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. 2023 Mar 13;9(3):e14557. doi: 10.1016/j.heliyon.2023.e14557

Table 5.

Limitations associated with disease modeling zebrafish.

Type of Limitations Description Reference
General Limitations Presence of duplicate copies of mammalian genes despite the high similarity in the homology of zebrafish to rodents and human beings with the genomic duplication being events that are independent and continuous. [108]
Availability of genetically characterized strains of zebrafish is constrained due to its loss of fertility upon inbreeding and those that have been developed aren't easy to maintain. [109]
Divergence of a few functional genes due to genomic duplication limit the accuracy of disease modeling in zebrafish [110]
Zebrafish don't have sex chromosomes unlike humans and hence there is a difference in the sex ratio of the teleosts in the majority of research designs leading to varying levels of sexual dimorphism in comparison to mammals. [6]
Water-insoluble drug administration is a problem and requires the administration of the drug through various other mechanisms including the use of vehicles or techniques such as developing oral gavage or microinjections through the oesophagus. [18]
Despite having a good amount of physiological homology, the environmental conditioning between zebrafish and humans remains with the teleosts being maintained at about a temperature of 28 °C. [5]
Even though zebrafish have a blood-brain barrier (BBB) that is substantially alike to its human counterpart, due to the effect of differences between species, the action of drugs keeps changing due to the change of the BBB permeability causing a hindrance to drug testing. Similar effects due to species differences are also observed in cases of metabolism and thermoregulation. This accounts for one of the more serious limitations associated with the teleost models. [18]
The dosage cannot be easily translated directly from zebrafish into rodent or human doses and vice versa due to differences in the physiology between the species.
Limitations in Bone Disease Modelling Mineral ossification pathway is widely different in zebrafish in comparison to mammals especially terrestrial mammals due to the variance in the uptake and excretion of calcium. [111]
The development of the teleost skeletal system is prone to environmental influences which is not the case for most placental organisms. [112]
Limitations in Cardiovascular Disease Modelling Studying septal development including blood pressure and metabolism is a hindrance. [113]
There are differences in cardiac electrophysiology due to the variation in the cycling of calcium and ionic currents. [114]
There is a possibility of ventricular amputation due to the smaller size of zebrafish during ECG studies affecting the heart rate and the heart rate variability. [115]
Limitations in Renal Disease Modelling Disruption of the functionality of the glomerulus in the kidneys of zebrafish embryos causes the death of the embryos within a few days. [116]
Limitations in Cancer Modelling Most of the present zebrafish disease models for cancer are made by knocking out certain genes deviating from their corresponding syndromes which usually show missense mutations failing to truncate proteins. This doesn't allow for a proper investigation into the protein interactions or the genetic basis of the disease. [117]
Limitations in Blood Disease Modelling Studying lymphocyte subtypes and the biology of leukocytes is difficult due to the scarcity of well-characterized monoclonal antibodies acting on the leukocyte surface molecule. [118]
The difference in the morphology of some blood cells like erythrocytes and thrombocytes which are nucleated in zebrafish models might cause a hindrance in drawing parallels with humans and translating research.