Alternative model organisms for toxicological fingerprinting of relevant parameters in food and nutrition

Figures & data

Figure 1. Overview of the reviewed alternative model systems for prediction of toxicity in food matter.

Table 1. Comparison of selected alternative models.

traits	C. elegans	D. rerio	Drosophila
adult size	1 mm	400 mm	3-4 mm
brood size	140 eggs/day	250 eggs/day	20 eggs/day
ethical constraints	no	no: under 5 dfp	no
data bases	Wormbase	ZFIN	Flybase
gene homology (human)	60%	70%	65%
genome completely sequenced	yes	yes	yes
genome size	97 Mb	1412 Mb	165 Mb
number of chromosomes	6-7	25	4
growth conditions	liquid/plates	liquid	vials
high-throughput screening	yes	yes	yes
life cycle	3 days	90 days	10 days
life span	21 days	730 days	50–60 days
toxicological assessment	yes	yes	yes
transgenic mutants	yes	yes	yes
source	(Lai et al. 2000; Strange 2016; Hunt, Camacho, and Sprando 2020)	(Howe et al. 2013; Strange 2016; Horzmann and Freeman 2018)	(Strange 2016; Staats and Lüersen et al. 2018; Nobrega and de Lyons 2020)

Table 2. Food related toxicants analyzed by alternative model systems.

