Zebrafish Developmental and Reproductive Toxicity

The primary goal of preclinical safety testing is to predict and prevent toxicities that may occur in the clinic. It has been estimated that preclinical toxicity is responsible for approximately 20% of drug attrition, and developmental and reproductive toxicity (DART) issues account for over 10% of preclinical toxicology-related attrition. Currently, achieving registration of a drug translates into the use of abundant animals, generally rats and rabbits, for the teratogenicity safety assessment, which is not following the current trend of applying the 3R principle (replacement, reduction or refinement of animal use).

From the alternative testing methods, the larval zebrafish appears to be an ideal model for the evaluation of adverse drug reactions and the zebrafish developmental toxicity assay could be used to identify compounds harmful to embryofoetal development early in drug development. The development process is highly conserved across vertebrate species, making zebrafish development greatly comparable to that of mammalians. Besides, the developing larvae are translucent and hence no complex, time-consuming or expensive imaging systems are demanded. Thus the zebrafish could be well-positioned to bridge the gap between in vitro and in vivo toxicity testing.

Figure 1. Zebrafish embryos and larvae at stages. (Brannen K C, et al., 2017)

Creative Biogene, a zebrafish research company with experienced scientists and advanced technology, can provide developmental and reproductive toxicology tests to predict the safety of new compounds during drug development, and the results can provide the basis for internal decision-making.

Zebrafish embryo toxicity assay: We have developed the zebrafish embryo toxicity assays by using newly fertilized zebrafish eggs, and can assess for 4 toxic endpoints: the coagulation of eggs and embryos, lack of heartbeat, failure to develop somites, as well as non-detachment of the tail from the yolk. Embryo toxicity assays of multiple drugs, endogenous signaling molecules and hormones have also been evaluated in zebrafish.
Developmental toxicity and teratogenicity assessment: We assess developmental toxicity and teratogenicity of chemicals and drugs in embryonic and larval zebrafish using 12 major endpoints and 8 minor endpoints. The 12 major endpoints are the heart, brain, eye, jaw, liver, intestine, trunk/tail/notochord, muscle/somite, body pigmentation, circulation, body edema and hemorrhage. The 8 minor endpoints are the fin, ear, red blood cell formation, swim bladder, kidney cysts, pancreas, motility and body length.
Reproductive toxicity assessment: Reproductive toxicity assessment using zebrafish is focused on: (1) the gonad growth index (gonad weight, GSI); (2) the gonad histology; (3) reproduction ability: the egg-laying amount; (4) the vitellogenin (Vtg) expression assay; and (5) the hypothalamus-pituitary-gonad (HPG) axis gene expression analysis.
Behavioral toxicity assessment: DART could cause abnormal or dysfunctional behaviors. Zebrafish locomotor behavior can be visually assessed by performing touch response or escape response. Quantitative analysis can be performed by continuous image acquisition using an infrared camera to measure the duration and number of movements and the distance traveled in a given period.

References

He J H, et al. Zebrafish models for assessing developmental and reproductive toxicity. Neurotoxicology and teratology, 2014, 42: 35-42.
Busch W, et al. The zebrafish embryo model in toxicology and teratology, September 2–3, 2010, Karlsruhe, Germany. Reproductive Toxicology, 2011, 31(4): 585-588.
Van den Bulck K, et al. Zebrafish developmental toxicity assay: a fishy solution to reproductive toxicity screening, or just a red herring?. Reproductive Toxicology, 2011, 32(2): 213-219.
Brannen K C, et al. Alternative models of developmental and reproductive toxicity in pharmaceutical risk assessment and the 3Rs. ILAR journal, 2017, 57(2): 144-156.

For research use only. Not intended for any clinical use.

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