be toxic to the reproductive system have been observed to interfere with the development of the offspring following parental exposure. This study was aimed at determining the gender-dependent intergenerational effects of BPAF on offspring development following either paternal or maternal exposure of adult zebrafish to an environmental concentration of BPAF. Four-month-old zebrafish (F0) were exposed to 10 µg/L of BPAF for 28 days, the developmental endpoints of F1 embryos were then tested without further treatment with BPAF. The results show that paternal BPAF exposure decreased the hatching rate, increased mortality, and shortened the body lengths of F1 larval offspring. In addition, it changed DNA and m6A RNA methylation gene expression levels in F0 testes and F1 larvae. Although maternal exposure increased mortality and enhanced antioxidant enzyme activities in F1 larvae, only DNA methylation gene expression was altered in F0 ovaries and F1 larvae. In addition, a short term BPAF exposure of zebrafish embryos from 4 h post-fertilization (hpf) until 120 hpf similarly impaired the early development of the larvae but only at a level relatively higher than 10 µg/L; and DNA and RNA methylation gene expression was regulated to some extent in BPAF exposure groups. Overall, our results indicate the gender-specific effects of BPAF on offspring development and epigenetic modulations, suggesting a relatively high susceptibility within the exposure window during gametogenesis and early embryonic developmental stages to environmental chemicals.

Degradation and toxicity of the antidepressant fluoxetine in an aqueous system by UV irradiation.

Fluoxetine (FLU), a selective serotonin reuptake inhibitor, is commonly found in aquatic environments. Ultraviolet (UV) photolysis is widely used to remove certain pharmaceuticals from water and wastewater. The present study aimed to investigate the toxicity of FLU and its transformed products formed during UV photolysis by using zebrafish embryos (Danio rerio) as a model. The degradation rates of FLU for five days were approximately 63.6% ± 2.14%, 84.6% ± 0.99%, and 97.5% ± 0.25% after 15, 30, and 60 min of UV irradiation, respectively. Furthermore, the degradation mechanism was explored using LC-MS measurements and density flooding theory (DFT) theoretical calculations. Comprehensive toxicity preassessment of FLU and its degradation products was carried out using the T.E.S.T. software. The effects of physiological and biochemical parameters and neuron- and apoptosis-related gene expression were examined in zebrafish embryos exposed to non-irradiated (0-min) and irradiated (15, 30- and 60-min) solutions from 4 h post-fertilization (hpf) to 120 hpf. The hatching time of zebrafish embryos exposed to the non-irradiated solution (0-min) and irradiated solution (60-min) was delayed, their heart rate at 48 and 72 hpf increased, and their body length at 120 hpf decreased. Significant differences were found between the non-irradiated (0-min) and UV-irradiated (15- or 30-min) groups. A dynamic response involving acetylcholinesterase (AChE) and superoxide dismutase (SOD) activity was also observed in the non-irradiated and UV-irradiated groups. During the UV treatment experiments, the expression levels of neuron-related and apoptosis-related genes were significantly reduced over time alongside the formation of FLU degradation products. Overall, this study provides new concepts to remove and assess the toxicity of emerging contaminants in aquatic environments and highlights the need to consider the formation and persistence of toxic transformation products.

Effective Connectivity of Right Amygdala Subregions Predicts Symptom Improvement Following 12-Week Pharmacological Therapy in Major Depressive Disorder.

The low rates of treatment response still exist in the pharmacological therapy of major depressive disorder (MDD). Exploring an optimal neurological predictor of symptom improvement caused by pharmacotherapy is urgently needed for improving response to treatment. The amygdala is closely related to the pathological mechanism of MDD and is expected to be a predictor of the treatment. However, previous studies ignored the heterogeneousness and lateralization of amygdala. Therefore, this study mainly aimed to explore whether the right amygdala subregion function at baseline can predict symptom improvement after 12-week pharmacotherapy in MDD patients. We performed granger causality analysis (GCA) to identify abnormal effective connectivity (EC) of right amygdala subregions in MDD and compared the EC strength before and after 12-week pharmacological therapy. The results show that the abnormal EC mainly concentrated on the frontolimbic circuitry and default mode network (DMN). With relief of the clinical symptom, these abnormal ECs also change toward normalization. In addition, the EC strength of right amygdala subregions at baseline showed significant predictive ability for symptom improvement using a regularized least-squares regression predict model. These findings indicated that the EC of right amygdala subregions may be functionally related in symptom improvement of MDD. It may aid us to understand the neurological mechanism of pharmacotherapy and can be used as a promising predictor for symptom improvement in MDD.

