Effective protective agents against the organ toxicity of T-2 toxin and corresponding detoxification mechanisms: A narrative review

Abstract

T-2 toxin is one of the most widespread and toxic fungal toxins in food and feed. It can cause gastrointestinal toxicity, hepatotoxicity, immunotoxicity, reproductive toxicity, neurotoxicity, and nephrotoxicity in humans and animals. T-2 toxin is physicochemically stable and does not readily degrade during food and feed processing. Therefore, suppressing T-2 toxin-induced organ toxicity through antidotes is an urgent issue. Protective agents against the organ toxicity of T-2 toxin have been recorded widely in the literature, but these protective agents and their molecular mechanisms of detoxification have not been comprehensively summarized. In this review, we provide an overview of the various protective agents to T-2 toxin and the molecular mechanisms underlying the detoxification effects. Targeting appropriate targets to antagonize T-2 toxin toxicity is also an important option. This review will provide essential guidance and strategies for the better application and development of T-2 toxin antidotes specific for organ toxicity in the future.

1. Introduction

T-2 toxin (T-2) is one of the most toxic fungal toxins and is the most common cause of poisoning in humans and animals resulting from the consumption of contaminated cereal food and feed (Tima et al., 2016; Van Der Fels-Klerx et al., 2012). The food and feedstuff most frequently contaminated with T-2 include wheat, maize, barley, oats and rye, along with their processed products, which results in huge economic losses (Tutelyan et al., 2013; Zakharova et al., 2009). T-2 was detected in 92.59% of maize in Sichuan, China (Halstensen et al., 2006), and caused gastrointestinal absorption disorders, immunosuppression or irritation, reproductive disorders, liver damage, neurotoxicity, cardiac and skeletal muscle toxicity in humans and livestock through contaminated feed and food (Janik et al., 2020). However, owing to the highly stable physicochemical properties of this toxin, 100% degradation is not feasible. Therefore, the use of antagonists to reduce organ toxicity caused by T-2 is an important method of detoxification.

An increasing number of studies have reported various protective agents that mitigate the organ toxicity of T-2. For example, rosmarinic acid (RA) was shown to protect the intestine from T-2-induced damage (Pomothy et al., 2020a). Selenomethionine (SeMet) effectively mitigated T-2-induced immunotoxicity by exerting strong antioxidant and anti-inflammatory effects (Zhang et al., 2022h). Betulinic acid (BA) ameliorated T-2-induced oxidative stress and inflammatory responses, thereby reducing renal damage (Huang et al., 2021). Thus, protective agents could effectively reduce the organ toxicity of T-2.

In recent years, researchers have reviewed findings on T-2 toxicity. Zhang et al. (2022c) systematically described T-2 metabolism, the mechanisms underlying T-2 immunotoxicity, and exposure assessment of the human gut microbiota. Li et al. (2022b) reviewed the mechanism of T-2 toxicity on protein synthesis. Wu et al. (2020) focused on novel findings related to the metabolism, immunotoxicity, and human exposure assessment of T-2 and its modified forms. However, these reviews did not specify antidotes for the organ toxicity of T-2.

Although Li et al. (2022c) outlined the poultry toxicity of T-2 and suggested potential strategies for T-2 detoxification in the poultry diet, to date, no researcher has systematically described the protective agents against the individual organ toxic effects of T-2 and the corresponding detoxification mechanisms and application prospects. Most importantly, previous reviews have barely discussed the protective agents in terms of the toxic targets of T-2.

In this review, we provide a comprehensive overview of protective agents (Table 1) for T-2-induced gastrointestinal toxicity, hepatotoxicity, immunotoxicity, nephrotoxicity, neurotoxicity, reproductive toxicity, cardiotoxicity, dermal toxicity, skeletal toxicity, and muscular toxicity and described in detail the detoxification mechanisms of the various protective agents. Importantly, we also summarize the toxic targets of T-2 (Table 2). This review reveals promising applications of protective agents and provides important strategies and guidance for the better application and development of protective agents against T-2 organ toxicity.

Table 1.

Summary of the protective agents against organ toxicity of T-2.