organism	compound	dose	mechanisms of action	reference
C. elegans	triazole fungicides	Epoxiconazole: 0.09–12.13 µM Prochloraz: 0.08–10.62 µM Cyproconazole: 2.68–342.72 µM Propiconazole:2.28–292.21 µM Tebuconazole: 0.76–97.46 µM	IC50 in C. elegans correlated with EC50 in rats. Toxicokinetic data revealed differences in substance accumulation: Prochloraz 1341%, epoxiconazole 655%, tebuconazole 636% and cyproconazole 144% accumulation was identified in the worm.	(Wittkowski et al. 2019)
C. elegans	essential oils (citrus, eucalyptus, rosemary)	0.1; 0.25%; 0.5% (v/v) wildtype 0.01%; 0.025%; 0.05% (v/v) bus-5	High correlation of the predicted mean LD50 from rats, indicating that the prediction of acute toxicity by alternative models might have sufficient potential. Significant changes in gene expression of xenobiotic and oxidative stress genes Cytochrome P450 (cyp-14a3), Glutathione-S-Transferase (gst-4), Glutathione peroxidase (gpx-6) and Superoxide dismutase (sod-3) were observed.	(Lanzerstorfer et al. 2021)
C. elegans	saccharin	0.3 mg/mL; 10 mg/mL	Mild impairment of lifespan at 0.3 mg/mL while 10 mg/mL showed reduced food intake and intestinal fat deposition.	(Zhang et al. 2019)
C. elegans	Bisphenol A (BPA), propyl paraben (PPB), and triclosan (TCS)	0.05–5000 µM of each compound	Reproduction and growth (BPA, TCS) were altered in an oxidative stress dependent manner. Also, increased lipid accumulation was observed in the worm. Paraben showed significant reduction in worm length and head thrash behavior as well as a downregulation of vitellogenin genes.	(García-Espiñeira, Tejeda-Benítez, and Olivero-Verbel 2018)
C. elegans	citrinin (CIT), zearalenone-14-sulfate (ZEA-14-S) and zearalenone (ZEA)	2.5 mg/L–62.5 mg/L mycotoxins	Significant decrease in brood size. ZEA and CIT showed reduced stress tolerance levels in C. elegans, while CIT additionally decreased mean lifespan.	(Keller et al. 2018)
C. elegans	Lactobacillus fermentum	10 mg of bacterial cells	Significant increase of median lifespan and delayed ageing processes (motility or pharyngeal pumping rate). Lipid droplet accumulation and oxidative stress were reduced.	(Schifano et al. 2019)
C. elegans	Cadmium	1 mg/L	Significantly lower microbiome change when worms were fed with soil microbial community (SMB).	(Lee, Kim, and Choi 2020)
C. elegans	Nano silica (E551)	25 mg/mL powder in ddH2O	Intestinal ballooning within 24 h of exposure.	(Piechulek, Berwanger, and Mikecz 2019)
C. elegans	Titanium dioxide (E171)	1-10 mg/L	Reduction in lifespan and increased age-associated vulval integrity defects.	(Ma et al. 2019)
C. elegans	Roasted pork nano particles (NPs)	10 mg/mL	Worms were significantly shorter in length. The locomotive behavior (body bends per minute) was changed. Laser confocal microscope images in C. elegans identified the epithelium of the gastrointestinal tract as the primary target of NPs.	(Zhao et al. 2019)
C. elegans	Arsenic, lead and mercury	LiOAc: 0-2000 µg/mL, NaAs: 0–400 µg/mL; PBOAc: 0–25 µg/mL; HgOAc: 0–25 µg/mL	Hyperactivity was detected at concentrations that also delayed development to the larval stages L3-L4 by 6–18%. Hypoactivity was found for arsenic and lead.	(Hunt et al. 2018)
Danio rerio	Curcuma longa	125 µg/mL; 62.5 µg/mL; 31.25 µg/mL; 15.63 µg/mL; and 7.8 µg/mL	Toxicity effects at dosage above 62.50 µg/mL; mortality at 125.0 µg/mL.	(Alafiatayo et al. 2019)
Danio rerio	Genistein and daidzein	1.25 mg/L to 20 mg/L	Genistein is more toxic (LC50: 4.41 mg/L) than daidzein (65.15 mg/L).	(Sarasquete, Úbeda-Manzanaro, and Ortiz-Delgado 2018)
Danio rerio	Clinacanthus nutans	15.63 µg/mL, 31.25 µg/mL, 62.5 µg/mL, 125 µg/mL, 250 µg/mL and 500 µg/mL	LC50 was determined to be 75.49 µg/mL; morphological defects such as less pigmentation, dented tail, spinal curvature, edema malformed yolk sac, reduced hatchability and growth retardation were observed at this concentration.	(Murugesu et al. 2019)
Danio rerio	Training set with 34 compounds	0.1, 1, 10, and 100 µM	Chorion-off assay is more sensitive (83%) compared to assay with intact chorion (63 − 74%).	(Panzica-Kelly, Zhang, and Augustine-Rauch 2015)
Danio rerio	Cannabinol	0.25 mg/L, 0.75 mg/L, 1.0 mg/L, 1.125 mg/L, 1.2 mg/L, 1.25 mg/L and 2.0 mg/L	CBN values greater than 0.75 mg/L resulted in abnormalities like ericardial edema, yolk sac anomalies and tail bending; LC50 was determined to be 1.12 mg/L.	(Chousidis et al. 2020)
Danio rerio	Zearalenone	350 mg/L, 550 mg/L, 750 mg/L and 950 mg/L	Oxidative stress at concentrations above 550 mg/L; neurotoxic effects above 750 mg/L.	(Muthulakshmi et al. 2018)
Danio rerio	Chemical contaminants	Diethylmaleate (DEM): 10 µM, 20 µM, 40 µM Acetaminophen (APAP): 1.25 µM, 2.5 µM, 5 µM Cisplatin: 10 mM, 50 mM, 100 mM Phenylhydrazine (PhZ): 0.0125 µM, 0.025 µM, 0.05 µM Copper: 0.2545 µg/L, 0.509 µg/L, 5.09 µg/L	Stable transgenic zebrafish line Tg (3EpRE:hsp70:mCherry) is sensitive for detection of cellular RedOx imbalances.	(Mourabit et al. 2019)
Danio rerio	o tertbutyl hydroperoxide (t-BHP)	1 or 2 mM	Novel procedures proved suitable for oxidative stress detection.	(Lackmann et al. 2018)
Danio rerio	Chitosan-nanoencapsulated quercetin	400 mg free quercetin per kg diet	Nanoencapsulation can improve the antioxidant efficacy of quercetin against oxidative stress caused by silver nanoparticles.	(Tayemeh et al. 2020)