Integrated analysis of mRNA and long non-coding RNA expression profiles reveals the potential roles of lncRNA-mRNA network in carp macrophage immune regulation.

Long non-coding RNAs (lncRNAs) have emerged as a hot topic in research as mounting evidence has indicated their transcriptional or post-transcriptional regulatory potential in multiple biological processes. Previous studies have revealed the involvement of lncRNAs in the immunoregulation of mammalian macrophages by changing mRNA expression; however, studies on the lncRNAs in fish macrophages and their potential roles in the immune system remain unknown. Primary macrophages were isolated from the head kidney (HK) of red common carp (Cyprinus carpio) and high-throughput lncRNA-mRNA sequencing was performed using the Illumina HiSeq platform. The results revealed that the most highly expressed mRNAs in primary HK macrophages were mainly involved in immune-related signal pathways. Furthermore, the most enriched immune-related GO term and KEGG pathway of the mRNAs were "immune system development" and "chemokine signaling pathway," respectively. A total of 20,333 lncRNAs, composed of 10,512 known and 9821 novel lncRNAs, were identified, and functional enrichment analysis of the lncRNA-mRNA network indicated that the expressed lncRNAs in primary HK macrophages could be associated with the regulation of multiple immune-related signaling pathways. In addition, the expressions of several selected lncRNAs and their related mRNAs were determined in carp macrophages following a 6-h exposure to lipopolysaccharide (LPS) and Poly(I: C), the results of which confirmed the co-expression regulation of lncRNAs and target mRNAs in the immune response of carp macrophages. These results suggest the correlative of the lncRNA-mRNA network in fish macrophage immune response, which may further affect the cross-talk of various signaling pathways by interaction with other network genes. Here, we provided fundamental data about the transcriptome profiles of primary HK macrophages from red common carp by analysis of the lncRNA-mRNA network, and ultimately suggest the potential roles of lncRNA-mRNA networks in immune regulation in teleost fish.

Individualized diagnosis of major depressive disorder via multivariate pattern analysis of thalamic sMRI features.

BACKGROUND: Magnetic resonance imaging (MRI) studies have found thalamic abnormalities in major depressive disorder (MDD). Although there are significant differences in the structure and function of the thalamus between MDD patients and healthy controls (HCs) at the group level, it is not clear whether the structural and functional features of the thalamus are suitable for use as diagnostic prediction aids at the individual level. Here, we were to test the predictive value of gray matter density (GMD), gray matter volume (GMV), amplitude of low-frequency fluctuations (ALFF), and fractional amplitude of low-frequency fluctuations (fALFF) in the thalamus using multivariate pattern analysis (MVPA). METHODS: Seventy-four MDD patients and 44 HC subjects were recruited. The Gaussian process classifier (GPC) was trained to separate MDD patients from HCs, Gaussian process regression (GPR) was trained to predict depression scores, and Multiple Kernel Learning (MKL) was applied to explore the contribution of each subregion of the thalamus. RESULTS: The primary findings were as follows: [1] The balanced accuracy of the GPC trained with thalamic GMD was 96.59% (P < 0.001). The accuracy of the GPC trained with thalamic GMV was 93.18% (P < 0.001). The correlation between Hamilton Depression Scale (HAMD) score targets and predictions in the GPR trained with GMD was 0.90 (P < 0.001, r2 = 0.82), and in the GPR trained with GMV, the correlation between HAMD score targets and predictions was 0.89 (P < 0.001, r2 = 0.79). [2] The models trained with ALFF and fALFF in the thalamus failed to discriminate MDD patients from HC participants. [3] The MKL model showed that the left lateral prefrontal thalamus, the right caudal temporal thalamus, and the right sensory thalamus contribute more to the diagnostic classification. CONCLUSIONS: The results suggested that GMD and GMV, but not functional indicators of the thalamus, have good potential for the individualized diagnosis of MDD. Furthermore, the thalamus shows the heterogeneity in the structural features of thalamic subregions for predicting MDD. To our knowledge, this is the first study to focus on the thalamus for the prediction of MDD using machine learning methods at the individual level.

