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To improve our ability to extrapolate preclinical toxicity to humans, there is a need to understand and quantify the concordance of adverse events (AEs) between animal models and clinical studies. In the present work, we discovered 3011 statistically significant associations between preclinical and clinical AEs caused by drugs reported in the PharmaPendium database of which 2952 were new associations between toxicities encoded by different Medical Dictionary for Regulatory Activities terms across species. To find plausible and testable candidate off-target drug activities for the derived associations, we investigated the genetic overlap between the genes linked to both a preclinical and a clinical AE and the protein targets found to interact with one or more drugs causing both AEs. We discuss three associations from the analysis in more detail for which novel candidate off-target drug activities could be identified, namely, the association of preclinical mutagenicity readouts with clinical teratospermia and ovarian failure, the association of preclinical reflexes abnormal with clinical poor-quality sleep, and the association of preclinical psychomotor hyperactivity with clinical drug withdrawal syndrome. Our analysis successfully identified a total of 77% of known safety targets currently tested in in vitro screening panels plus an additional 431 genes which were proposed for investigation as future safety targets for different clinical toxicities. This work provides new translational toxicity relationships beyond AE term-matching, the results of which can be used for risk profiling of future new chemical entities for clinical studies and for the development of future in vitro safety panels.

Supplementary data related to this article: Supplementary material, available at https://ars.els-cdn.com/content/image/1-s2.0-S0048969722047647-mmc1.docx (Word document35, 5KB)); Supplementary Data 1. These are the chemicals along with their properties and the calculated doses given for the C. elegans (Caenorhabditis elegans), available at https://ars.els-cdn.com/content/image/1-s2.0-S0048969722047647-mmc2.xls (spreadsheet, 68KB); Supplementary Data 2. These are the chemicals and the doses given for the trout gill cell line (Rtgill-WT1). The codes here relate to the same codes on the microarray data, available at https://ars.els-cdn.com/content/image/1-s2.0-S0048969722047647-mmc3.xlsx (spreadsheet; 11KB); Supplementary Data 3. These are the probes found to be significantly different between exposed and unexposed C. elegans for each of the narcotic chemicals tested, available at https://ars.els-cdn.com/content/image/1-s2.0-S0048969722047647-mmc4.xlsx (spreadsheet, 363KB); Supplementary Data 4. The file provide the metabolite composition of the three clusters identified by running a metabolic-based predictive model, available at https://ars.els-cdn.com/content/image/1-s2.0-S0048969722047647-mmc5.xlsx (spreadsheet, 10KB). Copyright © 2022 The Authors. With the large numbers of man-made chemicals produced and released in the environment, there is a need to provide assessments on their potential effects on environmental safety and human health. Current regulatory frameworks rely on a mix of both hazard and risk-based approaches to make safety decisions, but the large number of chemicals in commerce combined with an increased need to conduct assessments in the absence of animal testing makes this increasingly challenging. This challenge is catalysing the use of more mechanistic knowledge in safety assessment from both in silico and in vitro approaches in the hope that this will increase confidence in being able to identify modes of action (MoA) for the chemicals in question. Here we approach this challenge by testing whether a functional genomics approach in C. elegans and in a fish cell line can identify molecular mechanisms underlying the effects of narcotics, and the effects of more specific acting toxicants. We show that narcosis affects the expression of neuronal genes associated with CNS function in C. elegans and in a fish cell line. Overall, we believe that our study provides an important step in developing mechanistically relevant biomarkers which can be used to screen for hazards, and which prevent the need for repeated animal or cross-species comparisons for each new chemical. Unilever Ltd.