Danio rerio	Phytochemicals derived from spices	1, 5, 25 and 125 µM	Curcumin, diallyl trisulfide and quercetin reduced hydrogen peroxide toxicity; cinnamaldehyde, isoeugenol and 6-(methylsulfinyl)hexyl isothiocyanate reduced arsenite toxicity.	(Endo et al. 2020)
Danio rerio	Daxitoxin	0.05 and 0.1 µM	Saxitoxin induced adverse effect on development of zebrafish embryos	(Chen et al. 2020)
Danio rerio	Psoralen	1.06 µM, 3.54 µM, 10.61 µM and 13.54 µM	psoralen exerted toxic effects on the development of the heart, liver, phagocytes, and nervous system.	(Xia et al. 2018)
Danio rerio	Neurotoxicants	1 nM to 100 µM	Six of the ten tested neurotoxicants provoked developmental neurotoxicity; the triple-transgenic zebrafish line can be used to assess developmental neurotoxicity during neuronal differentiation	(Koiwa et al. 2019)
Danio rerio	Caffeine	0.001 mg/L to 186.67 mg/L	Caffeine at concentrations above at concentrations ≥0.039 mg/L significantly altered zebrafish behavior.	(Steele, Mole, and Brooks 2018)
Danio rerio	Coriandrum sativum extract	25, 50 or 100 mg/kg	Coriandrum sativum extract presents anxiolytic effects against alarm substance-induced locomotor and anxiogenic responses	(Zenki et al. 2020)
Danio rerio	Δ9-tetrahydrocannabinol (THC) or cannabidiol (CBD)	THC (0.08, 0.4, 2 µM) or CBD (0.02, 0.1, 0.5 µM)	Support of cannabinoid-related developmental neurotoxicity.	(Carty et al. 2019)
Drosophila	Acrylamide	0.5 mM, 1.0 mM, 1.5 mM, 2.0 mM	Reduced life span along with impaired locomotor functions as an indication of neural impairment (at 2 mM); a combination of thymoquinone and curcumin improved the locomotor functions in adult flies.	(Senthilkumar et al. 2020)
Drosophila	Titanium dioxide nanoparticles (E171)	12.25 + 0.44 mg/kg	Larval stages were at a higher risk of sustaining damage from E171.	(Jovanović et al. 2018)
Drosophila	Riboflavin, Tartrazine, Carminic Acid, Erythrosine, Indigotine, and Brilliant Blue FCF	acceptable daily intake (ADI) concentrations	Food colorings increased tumor cell growth but did not induce DNA damage	(Merinas-Amo, Martínez-Jurado, et al. 2019)
Drosophila	Czech beers and their constituents	3.125–50 mg/mL	Safety for all analyzed substances and general protective effects against H2O2.	(Merinas-Amo, Merinas-Amo, et al. 2019)
Drosophila	Resveratrol	500 µmol/L	Resveratrol does not affect life span, body composition, locomotor activity, stress response, and longevity-associated gene expression.	(Staats and Wagner et al. 2018)
Drosophila	Curcumin	0.2 mg/g	Curcumin increases the survival rate of Drosophila by enhancing thermal tolerance.	(Chen, Liu, et al. 2018)
Drosophila	Kolaviron	100–500 mg/kg diet	Kolaviron (200, 100, 300 and 400 mg/kg) extended lifespan of flies by 38.2%, 20.6%, 11.8% and 2.9% respectively.	(Farombi et al. 2018)
Drosophila	Ellagic acid	200 µM	Female flies fed laid a smaller number of eggs than control, but the mean and maximum lifespan of male flies was extended.	(Kharat et al. 2020)
Drosophila	Hesperidin	10 µM	Hesperidin ameliorates iron-induced mortality, oxidative stress and mitochondrial dysfunction.	(Poetini et al. 2018)
Drosophila	Paraquat (PQ) and caffeic acid (CA)	PQ (0.44 mg/g of diet) and CA (0.25; 0.5; 1 and 2 mg/g of diet)	Protective effect of caffeic acid against paraquat-induced oxidative damage.	(Dos Santos Nunes et al. 2019)
Hen’s egg	Dorema Ammoniacum (DA) extract	50 or 100 mg of DA extract per kg egg-weight	Decreased vascular parameters, like vessels area, total vessels length, vascular branch and increased lacunarity.	(Tavakkoli et al. 2020)
Hen’s egg	Food-grade titanium dioxide nanoparticles (E171)	10 µg of E171 dispersed in saline solution	No significant effect on the average of maximum branches length and microvascular density.	(Freyre-Fonseca et al. 2018)
Hen’s egg	Chitosan nanoparticles	A sterile disk loaded with a chitosan scaffold	No difference in the growth of blood vessels.	(Balan et al. 2020)
Hen’s egg	Bellis perennis (BE) extract	∼300 mg/L of BE extract for 1 and 2 hours	reduced blood glucose levels and caused no adverse effects on the vessel network.	(Haselgrübler and Stadlbauer et al. 2018)
Hen’s egg	Glucose solution (simulation of gestational diabetes)	50 mL glucose solutions (25 mM, 50 mM and 100 mM)	Inhibited angiogenesis and reduced vascular density.	(Jin et al. 2019)
Hen’s egg	Glucose and baicalein	high glucose (50 mM) and / or 6 µM baicalein for 48 h	Significantly reversed the reduction of blood vessels under high glucose conditions.	(Wang et al. 2018)
Chip-based intestinal barrier	Ergotaminine	10 µg/mL (apical)	The natural toxin ergotaminine was transported across the intestinal barrier and thus could become bioavailable.	(Santbergen et al. 2020)
Chip-based gut	Dioxins (toxin)	0.2 ng/mL of each of the ten congeners of dioxin (apical)	Toxic dioxins were absorbed by the gut model and thus could become bioavailable.	(Kulthong et al. 2018)
Chip-based placental barrier	Titanium dioxide (E171) nanoparticles	low (short, 50 µg/mL) and high (chronic, 200 µg/mL) concentrations of E171 for 24 hours	Short exposure: reduced expression of tight junction proteins (E- and VE-cadherin) and an increase in the permeability for FITC-Dextran indicating disruption of the barrier. Chronic exposure: increased ROS production, cell death rates and interleukin (IL)-6 levels	(Yin et al. 2019)

