The zebrafish has become a widely used model organism because of its fecundity, its morphological and physiological similarity to mammals, the existence of many genomic tools and the ease with which large, phenotype-based screens can be performed. Because of these attributes, the zebrafish might also provide opportunities to accelerate the process of drug discovery. By combining the scale and throughput of in vitro screens with the physiological complexity of animal studies, the zebrafish promises to contribute to several aspects of the drug development process, including target identification, disease modelling, lead discovery and toxicology.

In vivo drug discovery in the zebrafish

https://research.birmingham.ac.uk/portal/files/41988116/Anekwe_et_al_2017.pdf

Pharmaceuticals and personal care products (PPCPs) in the freshwater aquatic environment

Zebrafish as a model vertebrate for investigating chemical toxicity.

Ecotoxicological impact of pharmaceuticals found in treated wastewaters: study of carbamazepine, clofibric acid, and diclofenac

Steroidal estrogens, originating principally from human excretion, are likely to play a major role in causing widespread endocrine disruption in wild populations of the roach (Rutilus rutilus), a common cyprinid fish, in rivers contaminated by treated sewage effluents. Given the extent of this problem, risk assessment models are needed to predict the location and severity of endocrine disruption in river catchments and to identify areas where regulation of sewage discharges to remove these contaminants is necessary. In this study we attempted to correlate the extent of endocrine disruption in roach in British rivers, with their predicted exposure to steroid estrogens derived from the human population. The predictions of steroid estrogen exposure at each river site were determined by combining the modeled concentrations of the individual steroid estrogens [17beta-estradiol (E2), estrone (E1), and 17alpha-ethinylestradiol (EE2)] in each sewage effluent with their predicted dilution in the immediate receiving water. This model was applied to 45 sites on 39 rivers throughout the United Kingdom. Each site studied was then categorized as either high, medium, or low "risk" on the basis of the assumed additive potency of the three steroid estrogens calculated from data derived from published studies in various cyprinid fish species. We sampled 1,438 wild roach from the predicted high-, medium-, and low-risk river sites and examined them for evidence and severity of endocrine disruption. Both the incidence and the severity of intersex in wild roach were significantly correlated with the predicted concentrations of the natural estrogens (E1 and E2) and the synthetic contraceptive pill estrogen (EE2) present. Predicted steroid estrogen exposure was, however, less well correlated with the plasma vitellogenin concentration measured in the same fish. Moreover, we found no correlation between any of the end points measured in the roach and the proportion of industrial effluents entering the rivers we studied. Overall, our results provide further and substantive evidence to support the hypothesis that steroidal estrogens play a major role in causing intersex in wild freshwater fish in rivers in the United Kingdom and clearly show that the location and severity of these endocrine-disrupting effects can be predicted.

/pdf/predicted-exposures-to-steroid-estrogens-in-u-k-rivers-1cpvhy3qlx.pdf

Predicted exposures to steroid estrogens in U.K. rivers correlate with widespread sexual disruption in wild fish populations.

Impacts of 17β-estradiol, including environmentally relevant concentrations, on reproduction after exposure during embryo-larval-, juvenile- and adult-life stages in zebrafish (Danio rerio)

Laboratory and field studies were carried out in order to assess, in a common cyprinid freshwater fish, the chub (Leuciscus cephalus), the feasibility of biological methods to detect and quantify estrogenic effects. In the laboratory the effects of 17beta estradiol were investigated on Vitellogenin (Vtg) induction and on testis organisation. Vtg was quantified by immunodetection using an established ELISA for carp (Cyprinus carpio) Vtg. Estradiol exposure resulted in a significant and rapid increase in plasma Vtg in both male and female chub, indicating that vitellogenic response in the chub is sensitive to estrogen(s). Histological examination of the testis in males exposed to estradiol also showed effects on the testis. Preliminary field studies on wild chub showed that fish living in a polluted river had elevated concentrations of plasma Vtg and had some alterations in the testis compared with wild fish from a reference site. Together these preliminary laboratory and field results show that chub could be an interesting fish species for further studies of biological effects of environmental estrogens in the aquatic environment

Induction of Fish Vitellogenin and Alterations in Testicular Structure: Preliminary Results of Estrogenic Effects in Chub (Leuciscus cephalus)

Effect of estradiol on vitellogenesis and reproductive parameters in Zebrafish (Danio rerio)

Beagle dogs are a key nonrodent species in nonclinical safety evaluation of new biomedical products. The Society of Toxicologic Pathology (STP) has published “best practices” recommendations for nervous system sampling in nonrodents during general toxicity studies (Toxicol Pathol 41[7]: 1028-1048, 2013), but their adaptation to the Beagle dog has not been defined specifically. Here we provide 2 trimming schemes suitable for evaluating the unique neuroanatomic features of the dog brain in nonclinical toxicity studies. The first scheme is intended for general toxicity studies (Tier 1) to screen test articles with unknown or no anticipated neurotoxic potential; this plan using at least 7 coronal hemisections matches the STP “best practices” recommendations. The second trimming scheme for neurotoxicity studies (Tier 2) uses up to 14 coronal levels to investigate test articles where the brain is a suspected or known target organ. Collection of spinal cord, ganglia (somatic and autonomic), and nerves for dogs during nonclinical studies should follow published STP “best practices” recommendations for sampling the central (Toxicol Pathol 41[7]: 1028-1048, 2013) and peripheral (Toxicol Pathol 46[4]: 372-402, 2018) nervous systems. This technical guide also demonstrates the locations and approaches to collecting uncommonly sampled peripheral nervous system sites.

A Technical Guide to Sampling the Beagle Dog Nervous System for General Toxicity and Neurotoxicity Studies

Nonclinical toxicology studies that are required to support human clinical trials of new drug candidates are generally conducted in a rodent and a non-rodent species. These studies typically contain a vehicle control group and low, intermediate, and high dose test article groups. In addition, a dosing-free recovery phase is sometimes included to determine reversibility of potential toxicities observed during the dosing phase and may include additional animals in the vehicle control and one or more dose groups. Typically, reversibility is determined by comparing the test article–related changes in the dosing phase animals to concurrent recovery phase animals at the same dose level. Therefore, for interpretation of reversibility, it is not always essential to euthanize the recovery vehicle control animals. In the absence of recovery vehicle control tissues, the pathologist’s experience, historical control database, digital or glass slide repositories, or literature can be used to interpret the findings in the context of background pathology of the species/strain/age. Therefore, in most studies, the default approach could be not to euthanize recovery vehicle control animals. This article provides opinions on scenarios that may or may not necessitate euthanasia of recovery phase vehicle control animals in nonclinical toxicology studies involving dogs and nonhuman primates.

Xavier Palazzi

Papers

Impacts of 17β-estradiol, including environmentally relevant concentrations, on reproduction after exposure during embryo-larval-, juvenile- and adult-life stages in zebrafish (Danio rerio)

Induction of Fish Vitellogenin and Alterations in Testicular Structure: Preliminary Results of Estrogenic Effects in Chub (Leuciscus cephalus)

Effect of estradiol on vitellogenesis and reproductive parameters in Zebrafish (Danio rerio)

A Technical Guide to Sampling the Beagle Dog Nervous System for General Toxicity and Neurotoxicity Studies

Toxicologic Pathology Forum: Opinion on Not Euthanizing Control Animals in the Recovery Phase of Non-Rodent Toxicology Studies