Inflammatory bowel disease: New insights into the interplay between environmental factors and pparγ

The pathophysiological processes of inflammatory bowel diseases (IBDs), i.e., Crohn’s disease (CD) and ulcerative colitis (UC), are still not completely understood. The exact etiology re-mains unknown, but it is well established that the pathogenesis of the inflammatory lesions is due to a dysregulation of the gut immune system resulting in over-production of pro-inflammatory cy-tokines. Increasing evidence underlines the involvement of both environmental and genetic factors. Regarding the environment, the microbiota seems to play a crucial role. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert pleiotropic effects on glucose homeo-stasis, lipid metabolism, inflammatory/immune processes, cell proliferation, and fibrosis. Further-more, PPARs modulate interactions with several environmental factors, including microbiota. A significantly impaired PPARγ expression was observed in UC patients’ colonic epithelial cells, suggesting that the disruption of PPARγ signaling may represent a critical step of the IBD pathogenesis. This paper will focus on the role of PPARγ in the interaction between environmental factors and IBD, and it will analyze the most suitable in vitro and in vivo models available to better study these relationships

Sodium valproate exposure influences the expression of pparg in the zebrafish model

Valproic acid (VPA) is an anti-epileptic drug used alone or in combination with other medications to treat seizures, mania, and bipolar disorder. VPA recognized as a teratogenic chemical can cause severe birth defects mainly affecting the brain and spinal cord when administered during pregnancy. However, the potential mechanisms of developmental toxicity are still less studied, and in the present study, the influence of VPA exposure was evaluated on zebrafish early-life stages. Zebrafish were exposed to two sublethal concentrations of sodium valproate (SV) (0.06 mM and 0.15 mM) from 24 hours post-fertilization (hpf) to 96 hpf and the SV teratogenic potential was investigated through morphometric analysis of zebrafish larvae combined with the evaluation of cartilage profile. Moreover, the effect of SV on the transcription level of pparg was also performed. The results of the study showed the teratogenic potential of SV, which disrupts the morphometric signature of the head and body. The marked distortion of cartilage structures was paralleled to a malformation of telencephalon and optic tectum in both concentrations suggesting a high teratogen effect of SV on the brain. These data were further confirmed by the increased expression of pparg in the zebrafish head. Overall, the present study confirms the teratogenic activity of SV in the zebrafish model and, for the first time, points out the potential protective role of pparg in the SV dose-dependent toxicity

Benefits under the Sea: The Role of Marine Compounds in Neurodegenerative Disorders

Marine habitats offer a rich reservoir of new bioactive compounds with great pharmaceutical potential; the variety of these molecules is unique, and its production is favored by the chemical and physical conditions of the sea. It is known that marine organisms can synthesize bioactive molecules to survive from atypical environmental conditions, such as oxidative stress, photodynamic damage, and extreme temperature. Recent evidence proposed a beneficial role of these compounds for human health. In particular, xanthines, bryostatin, and 11-dehydrosinulariolide displayed encouraging neuroprotective effects in neurodegenerative disorders. This review will focus on the most promising marine drugs' neuroprotective potential for neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. We will describe these marine compounds' potential as adjuvant therapies for neurodegenerative diseases, based on their antioxidant, anti-inflammatory, and anti-apoptotic properties

The role of propylparaben in zebrafish brain development

Humans are exposed to increasing amount of chemicals, and the concern about these substances is related to their unknown effects. In particular, recent studies focused on the controversial role of parabens, used as preservatives in food and cosmetics. They have estrogenic properties [1], which could influence the brain development in Vertebrates. In this work we examine the effect of (PrP) on brain development during early-life stages of zebrafish. PrP treatment induces an alteration in brain morphology evaluated by NeuN staining; particularly we detect an increase in nuclei positive for NeuN in PrP treated embryo respect to control. This morphological anomaly may be related to the altered lipid metabolism and development of head cartilage observed by us in embryos exposed to PrP [2]. In the present study we also investigate the expression in genes involved in neurodevelopment and synapse formation, such as Shank3a, Nrxn1 and Ngln3. Our preliminary data open to further studies to explore the toxicity associated with parabens. Since PrP acts as agonist for peroxisome proliferator–activated receptor g (PPARg) [3] that it is strongly involved in neurogenesis we hypothesize its connection in PrP action. 1 Darbre P.D., & Harvey P.W. (2008). Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J Appl Toxicol, 28(5), 561–578. 2 Perugini M,, Merola C., Amorena M., D’Angelo M., Cimini A., Benedetti E. (2019). Sublethal exposure to propylparaben leads to lipid metabolism impairment in zebrafish early-life stages. J Appl Toxicol, 1–11. https://doi.org/10.1002/jat.3921. 3 Hu P., Chen X., Whitener R.J., Boder E.T., Jones J.O., Porollo A., Chen J., Zhao L. (2013). Effects of parabens on adipocyte differentiation. Toxicol Sci, 131(1):56-70. doi:10.1093/toxsci/kfs262