Table 3. List of abbreviations.

abbreviation	explanation
AChE	acetylcholinesterase
ADME	absorption, distribution, metabolism and excretion
ARE	antioxidant response element
CAT	catalase
CBD	cannabinol
CIT	citrinin
dpf	day post fertilization
E171	titanium dioxide
E551	nano silica
EC50	half maximal effective concentration
EpRE	electrophile response element
FET	fish embryo acute toxicity
GPx	glutathione peroxidase
GSH	reduced glutathione
GST	glutathione S-transferase
HET-CAM	hen’s egg test – chorioallantoic membrane
hpf	hours post fertilization
IC50	half maximal inhibitory concentration
IFD	intestinal fat deposition
LC50	lethal concentration 50%
LD50	lethal dose 50%
LDH	lactate dehydrogenase
LPO	lipid peroxidation
MET	mean elution time
NAMs	new approach methodologies
NO	nitric oxide
NPs	nanoparticles
OOC	organ-on-chip
PDMS	polydimethylsiloxane
PE	proboscis extension
PMR	photomotor response
pVDCs	putative vascular disruptor compounds
QSAR	quantitative structure-activity relationship
RING	rapid iterative negative geotaxis
ROS	reactive oxygen species
SAC	saccharin
SMB	soil microbial community
SOD	superoxide dismutase
THC	Δ9-tetrahydrocannabinol
wDAT	worm Development and Activity Test
ZEA	zearalenone
ZEA-14-S	zearalenone-14-sulfate

Lai, C. H., C. Y. Chou, L. Y. Ch'ang, C. S. Liu, and W. Lin. 2000. Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Research 10 (5):703–13. doi: 10.1101/gr.10.5.703.

 PubMed Web of Science ®Google Scholar

Strange, K. 2016. Drug Discovery in Fish, Flies, and Worms. ILAR Journal 57 (2):133–43. doi: 10.1093/ilar/ilw034.

 PubMed Web of Science ®Google Scholar

Hunt, P. R., J. A. Camacho, and R. L. Sprando. 2020. Caenorhabditis elegans for predictive toxicology. Current Opinion in Toxicology 23-24:23–8. doi: 10.1016/j.cotox.2020.02.004.

 Web of Science ®Google Scholar

Howe, K., M. D. Clark, C. F. Torroja, J. Torrance, C. Berthelot, M. Muffato, J. E. Collins, S. Humphray, K. McLaren, L. Matthews, et al. 2013. The zebrafish reference genome sequence and its relationship to the human genome. Nature 496 (7446):498–503. doi: 10.1038/nature12111.

 PubMed Web of Science ®Google Scholar

Horzmann, K. A., and J. L. Freeman. 2018. Making Waves: New Developments in Toxicology With the Zebrafish. Toxicological Sciences: An Official Journal of the Society of Toxicology 163 (1):5–12. doi: 10.1093/toxsci/kfy044.

 PubMed Web of Science ®Google Scholar

Staats, S., K. Lüersen, A. E. Wagner, and G. Rimbach. 2018. Drosophila melanogaster as a versatile model organism in food and nutrition research. Journal of Agricultural and Food Chemistry 66 (15):3737–53. doi: 10.1021/acs.jafc.7b05900.