Protective agents	Models	Dose and time	Organ toxicity	Effects	Mechanisms	References
Alfalfa meal	Rats	Alfalfa meal (5%, 12.5%, 20%) + T-2 (3 μg/g feed) for 2 weeks.	Gastrointestinal toxicity	-Antagonizing food refusal and growth inhibition toxicity in rats.	-Binding T-2 in gastrointestinal tract and thus promoting fecal excretion.	Carson and Smith (1983a)
RA	IPEC-J2 cells	Pre-incubated with RA (50 μmol/L) for 24 h; T-2 (5 nmol/L) for 48 and 72 h.		-Alleviating intestinal cell damage.	-Antioxidant; -Anti-inflammation.	Pomothy et al. (2020a)
BA	Mice	Pretreated with BA (0.25, 0.5, 1 mg/kg BW i.g.) for 2 weeks; T-2 (4 mg/kg BW i.p.) once.		-Improving the antioxidant capacity and the intestinal inflammatory response of the intestine; -Alleviating intestinal immune barrier dysregulation.	-Antioxidant; -Anti-inflammation.	Luo et al. (2020)
FWGE	IPEC-J2 cells	FWGE (1% and 2%) + T-2 (5 nmol/L) for 24 h.		-Improving cell viability and cell monolayer integrity.	-Antioxidant.	Pomothy et al. (2020b)
Bentonite	Rats	Pretreated with bentonite (5%, 7.5% or 10%) for 2 weeks; T-2 (3 μg/g feed) once.		-Overcoming the toxic symptoms of growth inhibition and food refusal in rats.	-Shortening the transit time of T-2 in the intestine.	Carson and Smith (1983b)
Smectite	Mice	T-2 was incubated with smectite for 24 h before oral administration; T-2 (1 mg/kg BW/d, p.o.); Smectite (2 g/kg/d).		-Protecting mice against T-2-induced disturbances of gastrointestinal transit.	-Smectite reinforced the natural defense of the gastric mucosa.	Fioramonti et al. (1987)
Mineral clays	Caco-2 cells	T-2 (100 μmol/L) + 0.1 mg/mL of each clay (diosmectite, montmorillonite, and illite) for 24 h.		-Restoring intestinal barrier permeability.	-Reversing T-2-induced reduction in the tight junction constituents claudin-3, claudin-4 and occludin expression and trans-epithelial electrical resistance.	Romero et al. (2016)
HSCAS	Broilers	0.05% HSCAS + T-2 (6.0 mg/kg feed) for 2 weeks.		-Reducing the toxicity of T-2 in broilers.	-Reducing T-2-induced toxicity in growth performance, nutrient digestibility, and small intestinal morphology.	Wei et al. (2019)
MycoRaid	Broilers	MycoRaid (1 or 3 g/kg feed) + T-2 (1 mg/kg feed) for 1–10 d.		-Improving broilers performance.	-Restoring feed consumption and body weight; -Increasing the concentration of total protein and albumin in the blood.	Riahi et al. (2021)
SeMet	Rabbits	Orally administered with SeMet (0.2, 0.4 and 0.6 mg/kg feed) for 21 d; On 17th d, each group began to take 0.4 mg/kg feed of T-2 orally/d for 5 d.		-Protecting the intestine from damage caused by T-2.	-Alleviating oxidative stress, jejunal inflammation; -Preserving the integrity of the intestinal barrier.	Liu et al. (2020)
FPH	Human colon cancer TC7 cells and Caco-2.	FPH (0.0625 mg/mL) + T-2 (60 nmol/L) for 24 h.		-Protecting against T-2-induced cytotoxicity.	-Improving cell viability.	Taroncher et al. (2021)
Prednisolone and hydrocortisone	Mice	Pretreated i.p. with 100 mg/kg BW of prednisolone or hydrocortisone for 3 d; T-2 (1.8 mg/kg BW, s.c.) for 4 d.		-Suppressing the lethal toxicity.	-Anti-inflammation.	Mutoh et al. (1988)
Dietary nucleotides	Male broiler chickens	Exposed T-2 (10 mg/kg feed) with nucleotides (2 g/kg feed) for 17 d.	Immunotoxicity	-Having beneficial effect on the immune system in T-2 intoxication.	-Reducing T-2-induced DNA fragmentation in spleen leukocytes.	Frankic et al. (2006)
Se	Mice	The sublethal dose of T-2.		-Asserting an important effect against the immunotoxic effects of T-2.	-Suppressing the T-2-induced reduction in peripheral blood B lymphocytes (CD19+) abundance.	Ahmadi et al. (2015)
SeMet	Rabbits	Orally administered with SeMet (0.2, 0.4 and 0.6 mg/kg feed) for 21 d. On 17th d, each group began to take 0.4 mg/kg BW of T-2 orally every day for 5 d.		-Attenuating T-2-induced immunotoxicity.	-Improving its antioxidant and anti-inflammatory capabilities in the spleen and thymus.	Zhang et al. (2022h)
Arginine	Chinese mitten crab	Pretreated with 3.17% arginine for 8 weeks; Injected with T-2 (1.5 mg/kg BW).		-Resistance to T-2-induced immune damage in the hepatopancreas.	-Increasing the antioxidant capacity.	Zhang et al. (2020a)
BA	Mice	Pretreated with BA (0.25, 0.5, or 1 mg/kg BW i.g.) for 2 weeks, T-2 (4 mg/kg BW single i.p.).		-Exerting the antioxidative and immunomodulatory activities of BA on spleen oxidative damage induced by T-2.	-Elevating the activities of antioxidant enzymes, reducing lipid peroxidation and ROS accumulation, and decreasing splenocyte apoptosis.	Kong et al. (2021)
				-Protecting the thymus against the oxidative damage challenged by T-2.	-Activating Nrf2 and suppressing the MAPK signaling pathway.	Zhu et al. (2020)
NAC	Neuroblastoma- 2a cells	Pretreated with NAC (5 mmol/L) for 2 h, followed by treatment with T-2 (20 ng/mL) for 24 h.	Neurotoxicity	-Reducing neurotoxicity.	-Inhibiting caspase activation and apoptosis.	Zhang et al. (2018)
	Mouse microglia BV2 cell line.	Pretreated with NAC at 2.5 mmol/L for 1 h, followed by co-treatment with T-2 at 2.5 ng/mL for additional 24 h.		-Reducing oxidative stress and apoptosis.	-Preventing ROS production and mitochondrial dysfunction; -Reducing mitochondrial transmembrane potential.	Sun et al. (2022)
BA	Mice	Pretreated with BA (0.25, 0.5, and 1.00 mg/kg BW) for 14 d; T-2 (4 mg/kg BW, single i.p.).		-Protecting against brain damage induced by T-2.	-Increasing the levels of the brain neurotransmitters dopamine, 5-hydroxytryptamine, and acetylcholine, thus improving cognitive function. -Enhanced antioxidant and anti-inflammatory capacity in the brain.	Huang et al. (2022b)
Minocycline	Mice	Injected with T-2 (4 mg/kg BW) + minocycline (50 mg/kg BW).		-Suppressing the neurotoxicity caused by T-2.	-Inhibiting microglia activation, thus improving T-2-induced learning and memory impairment and locomotor inhibition.	Li et al. (2023)
L-arginine	Mouse Leydig cells	Treated with T-2 (10 nmol/L) + L-arginine (0.25, 0.5, or 1.0 mmol/L) for 24 h.	Reproductive toxicity	-Ameliorating T-2–induced cytotoxicities.	-Elevating antioxidative ability.	Yang et al. (2018)
				-Ameliorated the testosterone levels decreased by T-2.	-Regulating the mRNA expression and activities of StAR.	Yang et al. (2019b)
				-Blocking T-2-induced apoptosis	-Regulating specific intracellular death-related pathways.	Zhang et al. (2020b)
	Mice	Pretreated with L-arginine (5, 15, 25 g/kg feed) for 7 d; T-2 (10 mg/kg BW/d i.p.) for 7 d.		-Protecting reproductive impairments induced with T-2.	-Improving semen quality and serum testosterone levels.	Zhang et al. (2019)
Melatonin	Bovine ovarian granulosa cells	-Pretreated with melatonin (100 μmol/L) for 12 h; HT-2 toxin 50 nmol/L for 24 h.		-Alleviating HT-2 toxin-induced cells damage.	-Having protective effects against mycotoxin-induced apoptosis and oxidative stress.	Yang et al. (2019a)
Quercetin	Porcine ovarian granulosa cells	Quercetin (100 ng/mL) + T-2 (100 ng/mL) for 24 h.		-Mitigating cellular oxidative damage due to T-2 exposure.	-Increasing the antioxidant capacity.	Capcarova et al. (2015)
BA	Mice	Pretreated orally with BA (0.25, 0.5, and 1.0 mg/kg feed/d) for 14 d, T-2 (4 mg/kg BW i.p.) once.		-Having protective effect of BA on T-2-induced testicular injury.	-Reducing the oxidative damage by the JAK2/STAT3 pathway.	Wu et al. (2019)
NAC	TM4 cells (The Sertoli cell line)	T-2 (4 nmol/L) + NAC (5 mmol/L) for 24 h.		-Relieving TM4 cell functional injury.	-Inhibiting low cell viability, oxidative stress and cell apoptosis caused by T-2.	Yang et al. (2021)
VE and Se	Bovine Leydig cells	100 nmol/L Se+10 nmol/L T-2; 100 μmol/L VE+10 nmol/L T-2; 100 nmol/L Se+100 μmol/L VE+10 nmol/L T-2 for 24 h.		-Ameliorating T-2-induced cytotoxicities.	-Preventing oxidative stress and DNA damage.	Yang et al. (2022)
Se	Rats	Pre-supplementation Se (0.5 and 2.5 mg/kg feed for 6 weeks); T-2 (3.8 mg/kg BW).	Hepatotoxicity	-Reducing mortality due to T-2.	-Se affected liver metabolism.	Kravchenko et al. (1990)
Se, VE, VC	Rats	Received Se (0.15 mg), VE (15 mg) and VC (6 mg) i.g. 16 h before the administration of T-2 (3.6 mg/kg BW orally a single dose).		-Alleviating liver injury.	-Reducing T-2-induced hepatic LPO and GSH depletion.	Rizzo et al. (1994)
Modified glucomannans and organic Se	Chicken	Mycosorb (1 g/kg feed) Sel-Plex (Se 0.3 mg/kg feed); T-2 (8.1 mg/kg feed for 21 d).		-Preventing T-2-induced oxidative stress damage and LPO in liver.	-Protecting against the detrimental effects of T-2 on the antioxidant defences in the chicken liver.	Dvorska et al. (2007)
SeMet	New Zealand rabbits	SeMet (0.2 mg/kg feed) for 21 d. On the 17th day, orally administered with T-2 (0.4 mg/kg BW) for 5 d.		-Improving T-2-induced liver injury.	-Inhibiting the mitochondrial- caspase apoptosis pathway.	Liu et al. (2021c).
CoQ10, VE	Mice	Gavage pretreatment with CoQ10 (6 mg/kg BW) and alpha-tocopherol (6 mg/kg BW) for 4 weeks. T-2 (1.8 or 2.8 mg/kg BW, single oral dose).		-Blocking T-2-induced hepatocyte death and GSH depletion.	-Reducting T-2-induced DNA damage in livers.	Atroshi et al. (1997)
Lycopene	Broiler chickens	T-2 (1.5 mg/kg BW/d) + Lycopene (25 mg/kg BW/d) for 7, 14 and 21 d.		-Alleviated oxidative damage in the liver of chickens fed T-2.	-Stopping GSH depletion in liver cells.	Leal et al. (1999).
Food indoles	Rats	Fed with 0.1% food indoles for 8 d; T-2 (0.8 mg/kg BW).		-Attenuating the hepatotoxicity of T-2.	-Elevating activity of microsomal carboxylesterase and UDP-glucuronosyltransferase, the key enzymes for detoxification of T-2.	Kravchenko et al. (2001)
HSCAS	Broilers	0.05% modified HSCAS adsorbent + T-2 (6.0 mg/kg feed) for 2 weeks.		-Blocking T-2-induced AST elevation and mitigating hepatotoxicity.	-Increasing surface area and might be able to increase adsorbing mycotoxins and avoid adsorbing the nutrients in feed.	Wei et al. (2019)
Arginine	Chinese mitten crab	Pretreated with 3.17% Arg for 8 weeks; Injected with T-2 (1.5 mg/kg BW).		-Alleviating T-2-induced hepatotoxicity.	-Enhancing the antioxidant capacity of Chinese mitten crab against oxidative damage to the hepatopancreas induced by T-2.	Zhang et al. (2020a)
YCWE and PYCW	Broilers	Contaminated diet containing T-2 (104 g/kg feed) + 0.2% YCWE or 0.2% PYCW.		-Improving the negative effects of T-2 on growth performance and liver function.		Kudupoje et al. (2022)
CC2	Mice	20% CC-2 formulation was applied on the exposed dorsal surface at 5, 15, 30 and 60 min after T-2 (11.8 mg/kg BW percutaneous exposure).		-Protecting mice from T-2-induced hepatic LPO; -Reducing mortality.		Agrawal et al. (2012a)
L-Carnitine	Rats, primary rat hepatocytes	Received L-carnitine (50 or 500 mg/kg i.p.) for 5 d, rat hepatocytes were isolated and treated with T-2 (640 ng/mL) for 2 h.		-Alleviating liver injury.	-Antioxidant properties, mitochondrial protection and inhibition of apoptosis.	Moosavi et al. (2016)
CA	Broiler chickens	1% CA-supplemented diet for 4 d; T-2 (2.0 mg/kg BW) oral administration for 4 d.		-Alleviating T-2-induced liver damage and the broiler mortality.	-Inducing the expression of FXR, thus reducing inflammatory and oxidative stress in hepatocytes.	Dai et al. (2020)
Curcumin and taurine	Rats	Administrated T-2 sublethal oral dose (0.1 mg/kg BW i.p.) for 2 months, followed by curcumin (80 mg/kg BW) and taurine (50 mg/kg BW) for 3 weeks.		-Ameliorating T-2-induced hepatotoxicity.	-Improving antioxidant capacity.	Al-Zahrani et al. (2023)
SeMet	Rabbits	Fed diets containing SeMet (0.2 mg/kg) for 21 d; On the 17th day, perfused with T-2 (0.4 mg/kg BW) for 5 d.	Nephrotoxicity	-Restoring kidney function.	-Reducing T-2-induced ROS and inflammatory factor levels.	Liu et al. (2021b)
Se	Mice	Pretreated with Se (0.2 mg/kg BW/d) for 2 h, then exposed to T-2 (1.0 mg/kg BW/d) for 28 d.		-Alleviating T-2-induced nephrotoxicity.	-Inhibiting ROS-mediated renal apoptosis.	Zhang et al. (2022f)
BA	Porcine kidney cells	Pretreated with BA (0.25, 0.5, and 1 μmol/L) for 24 h, continued with subsequent T-2 (1 μmol/L) for 24 h.		-Alleviating renal cytotoxicity.	-Ameliorating T-2-induced oxidative stress damage and apoptosis by increasing SOD, GSH-Px, and CAT activity and reducing intracellular ROS and MDA production.	Li et al. (2021)
	Mice	Pretreated with BA (0.25, 0.5, and 1 mg/kg BW i.g.) for 14 d; T-2 (4 mg/kg BW) was injected intraperitoneally at the 9th h after the last oral administration of BA.		-Protecting against renal damage.	-Attenuating oxidative stress and inflammation via Nrf2 pathway.	Huang et al. (2021).
Catalase and VC	Rat cardiomyocytes	T-2 (6.0 × 10−3 and 6.0 × 10−4 μmol/L) + VC (10 μg/mL) or catalase (10 U/mL) for 24 h.	Cardiomyopathy	-Improving the mitochondrial dysfunction under T-2 exposure.	-Antioxidant effects.	Ngampongsa et al. (2013)
Se	Primary cardiomyocytes	T-2 (0.25−1 μmol/L)		-Selenium deficiency lowered cytoprotective autophagy in the primary cardiomyocytes treated by T-2.	-The combination effects of selenium deficiency and T-2 on the development of Keshan disease.	Chen et al. (2019)
Methylprednisolone	Rats	Methylprednisolone (a total single dose of 40 mg/kg i.m.) was given immediately after T-2 (0.23 mg/kg s.c.).		-Showing a significant cardioprotective efficacy.	-Anti-inflammatory activity.	Jacevic et al. (2019)
Se	Chondrocytes	T-2 (0.001–2 mg/L).	Skeletal toxicity	-Partly antagonizing the inhibitory effects of T-2 on aggrecan.		Chen et al. (2006; Li et al. (2008)
				-Inhibiting aggrecan degradation in chondrocytes induced by T-2.
	An artificial cartilage model	Se (0.1 μg/mL) for 14 d; T-2 (1, 10 and 20 ng/mL).		-Having a protective role on chondrocytes.	-Preventing the decrease in type II collagen protein induced by T-2 in engineered cartilage.	Chen et al. (2011)
	Cultured chondrocytes	T-2 (5, 10, 20, 40 and 80 ng/mL) supplemented with Na2SeO3 (50, 100 and 150 ng/mL), and incubated for 6, 12, 24, 36 and 48 h.		-Reducing T-2-induced cytotoxicity.	-Promoting metabolic conversion of T-2.	Yu et al. (2017)
	Rats, primary epiphyseal chondrocytes	Administered with low Se (0.09 ng/g) and/or T-2 (100 ng/g BW per day) for 4 weeks to establish a KBD animal model.		-Inhibiting the progress of KBD.	-Reversing the effects of T-2 on chondrocyte injury.	Shi et al. (2021)
	Rats	Administered with T-2 (200 ng/g BW per day) for 4 weeks under the Se-deficient diet.		-Se-supplementation partially antagonized the inhibitory effects of T-2 in chondrocytes and cartilages.	-Low selenium induced matrix degradation.	Zhang et al. (2021a)
NAC	Chicken tibial growth plate chondrocytes	NAC (0.5 mmol/L) was co-administered with T-2 (5, 50, and 500 nmol/L) for 48 h.		-Protecting chicken growth plate chondrocytes.	-Reducing T-2-induced oxidative stress.	He et al. (2012)
Mycotoxin adsorbents: EGM, HSCAS, CMA	Broilers	The mycotoxins-contaminated feed containing T-2 (320.5 μg/kg) + 0.05% EGM or +0.2% HSCAS or + 0.1% CMA for 10, 21, 35 and 42 d.	Muscle toxicity	-Preventing the adverse effects on meat quality of mycotoxins to varying extents.	-Improving growth performance and nutritional retention in broilers due to mycotoxins.	Liu et al. (2011)
Quercetin	Shrimps	Quercetin (2.00 to 32.00 g/kg feed) or tea polyphenols or rutin + T-2 (4.80–24.30 mg/kg feed) for 20 d.		-Having the protective effect on T-2-induced muscle toxicity.	-Preventing abnormal changes in the target protein and muscle composition; -Reducing the degree of muscle protein deterioration.	Huang et al. (2022a)
Tea polyphenols and rutin				-Ameliorating the T-2-induced damage to muscle proteins.	-Increasing the sarcoplasmic and myofibrillar protein content and decreasing the alkali-soluble protein content.
Menthol	Mice	T-2 (2.97 mg/kg BW) for 72 h and 120 h; 0.25% and 0.5% menthol.	Skin toxicity	-Having the protective effect against T-2- induced skin toxicity in mice.	- Anti-inflammatory effect.	Rachitha et al. (2023)
CC-2	Mice	The subcutaneous application of 20% CC-2 within 5 and 15 min of treatment with T-2 (23.76 mg/kg BW topical percutaneous smearing).		-CC-2 may be an effective skin decontaminant against lethal topical exposure to T-2.		Agrawal et al. (2012a)
Quince seed	Rabbits	100 μg T-2 was dissolved in 12 μL methanol and applied on the shaved skin of rabbit for 2 d. Quince seed mucilage (15%).		-Showing more and better healing effects on dermal toxicity caused by T-2.		Hemmati et al. (2012)

