Table 1.

Summary of ZEA-induced toxicity.

Toxic Type	Animal/Cell Model	Dose	Exposure Time	Phenotypic Modulation	Pathway	Reference
Reproductive toxicity	Postweaning piglets	3 mg/kg bw	28 d	Vulvar malformation, decreased immune response, and disorder of the level of serum hormones.	Hypothalamic–pituitary–ovarian axis pathway.	[43]
	TM4 cells	0~30 μM	24 h	TM4 cell autophagy, oxidative stress, and cytoskeletal structure destruction.	PI3K/Akt/mTOR and MAPK signaling pathway.	[62]
	TM3 cells	50 μM	24 h	Decreased cell viability and testosterone concentration, increased LDH, and cell apoptosis.	PI3K/Akt, PTEN/Nrf 2/Bip, and ER-stress signaling pathway.	[75]
	Sertoli cells (SCs)	0~80 μM	24 h	Cell cycle arrest, inhibited SCs proliferation, and cell morphological autophagy.	PI3K/Akt/mTOR signaling pathway.	[76]
Hepatotoxicity	Balb/c mice	40 mg/kg bw	24 h	Increased MDA level, protein carbonylation, SOD activity, CAT activity, and the expression level of HSP70.	Oxidative stress pathway.	[46]
	HepG2 cells	0~100 μM	72 h	Decreased cell viability and the expression of liver inflammation-related factors.	Inhibit inflammatory response and liver immunity.	[47]
	HepG2 cells	0~40 μM	24 h	Decreased cell viability, increased production of ROS, and regulated phase-I/II metabolism, resulting in autophagy and apoptosis.	Oxidative stress, ER-stress, and PERK/eIF2α pathway.	[49]
Immunotoxicity	T lymphocytes	0~40 μM	24 h	Decreased cell viability, damaged cell surface and intracellular ultrastructure of T lymphocytes, and decreased secretion of cytokines, resulting in cell apoptosis.	MAPK signaling pathway, TNF-α-independent JNK signaling pathway.	[53]
	HL-60, U937, PBMCs	0~50 μM	24 h	Decreased cell viability, increased production of ROS, and cell apoptosis.	The death receptor pathway with direct involvement of caspase-8, the mitochondrial pathway, and ER-stress pathway.	[35]
	T lymphocytes	0~40 μM	48 h	Surface and intracellular ultrastructural damage of T lymphocytes.	Chemokines MIP-1α and RANTES secreted by T lymphocytes and chemokine receptor CCR2 and CCR7.	[54]
	T lymphocytes	0~40 μM	24 h	Decreased cell viability and the expression of different activation signals in T cells inhibited the secretion of cytokines.	Co-stimulatory signal and PI3K/Akt/mTOR signaling pathway.	[77,78]
Genotoxicity	Kunming mice	40 mg/kg bw	28 d	Damaged kidney resulting in oxidative stress and renal cell apoptosis.	Bip, CHOP, caspase-12, and JNK signaling pathway	[59]
	TM4 cells	0~100 μM	24 h	Inhibited cell proliferation, cell cycle arrest, and cell apoptosis.	ROS and ER stress, ATP/AMPK pathway.	[61]
Carcinogenicity	INS-1 cells	0~800 μM	24 h	NLRP3 inflammasome activation, decreased cell viability, cell autophagy, and pyroptosis.	NF-κB p65 activation and nuclear translocation.	[79]
	Mouse granulosa cells	10&30 μM	72 h	Changed cell morphology, cell cycle arrest, and increased expression of genes related to tumorigenesis.	Hippo signaling pathway.	[64]
	TM3 cells	0~90 μM	24 h	Decreased cell viability.	Ras, Rap1, PI3K/AKT, Foxo, and AMPK signaling pathway.	[80]
Gastrointestinal health	IPEC-J2 cells	0~80 μM	24 h	Decreased the cell viability and increased LDH activity, and inhibited cell proliferation, resulting in cell cycle arrest.	Pathways involved in the cell cycle G2 phase.	[58]
	SD mice	0~5.0 mg/kg bw	28 d	Impaired intestinal barrier, increased permeability and imbalance of intestinal microbiota, and increased systematic intestinal inflammation.	RhoA/ROCK signal pathway.	[65]
	Balb/c mice	4.5 mg/kg bw	7 d	NLRP3 inflammasome activation and intestine inflammatory.	NLRP3 signaling pathway.	[66]
Endocrine-disrupting effects	Postweaning piglets	0~3.2 mg/kg bw	18 d	Inhibited LH secretion.	Kisspeptin–Gpr54–GnRH Pathway.	[68]
	Postweaning piglets	0~1.5 mg/kg bw	35 d	Inhibited follicles maturation and ovarian development.	ERs/GSK-3β-dependent Wnt-1/β-catenin signaling pathway.	[70]
	SD mice	0~5 mg/kg bw	5 d	Released gonadotropin early—resulted from the advancement of vaginal opening and enlargement of the uterus at the periphery.	Hypothalamic kisspeptin–GPR54 signaling pathway.	[81]