 PubMed Web of Science ®Google Scholar

Nobrega, A. K., and L. C. de Lyons. 2020. Aging and the clock: Perspective from flies to humans. The European Journal of Neuroscience 51 (1):454–81. doi: 10.1111/ejn.14176.

 PubMed Web of Science ®Google Scholar

Wittkowski, P., P. Marx-Stoelting, N. Violet, V. Fetz, F. Schwarz, M. Oelgeschläger, G. Schönfelder, and S. Vogl. 2019. Caenorhabditis elegans As a Promising Alternative Model for Environmental Chemical Mixture Effect Assessment-A Comparative Study. Environmental Science & Technology 53 (21):12725–33. eng. doi: 10.1021/acs.est.9b03266.

 PubMed Web of Science ®Google Scholar

Lanzerstorfer, P., G. Sandner, J. Pitsch, B. Mascher, T. Aumiller, and J. Weghuber. 2021. Acute, reproductive, and developmental toxicity of essential oils assessed with alternative in vitro and in vivo systems. Archives of Toxicology 95 (2):673–19. . doi: 10.1007/s00204-020-02945-6.

 PubMed Web of Science ®Google Scholar

Zhang, M., X. Yang, W. Xu, X. Cai, M. Wang, Y. Xu, P. Yu, J. Zhang, Y. Zheng, J. Chen, et al. 2019. Evaluation of the effects of three sulfa sweeteners on the lifespan and intestinal fat deposition in C. elegans. Food Research International (Ottawa, Ont.) 122:66–76. doi: 10.1016/j.foodres.2019.03.028.

 PubMed Web of Science ®Google Scholar

García-Espiñeira, M. C., L. P. Tejeda-Benítez, and J. Olivero-Verbel. 2018. Toxic Effects of Bisphenol A, Propyl Paraben, and Triclosan on Caenorhabditis elegans. International Journal of Environmental Research and Public Health 15 (4):684. doi: 10.3390/ijerph15040684.

 Web of Science ®Google Scholar

Keller, J., A. Borzekowski, H. Haase, R. Menzel, L. Rueß, and M. Koch. 2018. Toxicity assay for citrinin, zearalenone and zearalenone-14-sulfate using the nematode caenorhabditis elegans as model organism. Toxins (Basel) 10 (7):284. doi: 10.3390/toxins10070284.

 Web of Science ®Google Scholar

Schifano, E., P. Zinno, B. Guantario, M. Roselli, S. Marcoccia, C. Devirgiliis, and D. Uccelletti. 2019. The foodborne strain lactobacillus fermentum MBC2 triggers pept-1-dependent pro-longevity effects in caenorhabditis elegans. Microorganisms 7 (2):45. doi: 10.3390/microorganisms7020045.

 PubMed Web of Science ®Google Scholar

Lee, S., Y. Kim, and J. Choi. 2020. Effect of soil microbial feeding on gut microbiome and cadmium toxicity in Caenorhabditis elegans. Ecotoxicology and Environmental Safety 187:109777. doi: 10.1016/j.ecoenv.2019.109777.

 PubMed Web of Science ®Google Scholar

Piechulek, A., L. C. Berwanger, and A. v Mikecz. 2019. Silica nanoparticles disrupt OPT-2/PEP-2-dependent trafficking of nutrient peptides in the intestinal epithelium. Nanotoxicology 13 (8):1133–48. doi: 10.1080/17435390.2019.1643048.

 PubMed Web of Science ®Google Scholar

Ma, H., K. A. Lenz, X. Gao, S. Li, and L. K. Wallis. 2019. Comparative toxicity of a food additive TiO2, a bulk TiO2, and a nano-sized P25 to a model organism the nematode C. elegans. Environmental Science and Pollution Research International 26 (4):3556–68. doi: 10.1007/s11356-018-3810-4.

 PubMed Web of Science ®Google Scholar

Zhao, X., S. Shan, J. Li, L. Cao, J. Lv, and M. Tan. 2019. Assessment of potential toxicity of foodborne fluorescent nanoparticles from roasted pork. Nanotoxicology 13 (10):1310–23. doi: 10.1080/17435390.2019.1652943.