p.o. = oral administration; s.c. = subcutaneous injection; i.g. = intragastrical administration; i.p. = intraperitoneal injection; i.m. = intramuscular injection; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BA = betulinic acid; BW = body weight; CA = cholic acid; CC-2 = N,N′-dichloro-bis (2,4,6-trichlorophenyl) urea; CMA = compound mycotoxin adsorbent; CoQ10 = coenzyme Q10; EGM = esterified glucomannan; FPH = fish protein hydrolysates; FWGE = fermented wheat germ extract; FXR = farnesoid X receptor; GSH = glutathione; GSH-Px = glutathione peroxidase; HSCAS = hydrated sodium calcium alumino silicate; IPEC-J2 = intestinal porcine epithelial cell line-J2 cells; JAK2 = Janus kinase 2; KBD = Kashin-Beck disease; LPO = lipid peroxidation; MAPK = mitogen-activated protein kinase; MDA = malondialdehyde; MycoRaid = A novel multicomponent MYC; NAC = N-acetylcysteine; Nrf2 = nuclear factor erythroid 2-related factor 2; RA = rosmarinic acid; ROS = reactive oxygen species; Se = selenium; SeMet = selenomethionine; SOD = superoxide dismutase; StAR = steroidogenic acute regulatory protein; STAT3 = signal transducer and activator of transcription 3; T-2 = T-2 toxin; VC = vitamin C; VE = vitamin E; YCWE = yeast cell wall extract.

Table 2.

Primary targets and antagonistic effect for T-2 organ toxicity.

