Low salinity influences the dose-dependent transcriptomic responses of oysters to cadmium.

Species in estuaries tend to undergo both cadmium (Cd) and low salinity stress. However, how low salinity affects the Cd toxicity has not been fully understood. Investigating the impacts of low salinity on the dose-response relationships between Cd and biological endpoints has potential to enhance our understanding of the combined effects of low salinity and Cd. In this work, changes in the transcriptomes of Pacific oysters were analyzed following exposure to Cd (5, 20, 80 µg/L Cd2+) under normal (31.4 psu) and low (15.7 psu) salinity conditions, and then the dose-response relationship between Cd and transcriptome was characterized in a high-throughput manner. The benchmark dose (BMD) of gene expression, as a point of departure (POD), was also calculated based on the fitted dose-response model. We found that low salinity treatment significantly influenced the dose-response relationships between Cd and transcripts in oysters indicated by altered dose-response curves. In details, a total of 219 DEGs were commonly fitted to best models under both normal and low salinity conditions. Nearly three quarters of dose-response curves varied with salinity condition. Some monotonic dose-response curves in normal salinity condition even were replaced by nonmonotonic curves in low salinity condition. Low salinity treatment decreased the PODs of differentially expressed genes induced by Cd, suggesting that gene differential expression was more prone to being triggered by Cd in low salinity condition. The changed sensitivity to Cd in low salinity condition should be taken into consideration when using oyster as an indicator to assess the ecological risk of Cd pollution in estuaries.

Meta-analysis reveals the species-, dose- and duration-dependent effects of cadmium toxicities in marine bivalves.

Cadmium (Cd) is a typical pollutant in marine environment. Increasing studies have focused on the toxicological effects of Cd in marine bivalves. However, there were many conflicting findings of toxicological effects of Cd in marine bivalves. An integrated analysis performed on the published data of Cd toxicity in marine bivalves is still absent. In this study, a meta-analysis was performed on the toxic endpoints in bivalves exposed to aqueous-phase Cd from 87 studies screened from 1519 papers. Subgroup analyses were conducted according to the categories of species, tissue, exposure dose and duration. The results showed significant species-, duration- and dose-dependent responses in bivalves to aqueous-phase Cd exposure. In details, clams were more sensitive to Cd than oysters, mussels and scallops, indicated by the largest effect size in clams. Gill, hepatopancreas and hemolymph were top three tissues used to indicate Cd-induced toxicity and did not present a significant tissue-specific manner among them. With regard to toxicological effect subgroups, oxidative stress and detoxification were top two subgroups indicating Cd toxicities. Detoxification and genotoxicity subgroups presented higher response magnitudes. What is more, toxicological effect subgroups presented multiple dose- and duration-dependent curves. Oxidative stress and genotoxicity related endpoints presented significant increase trends with Cd exposure dose and were preferable biomarkers to marine Cd pollution. Detoxification and energy metabolism related endpoints showed inverted U-shaped and U-shaped dose-response curves, both of which could be explained by hormesis. The linear decrease in oxidative stress and energy metabolism related endpoints over time suggested their involvement into the adaptive mechanism in bivalves. Overall, this study provided not only a better understanding the responsive mechanisms of marine bivalves to Cd stress, but also a selection reference for biomarkers to aqueous-phase Cd pollution in marine environment.

Tetrabromobisphenol A induced reproductive endocrine-disrupting effects in mussel Mytilus galloprovincialis.

Tetrabromobisphenol A (TBBPA) pollution in marine environmental media poses great risks to marine organisms due to its potential endocrine-disrupting effects. However, limited attention of TBBPA's endocrine-disrupting effects has been paid on marine invertebrates. In this work, the reproductive endocrine-disrupting effects of TBBPA were evaluated by observing the gametes development, quantifying the gender-specific gene expression, and determining vertebrate sex hormones in mussels Mytilus galloprovincialis treated with TBBPA for 30 days. Additionally, transcriptomic profiling and enzymes activities were conducted to investigate the potential mechanisms of reproductive endocrine-disrupting effects. We found that promotion of gametogenesis and alterations of vertebrate sex hormones occurred in TBBPA-treated mussels of both sexes. Meanwhile, estrogen sulfotransferase (SULT1E1) and steroid sulfatase (STS) were up-regulated at transcript level as a result of TBBPA treatments, suggesting that TBBPA disrupted the steroidogenesis in mussels through promoting steroids sulfonation and hydrolysis of sulfate steroids. The induction of SULTs for TBBPA biotransformation might be responsible for the dysregulation of steroidogenesis and steroids metabolism. Overall, these findings provide a new insight into assessing impact of TBBPA as well as TBBPA biomonitoring in marine environment.

Evidence-based meta-analysis of the genotoxicity induced by microplastics in aquatic organisms at environmentally relevant concentrations.