 PubMed Web of Science ®Google Scholar

Hunt, P. R., N. Olejnik, K. D. Bailey, C. A. Vaught, and R. L. Sprando. 2018. C. elegans Development and Activity Test detects mammalian developmental neurotoxins. Food and Chemical Toxicology : An International Journal Published for the British Industrial Biological Research Association 121:583–92. doi: 10.1016/j.fct.2018.09.061.

 PubMed Web of Science ®Google Scholar

Alafiatayo, A. A., K.-S. Lai, A. Syahida, M. Mahmood, and N. A. Shaharuddin. 2019. Phytochemical Evaluation, Embryotoxicity, and Teratogenic Effects of Curcuma longa Extract on Zebrafish (Danio rerio). Evidence-Based Complementary and Alternative Medicine: eCAM 2019:3807207. doi: 10.1155/2019/3807207.

 PubMed Web of Science ®Google Scholar

Sarasquete, C., M. Úbeda-Manzanaro, and J. B. Ortiz-Delgado. 2018. Toxicity and non-harmful effects of the soya isoflavones, genistein and daidzein, in embryos of the zebrafish, Danio rerio. Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP 211:57–67. doi: 10.1016/j.cbpc.2018.05.012.

 PubMed Web of Science ®Google Scholar

Murugesu, S., A. Khatib, Q. U. Ahmed, Z. Ibrahim, B. F. Uzir, K. Benchoula, N. I. N. Yusoff, V. Perumal, M. F. Alajmi, S. Salamah, et al. 2019. Toxicity study on Clinacanthus nutans leaf hexane fraction using Danio rerio embryos. Toxicology Reports 6:1148–54. doi: 10.1016/j.toxrep.2019.10.020.

 PubMed Web of Science ®Google Scholar

Panzica-Kelly, J. M., C. X. Zhang, and K. A. Augustine-Rauch. 2015. Optimization and performance assessment of the chorion-off [dechorinated] zebrafish developmental toxicity assay. Toxicological Sciences : An Official Journal of the Society of Toxicology 146 (1):127–34. doi: 10.1093/toxsci/kfv076.

 PubMed Web of Science ®Google Scholar

Chousidis, I., T. Chatzimitakos, D. Leonardos, M. D. Filiou, C. D. Stalikas, and I. D. Leonardos. 2020. Cannabinol in the spotlight: Toxicometabolomic study and behavioral analysis of zebrafish embryos exposed to the unknown cannabinoid. Chemosphere 252:126417. doi: 10.1016/j.chemosphere.2020.126417.

 PubMed Web of Science ®Google Scholar

Muthulakshmi, S., K. Maharajan, H. R. Habibi, K. Kadirvelu, and M. Venkataramana. 2018. Zearalenone induced embryo and neurotoxicity in zebrafish model (Danio rerio): Role of oxidative stress revealed by a multi biomarker study. Chemosphere 198:111–21. doi: 10.1016/j.chemosphere.2018.01.141.

 PubMed Web of Science ®Google Scholar

Mourabit, S., J. A. Fitzgerald, R. P. Ellis, A. Takesono, C. S. Porteus, M. Trznadel, J. Metz, M. J. Winter, T. Kudoh, and C. R. Tyler. 2019. New insights into organ-specific oxidative stress mechanisms using a novel biosensor zebrafish. Environment International 133 (Pt A):105138. doi: 10.1016/j.envint.2019.105138.

 PubMedGoogle Scholar

Lackmann, C., M. M. Santos, S. Rainieri, A. Barranco, H. Hollert, P. Spirhanzlova, M. Velki, and T.-B. Seiler. 2018. Novel procedures for whole organism detection and quantification of fluorescence as a measurement for oxidative stress in zebrafish (Danio rerio) larvae. Chemosphere 197:200–9. doi: 10.1016/j.chemosphere.2018.01.045.

 PubMed Web of Science ®Google Scholar

Tayemeh, M. B., M. R. Kalbassi, H. Paknejad, and H. S. Joo. 2020. Dietary nanoencapsulated quercetin homeostated transcription of redox-status orchestrating genes in zebrafish (Danio rerio) exposed to silver nanoparticles. Environmental Research 185:109477eng. doi: 10.1016/j.envres.2020.109477.

 PubMed Web of Science ®Google Scholar

Endo, Y., K. Muraki, Y. Fuse, and M. Kobayashi. 2020. Evaluation of Antioxidant Activity of Spice-Derived Phytochemicals Using Zebrafish. International Journal of Molecular Sciences. 21 (3):1109. doi: 10.3390/ijms21031109.