Toxic targets	Model	Toxicity	The role of targets	Antagonistic effect	References
GLP-1 and CCK	Mice	Gastrointestinal toxicity	-GLP-1 and CCK promoted T-2-induced anorexia.	-The GLP-1 receptor antagonist Exendin9-39 or the CCK1/2 receptor antagonist SR27897 and L-365 caused attenuation of T-2-induced anorectic responses.	Wu et al. (2018)
GIP and NPY2	Nocturnal mouse food refusal model		-GIP and NPY2 are involved in T-2-induced anorexia.	-The GIP receptor antagonist Pro3GIP or NPY2 receptor antagonist JNJ-31020028 attenuated T-2-induced anorectic responses.	Sheng et al. (2018)
IRE1a	Human intestinal Caco-2 cells and HT-29 cells; mice		-IRE1α was a therapeutic target for intestinal damage caused by T-2.	-T-2 impaired the intestinal mucus barrier; IRE1α knock-down blocked T-2 to degrade mucin.	Lin et al. (2019)
5-HT and NK-1R	Nocturnal mouse food refusal model		-5-HT mediated T-2-induced anorexia.	-The 5-HT3 receptor antagonist granisetron or NK-1R antagonist Emend attenuated T-2-induced anorectic responses.	Sheng et al. (2019)
HIF-1α	RAW264.7 cells	Immunotoxicity	-HIF-1α is an important immunotoxicity target of T-2.	-HIF-1a inhibited T-2-mediated “immune evasion” process by negatively regulating PD-1/PD-L1 signaling.	You et al. (2022)
IGF-1R	Human C28/I2 chondrocytes and mouse hypertrophic ATDC5 chondrocytes	Skeletal toxicity	-Inhibition of IGF-1R may mediate chondrocyte death and extracellular matrix degeneration in T-2 induced-KBD.	-IGF-1R inhibitor (picropodophyllin) caused chondrocyte cell death of, decreased type II collagen expression and increased MMP-13 expression.	Zhang et al. (2021b)
MMP-10	Hypertrophic chondrocytes (ATDC5 cells)		-MMP-10 deficiency impaired endochondral osteogenesis in the pathogenesis of T-2-related KBD.	-MMP-10 knockdown exacerbated T-2-induced chondrocyte apoptosis, terminal differentiation, and death.	Zhang et al. (2022a)
Wnt/beta-catenin signaling	Mice		-T-2-induced femur lesion is associated with Wnt/β-linked protein signaling.	__	Zhang et al. (2022d)
MGMT	KBD patients and chondrocytes		-MGMT could provide a therapeutic target for T-2-induced KBD.	-DNA damage and apoptosis rates were increased in MGMT-silenced chondrocytes,	Zhang et al. (2022b)
TGF-βRs	Sprague Dawley rats; C28/I2 chondrocytes		-Inhibiting the expression of -TGF-βRs is a potential T-2-related KBD treatment.	-Blocking the TGF-βRs-Smad2 signaling pathway using GW788388 abrogated the effect of T-2 on upregulating MMP-13 expression.	Zhang et al. (2022g)
HSP47	C28/I2 and ATDC5 cells; rats.		-T-2 decreased the expression of HSP47, which mediated the reduction of type II collagen expression.	-Restoration of HSP47 expression may alleviate matrix degradation in chondrocytes.	Zhang et al. (2021a)
YAP	Rat chondrocyte		-T-2 increased total YAP protein, which played an important role in T-2-induced chondrocyte damage.	-YAP inhibitors alleviated chondrocyte damage.	Li et al. (2022a)
HMGB1	PC12 cell	Neurotoxicity	-HMGB1 played a critical role in T-2-stimulated PC12 cells simultaneously displayed apoptosis and inflammation.	-HMGB1's silence reduced T-2-mediated oxidative stress, apoptosis and neuroinflammatory outbreak.	Pei et al. (2021)
Nrf2	Human neuroblastoma SH-SY5Y cells		-Nrf2-mediated mitochondrial biogenesis contributed to T-2 -induced toxicity	-Nrf2 knockdown exacerbated T-2-induced cytotoxicity, oxidative stress, and mitochondrial dysfunction, as well as aggravated mitochondrial biogenesis impairment.	Pang et al. (2022)
HO-1	Mouse neuroblastoma-2a cells		__	-HO-1 inhibitor enhanced T-2-induced neurotoxicity.	Zhang et al. (2018)
NF-κB and MAPK	BV-2 cells		__	-Inhibitors of NF-κB and MAPK reversed T-2-induced microglia activation, thereby alleviating neurocytotoxicity.	Li et al. (2023)
CYP1A5	Chicken primary hepatocytes	Hepatotoxicity	-CYP1A5 can be significantly induced by T-2 in chicken primary hepatocytes and catalyze T-2 into a more toxic product, 3′–OH–T-2.	-CYP1A5 induction mediated by AhR enhanced the cytotoxicity of T-2 by reducing cell viability, activating oxidative stress and inducing DNA damage as well as apoptosis.	Liu et al. (2019)
CYP1A1	HepG2 cells		-Hepatotoxicity of T-2 might be related to the CYP1A1.	__	Ye et al. (2019)
SIRT1	HepG2 cells		-SIRT1 played an essential role in T-2-induced ROS production.	-The increase of ROS was linked to the upregulation of SIRT1 under T-2 exposure.	Ma et al. (2017)
FXR	Broiler chicken livers		-FXR played a hepatoprotection role in liver injury induced by T-2.	-Activated FXR promoted xenobiotic metabolism of T-2 and attenuated oxidative stress in broiler chicken liver.	Dai et al. (2020)
TET3	HepG2 cells		-TET3 may serve as a potential new target for toxicogenic detoxification.	-TET3-mediated CYP1A1 induction enhanced the cytotoxicity of T-2 toxin through inhibiting cell proliferation.	Zhu et al. (2023)
Nrf2	Mice	Nephrotoxicity	-Nrf2 pathway mediated T-2-induced nephrotoxicity by oxidative stress.	__	Zhang et al. (2021c)
PINK1/Parkin	C57BL/6N mice		-Knocking out Parkin inhibited the mitophagy.	-PINK1/Parkin-mediated mitophagy mitigates T-2-induced nephrotoxicity	Zhang et al. (2022e)
PERK	PK-15 cells		-PERK-mediated ER stress was involved in PK-15 apoptosis under T-2 exposure.	-The PERK inhibitor prevented the T-2-induced decrease in cell activity and apoptosis.	Liu et al. (2021a)
mTORC2	TM3 cells	Reproductive toxicity	-T-2 exposure induced apoptosis in TM3 cells by inhibiting mTORC2/AKT to promote Ca2+ production.	-BAPTA-AM (a Ca2+ chelator) and MHY1485 (an mTOR activator) could prevented T-2-induced TM3 cell apoptosis.	Wang et al. (2018)
PPAR-γ	Rats	Cardiomyopathy	-PPAR-γ has the potential to serve as an effective therapeutic target in T-2-induced cardiac fibrosis of rats.	-Increasing exogenous PPAR-γ play a role in relieving cardiac fibrosis caused by T-2.	Lu et al. (2021b)

5-HT = 5-hydroxytryptamine; AKT = protein kinase B; CCK = cholecystokinin; CYP1A5 = cytochrome P450 1A5; CYP1A1 = cytochrome P450 1A1; FXR = farnesoid X receptor; GLP-1 = glucagon-like peptide-17-36 amide; GIP = glucose-dependent insulinotropic polypeptide; HIF-1α = hypoxia-inducible factors-1 alpha; HMGB1 = high mobility group B1; HO-1 = heme oxygenase 1; HSP47 = heat shock protein 47; IRE1a = inositol-requiring enzyme 1 alpha; IGF-1R = insulin like growth factor 1 receptor; KBD = Kashin-Beck disease; MAPK = mitogen-activated protein kinase; MGMT = O6-methylguanine-DNA methyltransferase; MMP-10 = matrix metalloproteinase-10; MMP-13 = matrix metalloproteinase-13; mTORC2 = mammalian target of rapamycin complex 2; NF-κB = nuclear factor -kappa B; NK-1R = neurokinin-1 receptor; NPY2 = neuropeptide Y2; Nrf2 = nuclear factor erythroid 2 related factor 2; PINK1 = phosphatase and tensin homolog (PTEN)-induced putative kinase1; Parkin = E3 ubiquitin ligase PARK2; PD-1 = programmed cell death protein-1; PD-L1 = programmed cell death-ligand 1; PERK = protein kinase RNA-like ER kinase; PPAR-γ = peroxisome proliferator-activated receptor-γ; SIRT1 = silent information regulator sirtuin 1; TET3 = eleven translocation family protein 3; TGF-βRs = transforming growth factor-beta receptors; YAP = Yes-associated protein.