The use of probiotics has been recently considered a novel therapeutic strategy to prevent pathologies such as obesity; however, the specific mechanisms of action by which probiotics exert their beneficial effects on metabolic health remain unclear. The aim of the present study was to investigate the short-term effects of a probiotic Lactobacillus rhamnosus supplementation (PROB) on appetite regulation, growth-related markers, and microbiota diversity in zebrafish (Danio rerio) larvae, compared to a group subjected to a constant darkness photoperiod (DARK), as well as to evaluate the effects of both treatments on melatonin receptors' expression. After a 24 h treatment, both PROB and DARK conditions caused a significant increase in leptin a expression. Moreover, mRNA abundances of leptin b and proopiomelanocortin a were elevated in the PROB group, and DARK showed a similar tendency, supporting a negative regulation of appetite markers by the treatments. Moreover, both PROB and DARK also enhanced the abundances of melatonin receptors transcript (melatonin receptor 1 ba and bb) and protein (melatonin receptor 1) suggesting a potential involvement of melatonin in mediating these effects. Nevertheless, treatments did not exhibit a significant effect on the expression of most of the growth hormone/insulin-like growth factor axis genes evaluated. Finally, only the DARK condition significantly modulated gut microbiota diversity at such short time, altogether highlighting the rapid effects of this probiotic on modulating appetite regulatory and melatonin receptors' expression, without a concomitant variation of gut microbiota.

Gut microbiota plays a fundamental role in maintaining host's health by controlling a wide range of physiological processes. Administration of probiotics and manipulation of photoperiod have been suggested as modulators of microbial composition and are currently undergoing an extensive research in aquaculture as a way to improve health and quality of harvested fish. However, our understanding regarding their effects on physiological processes is still limited. In the present study we investigated whether manipulation of photoperiod and/or probiotic administration was able to alter microbial composition in zebrafish larvae at hatching stage. Our findings show that probiotic does not elicit effects while photoperiod manipulation has a significant impact on microbiota composition. Moreover, we successfully predicted lipid biosynthesis and apoptosis to be modulated by microbial communities undergoing continuous darkness. Interestingly, expression levels of caspase 3 gene (casp3) and lipid-related genes (hnf4a, npc1l1, pparγ, srebf1, agpat4 and fitm2) were found to be significantly overexpressed in dark-exposed larvae, suggesting an increase in the occurrence of apoptotic processes and a lipid metabolism impairment, respectively (p

The Mediterranean swordfish (Xiphias gladius) has been recently classified as overfished and in 2016, the International Commission for the Conservation of the Atlantic Tunas (ICCAT) established a multi-annual management plan to recover this stock. To successfully achieve this goal, knowledge about swordfish biology is needed. To date, few studies on swordfish have been performed and none of them has provided useful insights into the reproductive biology at molecular level. Here we set to characterise the molecular dynamics underlying ovarian maturation by employing a de novo transcriptome assembly approach. Differential gene expression analysis in mature and immature ovaries identified a number of differentially expressed genes associated with biological processes driving ovarian maturation. Focusing on ovarian steroidogenesis and vitellogenin uptake, we depict the molecular dynamics characterizing these processes while a phylogenetic analysis let us identify a candidate vitellogenin receptor. This is the first swordfish transcriptome assembly and these findings provide in-depth understanding of molecular processes describing ovarian maturation. Moreover, the establishment of a publicly available database containing information on the swordfish transcriptome aims to boost research on this species with the long-term of developing more comprehensive and successful stock management plans.

Circadian rhythm is well known to play a pivotal role in reproduction but the presence of a gonadal circadian rhythm is opening a lot of questions about a local regulation of reproduction. In the present study, we first set to identify the key genes driving circadian rhythmicity from the gonadal transcriptome of the swordfish, a commercially relevant species undergoing overfishing, and we then investigated whether their transcriptional activity was influenced by the maturation stage. Finally, we explored whether seasonality had the ability to modulate the expression of these genes. Interestingly, we identified a wide number of circadian rhythm related genes in the transcriptome of the swordfish gonad including, among the others, clock, bmal1, cry2 and per2, which have been found to be differentially expressed between sexually immature and mature individuals sampled during the breeding season. This differential modulation was also found for melatonin biosynthesis genes (mel1b, asmt and tph1) as well as opsin genes (opsin4, tmt opsin, parapinopsin, VA opsin, rho and sws), known to be the primary receptors of light stimuli. These differences were not observed between mature and immature individuals when considering the non-breeding season suggesting that, despite the molecular machinery of mature gonads is able to respond to signals driving ovarian maturation, these signals are not present hence highlighting the potential role of seasonality in modulating the gonadal circadian rhythm. These results confirm the presence of a gonadal circadian rhythm in the swordfish and open new interesting questions about its role in driving puberty onset.