 Web of Science ®Google Scholar

Chen, G., Z. Jia, L. Wang, and T. Hu. 2020. Effect of acute exposure of saxitoxin on development of zebrafish embryos (Danio rerio). Environmental Research 185:109432. doi: 10.1016/j.envres.2020.109432.

 PubMed Web of Science ®Google Scholar

Xia, Q., L. Wei, Y. Zhang, H. Kong, Y. Shi, X. Wang, X. Chen, L. Han, and K. Liu. 2018. Psoralen Induces Developmental Toxicity in Zebrafish Embryos/Larvae Through Oxidative Stress, Apoptosis, and Energy Metabolism Disorder. Frontiers in Pharmacology 9:1457. doi: 10.3389/fphar.2018.01457.

 PubMed Web of Science ®Google Scholar

Koiwa, J., T. Shiromizu, Y. Adachi, M. Ikejiri, K. Nakatani, T. Tanaka, and Y. Nishimura. 2019. Generation of a Triple-Transgenic Zebrafish Line for Assessment of Developmental Neurotoxicity during Neuronal Differentiation. Pharmaceuticals (Basel) 12 (12):14. doi: 10.3390/ph12040145.

 Google Scholar

Steele, W. B., R. A. Mole, and B. W. Brooks. 2018. Experimental protocol for examining behavioral response profiles in larval fish: application to the neuro-stimulant caffeine. Journal of Visualized Experiments. 137:57938. doi: 10.3791/57938.

 Google Scholar

Zenki, K. C., L. d Souza, A. M. Góis, B. D. S. Lima, AAdS. Araújo, J. S. Vieira, E. A. Camargo, E. Kalinine, D. d Oliveira, and C. I. B. Walker. 2020. Coriandrum sativum extract prevents alarm substance-induced fear- and anxiety-like responses in adult zebrafish. Zebrafish 17 (2):120–30. eng. doi: 10.1089/zeb.2019.1805.

 PubMed Web of Science ®Google Scholar

Carty, D. R., Z. S. Miller, C. Thornton, Z. Pandelides, M. L. Kutchma, and K. L. Willett. 2019. Multigenerational consequences of early-life cannabinoid exposure in zebrafish. Toxicology and Applied Pharmacology 364:133–43. doi: 10.1016/j.taap.2018.12.021.

 PubMed Web of Science ®Google Scholar

Senthilkumar, S., R. Raveendran, S. Madhusoodanan, M. Sundar, S. S. Shankar, S. Sharma, V. Sundararajan, P. Dan, and S. Sheik Mohideen. 2020. Developmental and behavioural toxicity induced by acrylamide exposure and amelioration using phytochemicals in Drosophila melanogaster. Journal of Hazardous Materials 394:122533. doi: 10.1016/j.jhazmat.2020.122533.

 PubMed Web of Science ®Google Scholar

Jovanović, B., N. Jovanović, V. J. Cvetković, S. Matić, S. Stanić, E. M. Whitley, and T. L. Mitrović. 2018. The effects of a human food additive, titanium dioxide nanoparticles E171, on Drosophila melanogaster - a 20 generation dietary exposure experiment. Scientific Reports 8 (1):17922. doi: 10.1038/s41598-018-36174-w.

 PubMedGoogle Scholar

Merinas-Amo, R., M. Martínez-Jurado, S. Jurado-Güeto, Á. Alonso-Moraga, and T. Merinas-Amo. 2019. Biological Effects of Food Coloring in In Vivo and In Vitro Model Systems. Foods 8 (5):176. doi: 10.3390/foods8050176.

 Web of Science ®Google Scholar

Merinas-Amo, T., R. Merinas-Amo, V. García-Zorrilla, A. Velasco-Ruiz, L. Chladek, V. Plachy, M. Del Río-Celestino, R. Font, L. Kokoska, and Á. Alonso-Moraga. 2019. Toxicological Studies of Czech Beers and Their Constituents. Foods 8 (8):328. doi: 10.3390/foods8080328.

 Web of Science ®Google Scholar

Chen, Y., X. Liu, C. Jiang, L. Liu, J. M. Ordovas, C.-Q. Lai, and L. Shen. 2018. Curcumin supplementation increases survival and lifespan in Drosophila under heat stress conditions. BioFactors (Oxford, England) 44 (6):577–87. doi: 10.1002/biof.1454.