2. Effective protective agents against organ toxicity of T-2 and their mechanisms of action

2.1. Protective agents against gastrointestinal toxicity

2.1.1. Protective agents

2.1.1.1. Protective agents from plants

Alfalfa meal (5%, 10%, 15%, 20% or 25%) with lignin could overcome T-2 (3 μg/g feed)-induced feed refusal and growth depression in rats by binding T-2 in the intestine and thus promoting fecal excretion (Carson and Smith, 1983a). Pomothy et al. (2020a) found that the pretreatment of intestinal porcine epithelial cell line-J2 cells (IPEC-J2) with RA (50 μmol/L) prevented the reduction of trans-epithelial electrical resistance (TEER) under T-2 exposure (5 nmol/L), prevented T-2-induced oxidative stress and interleukin (IL)-6 and IL-8 production (Fig. 1), and alleviated intestinal cell damage. Luo et al. (2020) reported that BA (0.25, 0.5, or 1 mg/kg BW) supplementation inhibited the loss of intestinal antioxidant capacity in T-2 (4 mg/kg BW)-exposed mice by increasing the levels of catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH), and reducing malondialdehyde (MDA) formation (Fig. 1). In addition, pretreatment with BA (0.5 and 1 mg/kg BW) alleviated T-2-triggered intestinal immune barrier dysregulation, inhibited the expression of pro-inflammatory cytokines interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) and increased the expression of the anti-inflammatory cytokine interleukin-10 (IL-10), thus improving the T-2-induced intestinal inflammatory response (Luo et al., 2020). Thus, BA exerts a protective effect against T-2-stimulated intestinal mucosal destruction in mice by enhancing intestinal antioxidant capacity, inhibiting the secretion of inflammatory cytokines, and repairing intestinal mucosal barrier function. In IPEC-J2 cells, 1% and 2% fermented wheat germ extract (FWGE) significantly reduced T-2 (5 nmol/L)-induced reactive oxygen species (ROS) levels, inhibited oxidative stress (Fig. 1), and increased cell viability and cell monolayer integrity (Pomothy et al., 2020b).

Fig. 1.

The mechanisms of rosmarinic acid (RA), betulinic acid (BA), fermented wheat germ extract (FWGE), selenomethionine (SeMet) and illite to mitigate T-2-induced enterotoxicity. CAT = catalase; Cla-3/4 = Claudin-3/4; GSH = glutathione; GSH-Px = glutathione peroxidase; H2O2 = hydrogen peroxide; IL-6 = interleukin-6; IL-8 = interleukin-8; IL-10 = interleukin-10; IL-1β = interleukin-1 beta; MDA = malondialdehyde; ROS = reactive oxygen species; SOD = superoxide dismutase; TNF-α = tumour necrosis factor alpha; T-2 = T-2 toxin; ZO-1 = Zonula occludens protein 1.

2.1.1.2. Adsorbents and other protective agents

Bentonite (10%) shortened the transit time of T-2 in the intestine to overcome the toxic symptoms of growth inhibition and food refusal in rats provoked by T-2 (3 μg/g feed) (Carson and Smith, 1983b). When T-2 was incubated with smectite for 24 h before oral administration, smectite slowed mice gastric emptying and small intestinal transmission induced by T-2 (1 mg/kg BW per day) by enhancing the natural defenses of the gastric mucosa (Fioramonti et al., 1987). Mineral clays, like diosmectite, montmorillonite, and illite protected Caco-2 cells from T-2 (1 to 100 μmol/L)-induced toxic effects, such as reduced viability and altered epithelial barrier function. Illite treatment reversed the T-2-induced reduction in TEER and in the expression of tight junction constituents like claudin-3, claudin-4, and occludin (Fig. 1), thereby making the intestinal barrier less susceptible to increased permeability and disruption (Romero et al., 2016). The addition of 0.05% modified hydrated sodium calcium aluminosilicate (HSCAS) sorbent prevented the reduction of body weight and feed intake in broilers exposed to T-2 (6.0 mg/kg) and also prevented T-2-induced intestinal damage in broilers (Wei et al., 2019).

A novel multicomponent mycotoxin detoxifying agent (MycoRaid) (3 g/kg feed) (containing modified zeolite, Bacillus subtilis, B. licheniformis, Saccharomyces cerevisiae cell walls, silymarin) accelerated the slow growth of broiler chickens in response to T-2 treatment (1 mg/kg feed) and effectively counteracted the harmful effects of T-2 (Riahi et al., 2021). SeMet (0.2 mg/kg feed) pre-supplementation reduced the ROS and MDA levels and enhanced superoxide dismutase (SOD) and GSH-Px activities, thereby alleviating oxidative stress caused by T-2 (0.4 mg/kg feed) in rabbits (Fig. 1). SeMet also attenuated T-2-induced jejunal inflammation and preserved the integrity of the intestinal barrier by upregulating the expression of zonula occludens protein 1 and occludin proteins (Liu et al., 2020). Fish protein hydrolysates (containing bioactive peptide) inhibited lipid peroxidation (LPO) and protected against T-2-induced cytotoxicity in human colon cancer TC7 cells (Taroncher et al., 2021). Pretreatment of prednisolone or hydrocortisone (100 mg/kg BW) reduced the lethal toxicity of T-2 (1.8 mg/kg BW) in mice; pre-administration of prednisolone or hydrocortisone (50 mg/kg BW) also inhibited T-2 (1.5 mg/kg BW)-induced increment of intestinal fluid volume in rats (Mutoh et al., 1988).

In summary, alfalfa meal, RA, BA, FWGE, adsorbents (bentonite, smectite, mineral clays, and HSCAS), MycoRaid, SeMet, fish protein hydrolysates, prednisolone or hydrocortisone administered at a range of doses could improve T-2-induced gastrointestinal toxicity (Fig. 1). Among these components, RA, BA, FWGE, and SeMet alleviated intestinal damage under T-2 exposure primarily through antioxidant and anti-inflammatory effects, whereas adsorbents and feed additives improved intestinal damage primarily by weakening the intestinal uptake of T-2. However, the potential of protective agents to counter the intestinal toxicity of T-2 needs to be validated in livestock, and the dose of protective agents needs to be controlled.

2.1.2. Toxic targets

Glucagon-like peptide-17-36 amide (GLP-1) and cholecystokinin (CCK) mediated the T-2-induced anorexia response, whereas the GLP-1 receptor antagonist (Exendin9-39) or the CCK receptor antagonists (SR 27897 and L-365 260) attenuated the T-2-induced anorexia response (Wu et al., 2018). Glucose-dependent insulinotropic polypeptide (GIP) mediated T-2-exposed anorexia; GIP receptor antagonist (Pro3GIP) dose-dependently alleviated T-2-triggered anorexia (Sheng et al., 2018). The neurotransmitters 5-hydroxytryptamine (5-HT) and substance P were shown to be involved in T-2-driven anorexia, whereas the 5-HT3 receptor antagonist granisetron or neurokinin-1 receptor (NK-1R) antagonist Emend was shown to suppress the T-2-induced anorexia response (Sheng et al., 2019). Therefore, GLP-1, CCK, GIP, 5-HT, NK-1R, NPY2 and inositol-requiring enzyme 1 alpha (IRE1α) (Table 2) may be used as potential targets of T-2 gastrointestinal toxicity, and inhibition or activation of these targets may alleviate gastrointestinal damage.

2.2. Protective agents for immunotoxicity

2.2.1. Protective agents

Dietary nucleotides reduced the extent of DNA damage induced by T-2 (10 mg/kg feed) in chicken leukocytes, suggesting that nucleotides benefit the immune system under T-2 exposure (Frankic et al., 2006). Selenium (sodium selenite) may exert a protective effect against the immunotoxic effects of T-2 on T lymphocyte sub-population (CD3+, CD4+ and CD8+ cells) in mice (Salimian et al., 2014). Ahmadi et al. (2015) found that selenium (sodium selenite) pre-supplementation suppressed the T-2-induced reduction in peripheral blood B-cell (CD19+) abundance in mice. Zhang et al. (2022h) observed that the treatment of SeMet (0.2 mg/kg feed) increased the levels of GSH-Px and SOD and decreased the levels of ROS and MDA in the spleen and the serum levels of IL-1β, IL-6, and TNF-α, thereby increasing the antioxidant and anti-inflammatory capacity and attenuating T-2 (0.4 mg/kg BW)-induced immunotoxicity in rabbits (Fig. 2). Notably, SeMet (0.4 and 0.6 mg/kg feed) did not effectively alleviate the immunotoxic effects caused by T-2 and caused some damage (Zhang et al., 2022h), which may be toxic effects of SeMet.

Fig. 2.

The mechanisms of selenomethionine (SeMet), arginine (Arg) and betulinic acid (BA) to attenuate T-2-induced immunotoxicity. GSH-Px = glutathione peroxidase; IL-1β = interleukin-1 beta; IL-6 = interleukin-6; MAPK = mitogen-activated protein kinase; MDA = malondialdehyde; Nrf2 = nuclear factor E2 related factor 2; ROS = reactive oxygen species; SOD = superoxide dismutase; T-2 = T-2 toxin; TNF-α = tumour necrosis factor alpha.