Microplastics (MPs) attract global concern due to their ubiquitous existence in aquatic environments. However, the genotoxic effect of MPs on aquatic organisms in the natural environment remains controversial. Therefore, this meta-analysis was conducted by recompiling 44 individual studies from 12 publications to determine whether MPs could induce genotoxicity in aquatic organisms at environmentally relevant concentrations (≤1 mg/L, median = 0.5 mg/L). Multiple genotoxic endpoints were involved, including the percentage of DNA in tail (TDNA%), tail length (TL), olive tail moment (OTM), and the number of micronuclei (NM), and their increases represented the biologically adverse effects (i.e. genotoxicity). The results showed that all included endpoints tended to increase after exposure to MPs, among which TDNA%, TL and NM were significantly increased by 20%, 32% and 81% compared with the control group, respectively. The overall estimate of all endpoints in the MPs-treated groups was remarkably increased by 24%, with high statistical power and no obvious publication bias, suggesting the evident genotoxicity caused by MPs. In addition, the magnitudes of MPs-induced genotoxicity were independent of selected endpoint, MP composition, morphology, exposure concentration and duration, but closely correlated with particle size, living habitat and tested species. Overall, this work provided a reference for the health risk assessment of MPs in the natural environment, contributing to our understanding the action mode of MPs at environmentally relevant concentrations.

Effect of microplastics on aquatic biota: A hormetic perspective.

As emerging pollutants, microplastics (MPs) have been found globally in various freshwater and marine matrices. This study recompiled 270 endpoints of 3765 individuals from 43 publications, reporting the onset of enhanced biological performance and reduced oxidative stress biomarkers induced by MPs in aquatic organisms at environmentally relevant concentrations (≤1 mg/L, median = 0.1 mg/L). The stimulatory responses of consumption, growth, reproduction and survival ranged from 131% to 144% of the control, with a combined response of 136%. The overall inhibitory response of 9 oxidative stress biomarkers was 71% of the control, and commonly below 75%. The random-effects meta-regression indicated that the extents of MPs-induced responses were independent of habitat, MP composition, morphology, particle size and exposure duration. The results implied that the exposure to MPs at low and high concentrations might induce opposite/non-monotonic responses in aquatic biota. Correspondingly, the hormetic dose response relationships were found at various endpoints, such as reproduction, genotoxicity, immunotoxicity, neurotoxicity and behavioral alteration. Hormesis offers a novel perspective for understanding the dose response mode of aquatic organisms exposed to low and high concentrations of MPs, highlighting the necessity to incorporate the hormetic dose response model into the ecological/environmental risk assessment of MPs.

Environmentally relevant concentrations of microplastics influence the locomotor activity of aquatic biota.

The occurrence of microplastics (MPs) in various marine and freshwater matrices has attracted great attention. However, the effect of MPs in natural environment on the locomotor performance of aquatic biota is still controversial. Therefore, this meta-analysis was conducted, involving 116 effect sizes from 2347 samples, to quantitatively evaluate the alteration in locomotor behavior of aquatic organisms induced by MPs at environmentally relevant concentrations (≤ 1 mg/L, median = 0.125 mg/L). It was shown that MP exposure significantly inhibited the average speed and moved distance of aquatic organisms by 5% and 8% (p < 0.05), respectively, compared with the control, resulting in an obvious reduction of locomotor ability by 6% (p < 0.05). Egger's test indicated that the results were stable without publication bias (p > 0.05). The complex influence of MPs on the locomotor ability were characterized through random-effects meta-regression analyses, presenting size-, time-, concentration-dependent manners and multi-factors interactions. In addition, several physiological changes, including energy reserve reduction, metabolism disorder, gut microbiota dysbiosis, inflammation response, neurotoxic response, and oxidative stress, of aquatic organisms triggered by MP exposure at environmentally relevant concentrations were also provided, which might account for the MPs-induced locomotor activity decline.

Dose-dependent responses of metabolism and tissue injuries in clam Ruditapes philippinarum after subchronic exposure to cadmium.

Marine cadmium (Cd) pollution has been globally occurring, which creates a pressing need to characterize toxicological effects and develop biomarkers for Cd. However, the dose-response relationships challenge toxicity characterization and biomarkers selection. Metabolic processes have been frequently targeted by Cd. In this work, we investigated the dose-dependent effects of Cd on metabolic endpoints in whole soft tissues as well as gill and hepatopancreas injuries in clam Ruditapes philippinarum, aiming to better understand the metabolic responses and develop biomarkers. Nuclear magnetic resonance (NMR)-based metabolomic analysis was conducted on clam whole soft tissues to identify metabolites. The enzymes and metabolites associated with tricarboxylic acid (TCA) cycle, glycolysis, and oxidative phosphorylation showed both monotonic and non-monotonic curves with the increase of Cd dose. In details, glutamine, glucose-1-phosphate, hexokinase (HK), and citrate synthase (CS) presented monotonic decreases with the increase of Cd dose, among which glutamine and CS were preferable biomarkers to Cd exposure based on lower benchmark dose (BMD) values. The monotonic decreases of HK and CS activities suggested Cd exposure potentially disrupted glycolysis and TCA cycle via inhibiting rate-limiting enzymes. In contrast, the non-monotonic responses of succinate dehydrogenase (SDH), alanine aminotransferase (ALT), and their substrates (succinate and alanine) were approximate to U- or J-shaped curves, suggesting the adaptive strategy of metabolic responses to different degrees of Cd stress, like induction of anaerobiosis as energy compensation. Especially, the alterations of succinate and SDH presented typical hormetic dose-response curves. What is more, clam hepatopancreas was more sensitive to Cd than gill in terms of injury occurrence. Overall, characterization of dose-dependent effect of Cd on metabolism and tissue injuries provides a new insight into understanding the metabolic adaptation in marine clams and risk assessment of Cd pollution.