Antidepressant Treatment-Induced State-Dependent Reconfiguration of Emotion Regulation Networks in Major Depressive Disorder.

Deficits in emotion regulation are the main clinical features, common risk factors, and treatment-related targets for major depressive disorder (MDD). The neural bases of emotion regulation are moving beyond specific functions and emphasizing instead the integrative functions of spatially distributed brain areas that work together as large-scale brain networks, but it is still unclear whether the dynamic interactions among these emotion networks would be the target of clinical intervention for MDD. Data were collected from 70 MDD patients and 43 sex- and age-matched healthy controls. The dynamic functional connectivity (dFC) between emotion regions was estimated via a sliding-window method based on resting-state functional magnetic resonance imaging (R-fMRI). A k-means clustering method was applied to classify all time windows across all participants into several dFC states reflecting recurring functional interaction patterns among emotion regions over time. The results showed that four dFC states were identified in the emotion networks. Their alterations of state-related occurrence proportion were found in MDD and subsequently normalized following 12-week antidepressant treatment. Baseline strong dFC could predict the reduction rate of Hamilton Depression Rating Scale (HAMD) scores. These findings highlighted the state-dependent reconfiguration of emotion regulation networks in MDD patients owing to antidepressant treatment.

Identification of novel long non-coding RNAs involved in bisphenol A induced immunotoxicity in fish primary macrophages.

Bisphenol A (BPA), a well-known environmental endocrine-disrupting chemical (EDC), could pose a great toxicity risk to aquatic organisms. The present study aimed to evaluate the underlying role of long non-coding RNAs (lncRNAs) in BPA-induced immunotoxicity in head kidney (HK) macrophages of the red common carp (Cyprinus carpio), using lncRNA-RNA sequencing (RNA-Seq). In BPA-exposed HK macrophages group, 2,095 and 1,138 differentially expressed mRNAs (DEGs) and lncRNAs (DE-lncRNAs) were obtained, respectively, compared with controls. The qRT-PCR validation results of DEGs and DE-lncRNAs were similar to the RNA-Seq results. The KEGG analysis of DEGs and target genes of DE-lncRNAs have shown that some immune-related signaling pathways, including NF-kappa B, Toll-like receptor, B-cell receptor, Jak-STAT, and Hippo signaling pathways, were severely disrupted by BPA exposure. Moreover, we observed the synergic regulation of some mRNAs involved in immune response such as two hub genes traf6 and mapk1/3 and their upstream lncRNAs in HK macrophages upon the BPA exposure or its analogue bisphenol S (BPS) exposure. This suggested the dysregulation of lncRNAs by BPA or BPS may lead to a change in the expression of hub genes, which affects the cross-talk of various signaling pathways by interaction with other network genes. In conclusion, the present study demonstrates the potential role of lncRNAs in immunotoxicity of bisphenol compounds in red common carp HK macrophages, and our results provide evidence for further exploring lncRNA's role in EDC-induced toxicity in aquatic organisms.

Seasonal variation of antibiotics in surface water of Pudong New Area of Shanghai, China and the occurrence in typical wastewater sources.