The addition of 3.17% arginine (Arg) to the diet increased the SOD and GSH-Px activities and decreased the concentration of MDA in the hepatopancreas of Chinese mitten crab, thereby resisting oxidative and immune damage caused by T-2 (1.5 mg/kg BW injected) (Fig. 2) (Zhang et al., 2020a). Feed supplementation with 0.5% Green Tea Powder (GTP) increased body weight gain, reduced plasma blood urea nitrogen and glutamate oxaloacetate transaminase concentrations, and mitigated T-2 (0.5 or 5 mg/kg feed, 3 weeks) toxicity in ducks (Tso et al., 2021). Moreover, GTP could improve humoral immune response in broiler chickens (Aziz-Aliabadi et al., 2023). Therefore, GTP may enhance immunity in broilers under T-2 exposure, however, the exact regulatory mechanism has yet to be explored.

In mouse mononuclear macrophages (RAW264.7) cells, silibinin dietary supplementation provided significant protection against T-2-induced cytotoxicity (Tran et al., 2020). BA exerted a protective effect against T-2-induced oxidative damage in the spleen. Specifically, BA restored the number of lymphocytes, reduced the accumulation of ROS and MDA and inflammatory cell infiltration, and enhanced SOD activity in the spleen of mice subjected to T-2. BA also significantly attenuated T-2-induced splenocyte apoptosis (Kong et al., 2021). In addition, BA protected the spleen and thymus from oxidative damage caused by T-2 through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and inhibition of mitogen-activated protein kinase (MAPK) signaling (Fig. 2) (Kong et al., 2021; Zhu et al., 2020).

In summary, selenium/SeMet, Arg, and BA ameliorated T-2-induced immunotoxicity primarily through antioxidant and anti-inflammatory effects (Fig. 2). Dietary nucleotides, GTP and silibinin could also reduce the immunotoxicity of T-2. However, the level of additives has to be controlled strictly when using these protective agents.

2.2.2. Toxic targets

T-2 can evade host immune surveillance and disrupt immune repair, exhibiting an “immune evasion” effect. There is evidence that hypoxia inducible factor-1α (HIF-1α) inhibited T-2-mediated “immune evasion” by negatively regulating programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signaling in RAW264.7 cells, indicating HIF-1α is an important toxicity target of T-2 immunotoxicity (You et al., 2022).

2.3. Protective agents against neurotoxicity

2.3.1. Protective agents

In mouse neuroblastoma 2a cells, n-acetylcysteine (NAC) pretreatment significantly inhibited T-2 (10, 20, 40, and 80 ng/mL)-induced caspase activation and apoptosis, thereby reducing neurotoxicity (Zhang et al., 2018). In a mouse microglia BV2 cell line, NAC supplementation prevented T-2 (1.25–5 ng/mL)-induced ROS production and mitochondrial dysfunction, reduced mitochondrial transmembrane potential, upregulated Bcl-2-associated X protein (Bax) protein expression, and suppressed B-cell lymphoma 2 (Bcl-2) protein expression. Overall, NAC reduced oxidative stress and apoptosis (Sun et al., 2022).

BA improved cognitive function by increasing the levels of the brain neurotransmitters dopamine, 5-HT, and acetylcholine, thereby protecting against brain damage induced by T-2 (4 mg/kg BW). BA also enhanced antioxidant and anti-inflammatory capacity by increasing SOD, CAT, GSH-Px, and GSH levels, inhibiting ROS and MDA production, suppressing the secretion of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in the brain, and eventually suppressing brain damage caused by T-2 (Huang et al., 2022b). T-2 (4 mg/kg BW) induced microglia activation and led to learning and memory deficits and motor inhibition in mice, whereas minocycline (50 mg/kg BW) inhibited microglia activation and suppressed the toxic effects of T-2 (Li et al., 2023).

Altogether, NAC, BA and minocycline can narrow the neurotoxicity of T-2 to some extent by antioxidant, anti-apoptotic and anti-inflammatory effects.

2.3.2. Toxic targets

T-2 (10 ng/mL) induced apoptosis in human neuroblastoma cells, whereas pretreatment with caspase inhibitor (Z-VAD-FMK) and MAPK inhibitors (PD 98059, SB 203580 and ZM 336372) decreased the level of apoptosis (Agrawal et al., 2015). Pretreatment of Nrf2 inhibitor (brusatol) or heme oxygenase 1 (HO-1) inhibitor (zinc protoporphyrin IX) enhanced T-2 (20 ng/mL)-induced neurotoxicity in mouse neuroblastoma-2a (N2a) cells (Zhang et al., 2018). Mitochondria-related p53 signaling exacerbated T-2-induced neuronal cell death (Dai et al., 2019). Silencing of high mobility group B1 (HMGB1) reduced the toxic effects of oxidative stress, apoptosis and inflammation in PC12 nerve cells caused by T-2 (Pei et al., 2021). Knockdown of Nrf2 exacerbated T-2-induced cytotoxicity, oxidative stress and mitochondrial dysfunction in human neuroblastoma SH-SY5Y, thereby inducing neurotoxicity (Pang et al., 2022). T-2 (5 ng/mL) induced activation of MAPKs and downstream NF-kappaB in BV-2 cells, and inhibitors of NF-kappaB and MAPKs could reverse T-2-induced microglia activation, thereby alleviating neurocytotoxicity (Li et al., 2023). Therefore, MAPK, NF-kappaB, Nrf2, HO-1, p53, and HMGB1 may be significant targets of T-2 neurotoxicity.

2.4. Protective agent for reproductive toxicity

2.4.1. Protective agents

L-Arg (0.25, 0.5, and 1.0 mmol/L) pretreatment upregulated activities of GSH-Px, SOD and CAT in T-2 (10 nmol/L)-treated mouse Leydig cells, thereby alleviating T-2-induced oxidative damage (Yang et al., 2018). In vivo studies have demonstrated that dietary supplementation with L-Arg protected mice from T-2-induced reproductive damage by improving semen quality and serum testosterone levels (Zhang et al., 2019). In isolated Leydig cells, L-Arg (0.25, 0.5, and 1.0 mmol/L) increased the testosterone levels and upregulated the activity of cholesterol side-chain cleavage enzyme, 3 beta-hydroxysteroid dehydrogenase/isomerase-1 and steroidogenic acute regulatory protein (StAR), thereby ameliorating T-2 (10 nmol/L)-induced reproductive toxicity (Yang et al., 2019b). It was further observed that L-Arg (0.25, 0.5, and 1.0 mmol/L) upregulated Bcl-2 expression, downregulated Bax and caspase-3 expression, and promoted Leydig cell proliferation and mitochondrial activity, thereby preventing T-2 (10 nmol/L)-induced apoptosis (Zhang et al., 2020b).

Quercetin (Que) (100 ng/mL) effectively increased total antioxidant status and the activities of SOD and glutathione peroxidase family (GPX) in T-2 (100 ng/mL)-exposed porcine granulosa cells in vitro (Capcarova et al., 2015). BA (0.25, 0.5, and 1.0 mg/kg feed) pretreatment significantly increased the total antioxidant capacity, the activities of SOD and CAT, and decreased GSH depletion, MDA content and caspase-3 and Bax protein expression, thereby reducing the rate of apoptosis and alleviating T-2 (4 mg/kg BW)-induced oxidative damage in mouse testes (Wu et al., 2019). BA also increased testosterone levels and sperm motility, thereby reversing the adverse effects of T-2 on reproduction (Wu et al., 2019). NAC (5 mmol/L) attenuated T-2 (8.10 nmol/L)-induced oxidative stress, apoptosis, and functional impairment in TM4 cells (testes-supporting cells) (Yang et al., 2021). In isolated bovine testicular mesenchymal cells, vitamin E and selenium significantly upregulated GSH-Px, SOD, and CAT activities, thereby reducing oxidative damage to ameliorate T-2-induced germ cell toxicity (Yang et al., 2022).

Additionally, melatonin protected against HT-2 toxin (a metabolite of T-2)-induced apoptosis and oxidative stress in bovine ovarian granulosa cells by reducing the expression of Bax/Bcl-2 and caspase-3, as well as the levels of ROS and MDA, and promoting the expression of SOD and CAT (Yang et al., 2019a).

In summary, L-Arg, BA, NAC, vitamin E, selenium, Que and melatonin ameliorated T-2-induced reproductive toxicity primarily through antioxidant, anti-inflammatory, and anti-apoptotic effects.