 PubMed Web of Science ®Google Scholar

Farombi, E. O., A. O. Abolaji, T. H. Farombi, A. S. Oropo, O. A. Owoje, and M. T. Awunah. 2018. Garcinia kola seed biflavonoid fraction (Kolaviron), increases longevity and attenuates rotenone-induced toxicity in Drosophila melanogaster. Pesticide Biochemistry and Physiology. 145:39–45. doi: 10.1016/j.pestbp.2018.01.002.

 PubMed Web of Science ®Google Scholar

Kharat, P., P. Sarkar, S. Mouliganesh, V. Tiwary, V. B. R. Priya, N. Y. Sree, H. V. Annapoorna, D. K. Saikia, K. Mahanta, and K. Thirumurugan. 2020. Ellagic acid prolongs the lifespan of Drosophila melanogaster. Geroscience 42 (1):271–85. doi: 10.1007/s11357-019-00135-6.

 PubMed Web of Science ®Google Scholar

Poetini, M. R., S. M. Araujo, M. Trindade de Paula, V. C. Bortolotto, L. B. Meichtry, F. Polet de Almeida, C. R. Jesse, S. N. Kunz, and M. Prigol. 2018. Hesperidin attenuates iron-induced oxidative damage and dopamine depletion in Drosophila melanogaster model of Parkinson's disease. Chemico-Biological Interactions 279:177–86. doi: 10.1016/j.cbi.2017.11.018.

 PubMed Web of Science ®Google Scholar

Tavakkoli, H., A. Derakhshanfari, J. Moayedi, and A. Poostforoosh Fard. 2020. Utilization of a chicken embryo membrane model for evaluation of embryonic vascular toxicity of Dorema ammoniacum. Journal of Phynomedicine 10 (2):152–160.

 Web of Science ®Google Scholar

Balan, P., J. Indrakumar, P. Murali, and P. S. Korrapati. 2020. Bi-faceted delivery of phytochemicals through chitosan nanoparticles impregnated nanofibers for cancer therapeutics. International Journal of Biological Macromolecules 142:201–11. doi: 10.1016/j.ijbiomac.2019.09.093.

 PubMed Web of Science ®Google Scholar

Jin, Y.-M., S.-Z. Zhao, Z.-L. Zhang, Y. Chen, X. Cheng, M. Chuai, G.-S. Liu, K. K. H. Lee, and X. Yang. 2019. High Glucose Level Induces Cardiovascular Dysplasia During Early Embryo Development. Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association 127 (9):590–7. doi: 10.1055/s-0043-109696.

 PubMed Web of Science ®Google Scholar

Wang, G., J. Liang, L.-R. Gao, Z.-P. Si, X.-T. Zhang, G. Liang, Y. Yan, K. Li, X. Cheng, Y. Bao, et al. 2018. Baicalin administration attenuates hyperglycemia-induced malformation of cardiovascular system. Cell Death & Disease 9 (2):234. eng. doi: 10.1038/s41419-018-0318-2.

 PubMedGoogle Scholar

Santbergen, M. J. C., M. van der Zande, A. Gerssen, H. Bouwmeester, and M. W. F. Nielen. 2020. Dynamic in vitro intestinal barrier model coupled to chip-based liquid chromatography mass spectrometry for oral bioavailability studies. Analytical and Bioanalytical Chemistry 412 (5):1111–22. doi: 10.1007/s00216-019-02336-6.

 PubMed Web of Science ®Google Scholar

Kulthong, K., L. Duivenvoorde, B. Z. Mizera, D. Rijkers, G. t Dam, G. Oegema, T. Puzyn, H. Bouwmeester, and M. van der Zande. 2018. Implementation of a dynamic intestinal gut-on-a-chip barrier model for transport studies of lipophilic dioxin congeners. RSC Advances 8 (57):32440–53. doi: 10.1039/C8RA05430D.

 PubMed Web of Science ®Google Scholar

Yin, F., Y. Zhu, M. Zhang, H. Yu, W. Chen, and J. Qin. 2019. A 3D human placenta-on-a-chip model to probe nanoparticle exposure at the placental barrier. Toxicology in Vitro: An International Journal Published in Association with BIBRA 54:105–13. doi: 10.1016/j.tiv.2018.08.014.

 PubMed Web of Science ®Google Scholar