The occurrence of 26 antibiotics from three groups of Sulfonamides, Quinolones and Macrolides were investigated in the surface water of Pudong New Area, Shanghai in March (dry season) and June (wet season). As a result, the detection rates of the three groups were 20%, 81% and 56% (n = 10) with the concentration range of not detected-9.73 ng L-1, 30-344 ng L-1, and 14-107 ng L-1, respectively. Comparably, during wet season, the detection rates were 20%, 56% and 25% with the range of ND-14 ng L-1, 32-92 ng L-1, and ND-22 ng L-1, respectively. This indicates higher concentrations in dry season than that in wet season, which was attributed to the water dilution and weaker self-purification of the river during dry season. In addition, significant correlations were observed between SMA and most of Quinolones during dry season, and Quinolones and Macrolides during wet season, due to the similar sources. Considering for the typical wastewater sources in the investigated area, Quinolones were identified to be the most significant group in the aquiculture water. Furthermore, pharmaceutical manufacturing factory (PMF) and sewage treatment plant (STP) should be the serious point source pollution as the concentration in their effluents could range from ng L-1 to mg L-1. The occurrence and fate of antibiotics in the aquatic system of Pudong New Area need to be paid more attention to prevent the potential risk for human beings in the future study.

Tissue bioconcentration and effects of fluoxetine in zebrafish (Danio rerio) and red crucian cap (Carassius auratus) after short-term and long-term exposure.

Fluoxetion (FLU) is an antidepressant pharmaceutical most commonly detected in the aquatic environment. The present study aims to elucidate the tissue accumulation and effects of FLU using two different fish models. First, the multiple effects and the FLU levels in fish, were examined in zebrafish (Danio rerio) embryos exposed to FLU concentrations (0, 0.1, 1, 10, 100, 1000 µg/L) from 4 h post-fertilization (hpf) until 120 hpf. Exposure to FLU accelerated heart rates, postponed hatching time, and increased swimming speed of fish. A dynamic response of acetylcholinesterase (AChE) activity was also displayed in the fish. Second, a 30-day exposure experiment using red crucian carp (Carassius auratus) was performed, and it found that the concentration of FLU in fish organs increased with increasing water concentrations, but the highest FLU bioconcentration was present in the lowest FLU exposure group (0.1 µg/L). Finally, 6 days of exposure to 0.1 µg/L of FLU followed by a 6-day clearance experiment was performed with both adult zebrafish and red crucian carp. The FLU levels in different fish organs increased as exposure time increased, but they sharply declined following the 6-day clearance. Correspondingly, the changes in brain AChE activity and in antioxidant parameters in the liver were consistent with the FLU levels in the fish organs. Our study provides fundamental data on the tissue accumulation and concentration-dependent effects in fish exposed to fluoxetine.

Parental exposure to bisphenol A and its analogs influences zebrafish offspring immunity.

Transgenerational effects of environmental pollutants on humans and animals are complex. Thus, we used zebrafish to evaluate the effects of parental whole-life cycle exposure to bisphenol A and its analogs (bisphenol S and F) on offspring innate immunity. At adulthood, offspring were examined with/without continued chemicals treatment until 72h post-fertilization (hpf). To measure offspring immune function, larvae at 72 hpf were expose for 24h with/without the viral mimic polyinosinic-cytidylic acid (Poly I:C) or the bacterial mimic Pam3Cys-Ser-Lys4 (PAM3CSK4). Data show modified immunity in offspring. Specifically, lysozyme activity was significantly induced in F1 larvae and respiratory burst response and oxidative defense genes were inhibited. Genes of the innate immune system including Toll-like receptors and their downstream molecules and inflammatory cytokines were significantly down-regulated, whereas matrix metalloproteinases were up-regulated in larvae. In addition, recombination-activating genes in the immature adaptive immune system were significantly reduced. Thus, immune defense is diminished by exposing parental generations of zebrafish to environmentally relevant concentration of bisphenols and this suggests that fish chronically exposed to bisphenols in the wild may be vulnerable to pathogens.

Polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDEs in human serum from Shanghai, China: a study on their presence and correlations.