2.4.2. Toxic targets

T-2 promoted TM3 cell apoptosis by increasing Ca²⁺ accumulation through the inhibition of the mammalian target of rapamycin complex 2 (mTORC2)/protein kinase B pathway. Meanwhile, BAPTA-AM (a Ca²⁺ chelator) and MHY1485 (an mTOR activator) prevented T-2-induced apoptosis (Wang et al., 2018). Pretreatment of endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid (4-PBA, 1 μmol/L for 2 h) alleviated ER stress and decreased apoptosis rate, thereby alleviating T-2 exposure (10 nmol/L for 24 h)-induced toxicity in goat endometrium epithelial cells (Yi et al., 2018). T-2 (0.5, 1 or 2 mg/kg BW, orally, 28 d) affected fertility in mice by interrupting the hypothalamic-pituitary-testicular (HPT) axis and impairing testicular function (Yang et al., 2019c). In porcine granulosa cells, T-2 (1, 10 and 100 nmol/L for 24 h) decreased the expression of cAMP-stimulated StAR which is a rate limiting protein in progesterone synthesis, suggesting StAR is a sensitive target for T-2 (Wu et al., 2015). Therefore, abnormal changes in Ca²⁺ concentration, mTORC2, ER stress, HPT axis and StAR may be important links in mitigating T-2 reproductive toxicity.

2.5. Protective agent for hepatotoxicity

2.5.1. Protective agents

2.5.1.1. Protective agents from plants

Lycopene (25 mg/kg BW per day) from fresh tomatoes reduced GSH depletion and alleviated oxidative damage in the liver of male broiler chickens fed T-2 (1.5 mg T-2/kg BW per day) (Leal et al., 1999). Diets containing 0.1% concentrate of food indoles (indole-3-carbinole and ascorbigen) fed to rats for 3 weeks increased the activity of hepatic microsomal carboxylesterase and UDP-glucuronosyltransferase (UDPG), thereby attenuating the toxic effects of T-2 (Kravchenko et al., 2001). Rutin reversed the T-2-mediated increase of LPO and SOD, as well as the decrease in GSH levels, in rat liver homogenate (Sawi and Seeni, 2009). Resveratrol (RES, 20 μmol/L) inhibited the aryl hydrocarbon receptor (AHR) – cytochrome P450 family 1 subfamily A polypeptide 5 (CYP1A5) pathway to enhance cell viability and reduce oxidative stress, DNA damage and apoptosis, thereby alleviating T-2 (100 nmol/L) cytotoxicity in leghorn male hepatocellular carcinoma epithelial cells (Fig. 3) (Liu et al., 2019). Treatment with curcumin (80 mg/kg BW per day) and taurine (50 mg/kg BW per day) ameliorated T-2 (0.1 mg/kg BW, intraperitoneal injections)-induced hepatotoxicity in Wistar rats through anti-inflammatory, antioxidant and anti-apoptotic effects (Al-Zahrani et al., 2023).

Fig. 3.

The mechanisms of selenium (Se), L-carnitine, resveratrol (RES) and 1% cholic acid (1%CA) to reduce T-2-triggered hepatotoxicity. AHR = aryl hydrocarbon receptor; Bcl-22 = B-cell lymphoma 2; Bax = Bcl-2-associated X protein; Cas3 = Caspase 3; Cas9 = Caspase 9; CoQ10 = coenzyme Q10; CYP1A5 = cytochrome P450 family 1 subfamily A polypeptide 5; FXR = farnesoid X receptor; GSH = glutathione; H2O2 = hydrogen peroxide; LPO = lipid peroxidation; MMP = membrane potential; ROS = reactive oxygen species; SeMet = selenomethionine; SOD = superoxide dismutase; T-2 = T-2 toxin; UDPG = UDP-glucuronosyltransferase.

2.5.1.2. Selenium/SeMet

Selenium (sodium selenate) supplementation (0.5 and 2.5 mg/kg feed) increased hepatic epoxide hydrolase and UDPG activity, thereby reducing T-2 (3.8 mg/kg BW)-induced toxicity and mortality in male rats (Kravchenko et al., 1990). The dietary use of selenium (sodium selenate), vitamin E and vitamin C eased T-2-induced hepatic lipid peroxide and GSH depletion, thereby alleviating liver injury in rats (Fig. 3) (Rizzo et al., 1994). The combination of selenium and modified glucomannan prevented T-2 (8.1 mg/kg feed)-induced oxidative stress damage and LPO in chicken liver (Dvorska et al., 2007). Low doses of SeMet (0.2 mg/kg feed) downregulated Bax, caspase-3, and caspase-9 and upregulated Bcl-2, thereby reducing the levels of oxidative stress and apoptosis in T-2 (0.4 mg/kg BW)-treated rabbit hepatocytes (Fig. 3) (Liu et al., 2021c).

2.5.1.3. Adsorbents

The dietary addition of HSCAS adsorbent blocked T-2-induced aspartate aminotransferase (AST) elevation and mitigates hepatotoxicity in chicks (Wei et al., 2019). Yeast cell wall extract (YCWE) supplemented with a post-biotic yeast cell wall-based blend improved the negative effects of T-2 (3.0 mg/kg feed) on growth performance and liver function in broilers (Kudupoje et al., 2022).

2.5.1.4. Amino acids and other protective agents

High-dose L-carnitine (500 mg/kg diet) pretreatment reduced GSH depletion, ROS overproduction, and mitochondrial membrane potential collapse and lowered caspase 3 activity and apoptosis in primary rat hepatocytes caused by T-2 exposure, thereby alleviating liver injury (Fig. 3) (Moosavi et al., 2016). Dietary 3.17% Arg administration significantly decreased alanine aminotransferase (ALT) and AST activity in the haemolymph, thereby alleviating T-2 (1.5 mg/kg BW)-induced hepatotoxicity in Chinese mitten crab (Zhang et al., 2020a).

Pretreatment with the antioxidant coenzyme Q10 (CoQ10) (6 mg/kg) and vitamin E (6 mg/kg) reduced DNA damage, cell death and GSH depletion in the liver of T-2 (1.8 or 2.8 mg/kg BW)-exposed mice (Atroshi et al., 1997). Dietary supplementation with 1% cholic acid (CA) promoted the xenobiotic metabolism of T-2 by inducing the expression of farnesoid X receptor (FXR), thereby enhancing SOD activity and reducing hepatic hydrogen peroxide (H2O2) level and oxidative stress, ultimately alleviating T-2-induced liver damage in broiler chickens (Fig. 3) (Dai et al., 2020). N,N′-dichloro-bis (2,4,6-trichlorophenyl) urea (CC-2) (20%) protected mice from T-2 (11.8 mg/kg BW)-induced hepatic LPO and reduced mortality (Agrawal et al., 2012a). Silibinin dietary supplementation protected HepG2 cells from T-2 toxicity (Tran et al., 2020).

In summary, selenium/SeMet, CoQ10, vitamin E, vitamin C, lycopene, food indoles, Rutin, RES, curcumin, taurine, L-carnitine, 1% CA, and 20% CC-2 ameliorated T-2-induced hepatotoxicity primarily through antioxidant, anti-apoptotic, or anti-inflammatory effects (Fig. 3). In addition, 3.17% Arg, HSCAS, YCWE, and silymarin dietary supplements may also alleviate hepatocyte injury caused by T-2 exposure. T-2 can induce hepatic LPO which is also one of the main features of ferroptosis (Ursini and Maiorino, 2020). The liver is an important organ for iron accumulation (Shah and Belonje, 1976); however, it remains unclear whether ferroptosis mediates T-2-induced hepatotoxicity and whether ferroptosis inhibitors alleviate hepatotoxicity.

2.5.2. Toxic targets

T-2-induced CYP1A5 in chicken embryonic hepatocyte cells catalyzed T-2 into a more toxic product, 3′–OH–T-2 (Shang et al., 2013). Therefore, inhibition of CYP1A5 activity may be a key step in alleviating T-2 hepatotoxicity. Upregulation of silent information regulator sirtuin 1 (SIRT1) is involved in T-2-induced mitochondrial dysfunction and ROS production in HepG2 (Ma et al., 2017). Thus, CYP1A5, cytochrome P450 1A1 (CYP1A1), FXR, SIRT1 and eleven translocation family protein 3 (TET3) (Table 2) may be targets of T-2 hepatotoxicity.

2.6. Protective agent for nephrotoxicity

2.6.1. Protective agent

SeMet (0.2 mg/kg feed) reduced T-2 (0.4 mg/kg feed)-induced ROS and inflammatory factor levels, thereby restoring renal function in rabbits (Liu et al., 2021b). Selenium (0.2 mg/kg diet) protected mouse kidney from T-2 (1.0 mg/kg diet)-induced damage by inhibiting ROS-mediated apoptosis in kidney cells, as evidenced by reduced cytochrome-c protein expression and caspase-3/9 activity (Zhang et al., 2022f). Short-term selenium-deficiency synergistic with T-2 (10 ng/g BW) could lead to rat kidney damage and even kidney fibrosis, which in turn proves that Se supplementation could mitigate nephrotoxicity under T-2 exposure (Guo et al., 2023).