Developmental toxicity induced by triclosan exposure in zebrafish embryos

Objectives: The present study aimed to investigate the acute toxicity and the developmental alterations induced by triclosan (TCS) exposure in zebrafish early-life stages using fish embryo acute toxicity tests as a methodological approach. Material and Methods: Zebrafish embryos were exposed to five concentrations of TCS and the four lethal alterations were daily recorded to determine the toxicological endpoints of acute toxicity. Furthermore, sublethal alterations were recorded to assess the effect of exposure concentrations on zebrafish embryo's development. Results: The TCS toxicity was determined at 96 h of exposure as lethal concentration 10, lethal concentration 20, lethal concentration 50, lowest observed effects concentration, and no observed effects concentration, reported the following values: 168, 197.2, 267.8, 300, and 200 μg/L. Exposed larvae showed a delay in hatching rate and developed sublethal alterations including reduced blood flow, pericardial oedemata, reduced heartbeat, blood congestion, and craniofacial malformations. The number of zebrafish larvae developing cardiovascular alterations changed according to the tested concentrations and time of evaluation. Conclusion: The data confirmed the developmental toxicity of TCS on aquatic organisms and the sublethal alterations developed by zebrafish larvae, indicated its cardiotoxicity and neurotoxicity. Moreover, the developmental toxicity was strongly influenced by the concentration tested and the number of survived zebrafish developing this alteration varying according to the time of exposure

An experimental approach to study the effects of realistic environmental mixture of Linuron and propamocarb on Zebrafish synaptogenesis

The reasons behind the extensive use of pesticides include the need to destroy vector organisms and promote agricultural production in order to sustain population growth. Exposure to pesticides is principally occupational, even if their persistence in soil, surface water and food brings the risk closer to the general population, hence the demand for risk assessment, since these compounds exist not only as individual chemicals but also in form of mixtures. In light of this, zebrafish represents a suitable model for the evaluation of toxicological effects. Here, zebrafish embryos were exposed for 96 h post fertilization (hpf) to sublethal concentrations (350 µg/L) of linuron and propamocarb, used separately and then combined in a single solution. We investigated the effects on morphological traits and the expression of genes known to be implicated in synaptogenesis (neurexin1a and neuroligin3b). We observed alterations in some phenotypic parameters, such as head width and interocular distance, that showed a significant reduction (p < 0.05) for the mixture treatment. After individual exposure, the analysis of gene expression showed an imbalance at the synaptic level, which was partially recovered by the simultaneous administration of linuron and propamocarb. This preliminary study demonstrates that the combined substances were responsible for some unpredictable effects, diverging from the effect observed after single exposure. Thus, it is clear that risk assessment should be performed not only on single pesticides but also on their mixtures, the toxicological dynamics of which can be totally unpredictable

Environmentally relevant concentrations of triclocarban affect morphological traits and melanogenesis in zebrafish larvae

Human activity is responsible for producing several chemical compounds, which contaminate the aquatic environment and adversely influence the survival of aquatic species and indirectly human health. Triclocarban (TCC) belongs to the category of emerging pollutants and its presence in aquatic environment is justified by its wide use as antimicrobial agent in personal care products. The concern about this chemical is due to the risk of persistence in water and soils and bioaccumulation, which contributes to human exposition through the contaminated food consumption. The present study evaluated the developmental toxicity of TCC in zebrafish early-life stages starting with the assessment of acute toxicity and then focusing on the integrative analyses of the observed phenotype on zebrafish development. For this purpose, lethal and sublethal alterations of zebrafish embryos were investigated by the Fish Embryo Acute Toxicity Tests (FET tests). Subsequently, two concentrations of TCC were used to investigate the morphometric features and defects in larvae developmental pigmentation: an environmentally relevant (5μg/L) and toxicological (50μg/L), derived from the No Observed Effect Concentration (NOEC) value concentration. Furthermore, the expression levels of a key transcription factor for melanocyte differentiation and melanin syntheses, such as mitfa (microphthalmia-associated transcription factor) and tyr (tyrosinase) and its activity, were evaluated