Global characterization of dose-dependent effects of cadmium in clam Ruditapes philippinarum.

Cadmium (Cd) is being frequently detected in marine organisms. However, dose-dependent effects of Cd challenged unraveling the toxicological mechanisms of Cd to marine organisms and developing biomarkers. Here, the dose-dependent effects of Cd on clams Ruditapes philippinarum following exposure to 5 doses of Cd (3, 9, 27, 81, 243 µg/L) were investigated using benchmark dose (BMD) method. By model fitting, calculation of BMD values was performed on transcriptomic profiles, metals concentrations, and antioxidant indices. Cd exposure induced not only significant Cd accumulation in clams, but also marked alterations of essential metals such as Ca, Cu, Zn, Mn, and Fe. Gene regulation posed little influence on essential metal homeostasis, indicated by poor enrichment of differentially expressed genes (DEGs) associated with metal binding and metal transport in lower concentrations of Cd-treated groups. BMD analysis on biological processes and pathways showed that peptide cross-linking was the most sensitive biological process to Cd exposure, followed by focal adhesion, ubiquitin mediated proteolysis, and apoptosis. Occurrence of apoptosis was also confirmed by TUENL-positive staining in gills and hepatopancreas of clams treated with Cd. Furthermore, many DEGs, such as transglutaminases (TGs), metallothionein (MT), STEAP2-like and laccase, which presented linear or monotonic curves and relatively low BMD values, were potentially preferable biomarkers in clams to Cd. Overall, BMD analysis on transcriptomic profiles, metals concentrations and biochemical endpoints unraveled the sensitiveness of key events in response to Cd treatments, which provided new insights in exploring the toxicological mechanisms of Cd in clams as well as biomarker selection.

Meta-analytic evidence for the anti-aging effect of hormesis on Caenorhabditiselegans.

Mild stress-induced hormesis, as a promising strategy to improve longevity and healthy aging, meets both praise and criticism. To comprehensively assess the applicability of hormesis in aging intervention, this meta-analysis was conducted focusing on the effect of hormesis on Caenorhabditis elegans. Twenty-six papers involving 198 effect size estimates met the inclusion criteria. Meta-analytic results indicated that hormesis could significantly extend the mean lifespan of C. elegans by 16.7% and 25.1% under normal and stress culture conditions (p < 0.05), respectively. The healthspan assays showed that hormesis remarkably enhanced the bending frequency and pumping rate of worms by 28.9% and 7.0% (p < 0.05), respectively, while effectively reduced the lipofuscin level by 15.9% (p < 0.05). The obviously increased expression of dauer formation protein-16 (1.66-fold) and its transcriptional targets, including superoxide dismutase-3 (2.46-fold), catalase-1 (2.32-fold) and small heat shock protein-16.2 (2.88-fold) (p < 0.05), was one of the molecular mechanisms underlying these positive effects of hormesis. This meta-analysis provided strong evidence for the anti-aging role of hormesis, highlighting its lifespan-prolonging, healthspan-enhancing and resistance-increasing effects on C. elegans. Given that dauer formation protein-16 was highly conservative, hormesis offered the theoretical possibility of delaying intrinsic aging through exogenous intervention among humans.

Residue Phe42 is critical for the catalytic activity of Escherichia coli major nitroreductase NfsA.

The major O2-insensitive nitroreductase (NfsA) of Escherichia coli shares low sequence homology but similar biochemical and structural features with NfsB, the E. coli minor O2-insensitive nitroreductase. A structural comparison revealed Phe42 was present in the active site of NfsA but not NfsB. F42Y, F42N and F42A were generated and had decreased activity toward nitrofurazone by 52, 96, and 99%, respectively. The kinetic parameters for other nitroaromatic substrates were also determined. Compared to wild type, the mutants did not have significantly altered K(m)s, but had dramatically decreased k(cat) and k(cat)/K(m) values. Far-UV CD spectral analysis of the mutants suggested that there were no significant conformational changes however F42A and F42N had changes from 208 to 222 nm, which was attributed to loss of helix content. These findings revealed that Phe42 is important for maintaining NfsA activity and structure.