In the present work, we assembled and characterized a de novo larval transcriptome of the Atlantic bluefin tuna Thunnus thynnus by taking advantage of publicly available databases with the goal of better understanding its larval development. The assembled transcriptome comprised 37,117 protein-coding transcripts, of which 13,633 full-length (>80% coverage), with an Ex90N50 of 3061 bp and 76% of complete and single-copy core vertebrate genes orthologues. Of these transcripts, 34,980 had a hit against the EggNOG database and 14,983 with the KEGG database. Codon usage bias was identified in processes such as translation and muscle development. By comparing our data with a set of representative fish species, 87.1% of tuna transcripts were included in orthogroups with other species and 5.1% in assembly-specific orthogroups, which were enriched in terms related to muscle and bone development, visual system and ion transport. Following this comparative approach, protein families related to myosin, extracellular matrix and immune system resulted significantly expanded in the Atlantic bluefin tuna. Altogether, these results provide a glimpse of how the Atlantic bluefin tuna might have achieved early physical advantages over competing species in the pelagic environment. The information generated lays the foundation for future research on the more detailed exploration of physiological responses at the molecular level in different larval stages and paves the way to evolutionary studies on the Atlantic bluefin tuna.

In recent years, decreases in fish populations have been attributed, in part, to the effect of environmental chemicals on ovarian development. To understand the underlying molecular events we developed a dynamic model of ovary development linking gene transcription to key physiological end points, such as gonadosomatic index (GSI), plasma levels of estradiol (E2) and vitellogenin (VTG), in largemouth bass ( Micropterus salmoides). We were able to identify specific clusters of genes, which are affected at different stages of ovarian development. A subnetwork was identified that closely linked gene expression and physiological end points and by interrogating the Comparative Toxicogenomic Database (CTD), quercetin and tretinoin (ATRA) were identified as two potential candidates that may perturb this system. Predictions were validated by investigation of reproductive associated transcripts using qPCR in ovary and in the liver of both male and female largemouth bass treated after a single injection of quercetin and tretinoin (10 and 100 μg/kg). Both compounds were found to significantly alter the expression of some of these genes. Our findings support the use of omics and online repositories for identification of novel, yet untested, compounds. This is the first study of a dynamic model that links gene expression patterns across stages of ovarian development.

Over the past 25 years, extensive research in vertebrate species has identified several genomic pathways altered by exposures to anthropogenic chemicals with hormone-like activity mediated by their interaction with nuclear receptors. In addition, many pollutants have been shown to interfere with non-genomic (non-classical) pathways, but this mechanism of endocrine disruption is still poorly understood. Recently, the number of publications describing the effects of Endocrine disrupting chemicals (EDCs) on fish reproduction, focusing on the deregulation of the hypothalamus-pituitary-gonadal axis as well as on gamete quality, significantly increased. Depending on their ability to mimic endogenous hormones, the may differently affect male or female reproductive physiology. Inhibition of gametogenesis, development of intersex gonads, alteration of the gonadosomatic index, and decreased fertility rate have been largely documented. In males, alterations of sperm density, motility, and fertility have been observed in several wild species. Similar detrimental effects were described in females, including negative outcomes on oocyte growth and maturation plus the occurrence of apoptotic/autophagic processes. These pathways may affect gamete viability considered as one of the major indicators of reproductive endocrine disruption. Pollutants act also at DNA level producing DNA mutations and changes in epigenetic pathways inducing specific mechanisms of toxicity and/or aberrant cellular responses that may affect subsequent generation(s) through the germline. In conclusion, this review summarizes the effects caused by EDC exposure on fish reproduction, focusing on gametogenesis, giving a general overview of the different aspects dealing with this issue, from morphological alteration, deregulation of steroidogenesis, hormonal synthesis, and occurrence of epigenetic process.