Polybrominated diphenyl ethers (PBDEs) are becoming a public health concern because of their potential toxicity, from endocrine disruption system to neurodevelopmental impairments. Nonetheless, information on their levels in human blood is scarce. In this study, human serum samples collected in Shanghai, China, were analyzed for the concentrations of PBDEs and their hydroxylated metabolites (OH-PBDEs). Eight PBDE congeners and six OH-PBDE congeners were quantified in serum samples by gas chromatography with mass spectrometry (GC-MS) and high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). As a result, total PBDE concentration ranged from 0.280 to 12.330 ng g-1 on a lipid weight basis lw (median: 1.100 ng g-1 lw) and the total OH-PBDE level ranged from 0.045 to 0.363 ng g-1 (lw) (median: 0.187 ng g-1 lw). Among them, BDE-47 and 6-OH-BDE-47 were the predominant PBDEs and OH-PBDEs, respectively. In addition, based on the results of the Bartelett X 2 test, BDE-47 significantly (p < 0.05) correlated with BDE-28, BDE-100, BDE-85, and BDE-154, whereas 3'-OH-BDE-7 significantly (p < 0.01) correlated with 3-OH-BDE-47, 2-OH-BDE-68, and 6'-OH-BDE-99. Among all donors, no significant association between age and PBDEs (or OH-PBDEs) was found. Further research on the exposure routes in the environment and metabolic processing of PBDEs in human blood is necessary.

Global transcriptomic analysis of zebrafish in response to embryonic exposure to three antidepressants, amitriptyline, fluoxetine and mianserin.

Antidepressants are among the most commonly detected pharmaceuticals in aqueous systems, and, as emerging organic pollutants, may exert negative effects on non-target aquatic organisms. Previously, it has been revealed that antidepressant exposure significantly inhibits the growth and development of fish during their early developmental stages. Thus, in the present study, we aimed to identify and compare the underlying mechanisms of action of different antidepressants at the transcriptional level using zebrafish (Danio rerio) embryos. Through high-throughput RNA sequencing (RNA-Seq) data analysis, 32, 34, and 130 differentially expressed genes (DEGs) were obtained from zebrafish larvae after 120h of embryonic exposure to sublethal concentrations of amitriptyline, fluoxetine, and mianserin, respectively. The expression profiles of the identified DEGs showed similar trends in response to the three antidepressant treatments, suggesting consistent toxic effects of low concentrations of these three drugs on the regulation of gene expression in fish. Several metabolic and signaling pathways, including glycolysis/gluconeogenesis and the insulin pathway, were affected in the exposed fish larvae. The expression profiles of selected DEGs were then verified by the qRT-PCR method, which indicated significant positive correlations with the RNA-Seq results. Next, we determined the concentration-dependent expression patterns of 6 selected DEGs in fish larvae exposed to three antidepressants at a series of environmentally relevant concentrations. The results revealed a significant concentration-dependent reduction in the levels of dual-specificity phosphatase 5 (dusp5) mRNA, as well as a non-concentration-dependent gene expression inhibition of prostaglandin D2 synthase b (ptgdsb); the circadian rhythm-related genes, i.e. those encoding nuclear receptor subfamily 1, group D, member 1 (nr1d1) and period 2 (per2); and genes encoding early growth response factors (egr1 and egr4), in the antidepressant-treated fish larvae. In summary, to our knowledge, our findings demonstrate, for the first time, that the three different categories of antidepressants have common effects on the gene expression involved in multiple biological processes and signaling pathways during the early development of fish and thus provide information for characterizing the adverse outcome pathways and on the ecological risk assessment of these pharmaceutical pollutants in the aquatic environment.

Aquatic photolysis of hydroxylated polybromodiphenyl ethers under direct UV irradiation: a case study of 2'-HO-BDE-68.

Hydroxylated polyhalodiphenyl ethers (HO-PXDEs) have attracted considerable scientific interest as examples of emerging aquatic pollutants. However, a comprehensive assessment of disposal methods for this particular pollutant was seldom investigated. This study examined the UV light degradation of HO-PXDEs, using 2'-HO-2, 3', 4, 5'-tetrabromodiphenyl ether (2'-HO-BDE-68) as a case study. The results showed that UV light was superior to visible light and electron beam irradiation for producing a high degradation rate of 2'-HO-BDE-68. At low concentrations of HO-BDE, the degradation rate was not obviously improved with decreasing initial concentration. The degradation efficiency was also found to be better in alkaline solutions. In a UV/H2O2 system, the hydroxyl radical provided by H2O2 was shown to enhance the degradation efficiency. The main photolysis products of 2'-HO-BDE-68 were identified, and the possible photodegradation pathways were proposed. 1, 3, 8-Tribromodibenzo-p-dioxin was one of the photoproducts, which indicates that secondary pollution must also be considered with the UV photolysis process.

Suppressive immunoregulatory effects of three antidepressants via inhibition of the nuclear factor-κB activation assessed using primary macrophages of carp (Cyprinus carpio).

Antidepressants, having been applied for the treatment of major depressive disorder and other conditions for decades, are among the most commonly detected human pharmaceuticals in the aquatic environment. This study evaluated the immunotoxicity of acute exposure to environmentally relevant concentrations of amitriptyline, fluoxetine and mianserin using an in vitro primary macrophage model isolated from red common carp (Cyprinus carpio), and also explored their potential mechanisms of action. A potential suppressive immunoregulatory effect of antidepressant exposure was suggested based on the observed suppressive effects on oxidative stress parameters, bactericidal activity, NO production, and NO synthase activity, as well as pro-inflammatory cytokine gene expression, and a significant stimulatory effect on anti-inflammatory interleukin-10 and interferon cytokine gene expression and ATPase activities in macrophages after 6h-exposure to three individual antidepressants and a combination thereof. Notably, we also found these effects were significantly associated with a corresponding decrease in nuclear factor-κB (NF-κB) activity after antidepressants exposure, and the NF-κB antagonist significantly restrained the effects of antidepressants on gene expression of cytokines, indicating that antidepressants could alter the response of various immune-associated components via the inhibition of NF-κB. Moreover, time-dependent lethal concentrations of three antidepressants on primary macrophages were firstly determined at mg/L levels, and the synergetic effects of antidepressant mixtures were suggested and in particular, for some parameters including total antioxidant capacity and cytokine genes expression, they could be significantly affected by antidepressants exposure at concentrations as low as 10ng/L, which together thereby revealed the potential risk of antidepressants to aquatic life.

Bioconcentration pattern and induced apoptosis of bisphenol A in zebrafish embryos at environmentally relevant concentrations.

Bisphenol A (BPA) is a well-known endocrine-disrupting chemical that is ubiquitously present in the environment. In the present study, 4-h post-fertilization (hpf) zebrafish embryos were exposed to various environmentally relevant concentrations of BPA (0.1, 1, 10, 100, and 1000 µg/L) until 72 and 168 hpf, and the accumulation pattern of BPA and its potential to induce toxicity through apoptosis were determined. Compared to BPA concentrations in larvae at 168 hpf, BPA concentrations in embryos exposed until 72 hpf were at relatively higher levels (p < 0.05) with higher bioconcentration factor (BCF) values. The nonlinear fitting analysis indicated that the BCF values of BPA in fish embryos/larvae were significantly correlated to the log10-transformed BPA exposure concentrations in water in an inverse concentration-dependent manner. Fish accumulated more BPA as the exposure concentrations increased; however, their accumulation capacity of BPA declined and tended to be saturated in the high exposure groups of BPA. Moreover, caspase-3 activity was significantly induced upon BPA exposure at 0.1, 1, 10, and 100 µg/L BPA at 72 hpf, and also at 10 and 100 µg/L BPA at 168 hpf. Correspondingly, exposure to 10 and 100 µg/L of BPA significantly increased the DNA fragmentation in the extracted DNA at 168 hpf as determined by DNA ladder analysis. In addition, the expression patterns of four genes related to apoptosis including caspase-3, bax, p53, and c-jun were significantly up-regulated (p < 0.05) in fish embryos/larvae upon BPA exposure at 72 and 168 hpf. Our results revealed that low and environmentally relevant concentrations of BPA could be significantly accumulated in zebrafish and induced apoptosis with involvement of the regulation of caspase-3 and other apoptosis-related genes.