In porcine kidney cells (PK-15), BA (0.25, 0.5, and 1 μmol/L) pretreatment ameliorated T-2 (1 μmol/L)-induced oxidative stress damage and apoptosis by increasing SOD, GSH-Px, and CAT activity and reducing intracellular ROS and MDA production, thereby alleviating renal cytotoxicity (Li et al., 2021). Huang et al. (2021) further showed that BA (0.25, 0.5, and 1 mg/kg BW) pretreatment attenuated T-2-induced oxidative stress and inflammatory responses (low expression of IL-1β, TNF-α) by activating the Nrf2 signaling pathway. This reduced T-2 (4 mg/kg BW)-triggered mice glomerular hemorrhage and inflammatory cell infiltration. Therefore, selenium/SeMet and BA in a certain concentration range could reduce the nephrotoxicity of T-2.

2.6.2. Toxic targets

Protein kinase RNA-like ER kinase (PERK)-mediated ER stress was involved in PK-15 apoptosis under T-2 treatment, whereas the ER stress inhibitor 4-PBA and the PERK-selective inhibitor (GSK2606414) prevented the T-2-induced decrease in cell activity and apoptosis, providing a new perspective to inhibit the nephrotoxicity of T-2 (Liu et al., 2021a). T-2 (0.5, 1.0, 2.0 mg/kg BW) increased nuclear Nrf2 protein expression and induced oxidative stress as well as apoptosis in the kidney of male mice (Zhang et al., 2021c). The phosphatase and tensin homolog (PTEN)-induced putative kinase1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy alleviated T-2-induced nephrotoxicity in mice (Zhang et al., 2022e). Thus, PERK, ER stress, Nrf2 and PINK1/Parkin may be targets to alleviate T-2 nephrotoxicity.

2.7. Protective agent for cardiotoxicity

2.7.1. Protective agent

CAT (10 U/mL) and vitamin C (10 μg/mL) improved the decrease in oxygen consumption rate in cardiomyocytes exposed to T-2 (6.0 × 10⁻³ and 6.0 × 10⁻⁴ μmol/L) (Ngampongsa et al., 2013). Selenium supplementation improved the effects of Keshan disease, which include congestive cardiomyopathy caused by T-2 (0.25–1 μmol/L) exposure in primary cardiomyocytes (Chen et al., 2019). Methylprednisolone (Meth) reduced the intensity of T-2 (0.23 mg/kg BW, subcutaneous injection)-induced myocardial degeneration and hemorrhage, thus protecting the myocardium from T-2-induced damage (Jacevic et al., 2019). Therefore, a range of concentrations of catalase, vitamin C, selenium and Meth can antagonize the cardiotoxicity of T-2.

2.7.2. Toxic targets

Lu et al. (2021) found that peroxisome proliferator-activated receptor (PPAR)-γ agonist (pioglitazone) alleviated T-2-induced H9C2 (rat cardiomyocyte) injury, indicating PPAR-γ may be a potential target for T-2 (2 mg/kg BW)-induced cardiac fibrosis in rats.

2.8. Protective agent for skeletal toxicity

2.8.1. Protective agent

T-2 exposure has been strongly associated with skeletal deformities such as incomplete ossification and bone loss and fusion, Kashin-Beck disease (Zhou et al., 2016). Thus, it is important to counter its toxic effects on the skeleton. Selenium partially inhibited the degradation of aggregated proteoglycans in chondrocytes and the increase in pro-inflammatory cytokines (IL-1β and TNF-α) caused by T-2 (0.001 to 2 mg/L) (Chen et al., 2006; Li et al., 2008). The addition of selenium (100 ng/mL) enhanced the metabolic transformation of T-2 and reduced its cytotoxicity to human chondrosarcoma cell lines (Yu et al., 2017). Selenium treatment rescued T-2-induced apoptosis and inflammation and reversed T-2-induced damage to primary epiphyseal chondrocytes (Shi et al., 2021). In addition, Selenium supplementation could ease the inhibitory effect of T-2 on chondrocytes (C28/I2 and ATDC5) and cartilage (Zhang et al., 2021a). NAC protected tibial growth plate chondrocytes in chickens against the cytotoxicity of T-2 (5, 50, and 500 nmol/L) in vitro by reducing oxidative stress (He et al., 2012). Therefore, certain concentrations of selenium and NAC could reduce the skeletal toxicity of T-2 through anti-inflammatory, anti-apoptotic or antioxidant mechanisms.

2.8.2. Toxic targets

Inhibition of insulin like growth factor 1 receptor (IGF-1R) may mediate chondrocyte death and extracellular matrix degeneration under T-2 exposure (Zhang et al., 2021b). Heat shock protein 47 (HSP47) is involved in T-2-driven reduced type II collagen expression, further promoting matrix degradation in chondrocytes (Zhang et al., 2021a). The matrix metalloproteinase-10 (MMP-10) deficiency rendered chondrocytes more sensitive to T-2-induced apoptosis, terminal differentiation and death (Zhang et al., 2022a). Yes-associated protein (YAP) was one of the targets of T-2-induced chondrocyte injury in rats, and the YAP-specific inhibitor (vetiporfin) increased MMP-13 expression and reduced human collagen Type II and proliferating cell nuclear antigen levels, thus ameliorating T-2-caused cartilage injury (Li et al., 2022a). T-2 (0.5, 1 or 2 mg/kg BW) induced femoral head lesions in mice accompanied by autophagy and apoptosis, which are associated with Wnt/beta-catenin signaling (Zhang et al., 2022d). Thus, IGF-1R, HSP47, MMP-10, YAP, Wnt/beta-catenin signaling, O6-methylguanine-DNA methyltransferase (MGMT) and transforming growth factor-beta receptorss (TGF-βRs) (Table 2) may be targets for antagonizing the skeletal toxicity of T-2.

2.9. Protective agent for dermal toxicity and muscle toxicity

T-2 (0.5, 1.5, 4.5 and 13.5 mg/kg feed) affected shrimp muscle fatty acid and water distribution, muscle histopathology, resulting in a decrease in quality and nutritional value of shrimp (Bi et al., 2019). Que (2.00 to 32.00 g/kg feed), tea polyphenols and rutin could prevent abnormal changes in the target protein (enolase, malate dehydrogenase, elongation factor 1-alpha and eukaryotic translation initiation factor 2 subunit alpha, actin 2, fast-type skeletal muscle actin 1), and muscle composition (the sarcoplasmic, myofibrillar and the alkali-soluble protein) of shrimp caused by T-2 (4.80 to 24.30 mg/kg feed) and ameliorated the degree of muscle protein deterioration (Huang et al., 2022a). Mycotoxins in feed (containing T-2 at 320.5 μg/kg) could retard broiler growth, nutrient retention and meat quality; while the addition of 0.05% esterified glucomannan, 0.2% HSCAS or 0.1% compound mycotoxin adsorbent (CMA) prevented the adverse effects of mycotoxins on chicken meat (Liu et al., 2011). Therefore, Que, tea polyphenols, rutin, esterified glucomannan, HSCAS, and CMA in a range of doses alleviated the muscle toxicity of T-2.

T-2 is lipophilic, easily penetrates the skin, and causes skin irritation and blistering in the body (Hayes and Schiefer, 1990). Research has shown that aqueous soap solution was largely effective in removing low doses of T-2 from the skin of rabbits, whereas polyethylene glycol 300 (PG300) washing is effective in removing large doses of T-2 from the skin of rabbits (Fairhurst et al., 1987). A topical skin protectant (ICD 2289) effectively relieved skin erythema and edema in animals exposed to T-2 (Liu et al., 1999). The quince seed mucilage (15%) effectively alleviated T-2 (8.34 μg/mL)-induced skin toxicity in rabbits (Hemmati et al., 2012). Mice handled by T-2 (23.76 mg/kg BW topical percutaneous smearing on the back of rat) died within 36 h of exposure. The subcutaneous application of CC-2 within 5 and 15 min of treatment with T-2 resulted in survival rates of 100% and 50%. Therefore, CC-2 may be an effective skin decontaminant against lethal topical exposure to T-2 (Agrawal et al., 2012a). T-2 (2.97 mg/kg BW) caused skin inflammation, erythema and skin tissue necrosis in mice; whereas topical application of 0.25% and 0.5% menthol prevented the development of erythema or inflammation through anti-inflammatory effects (Rachitha et al., 2023). Therefore, topical application of aqueous soap solution, PG300, skin protectant, quince seed mucilage, CC-2 and menthol may reduce the dermal toxicity of T-2 to some extent.

2.9.1. Toxic targets

High transforming growth factor-beta 1 (TGF-β1) levels may be closely related to T-2-induced apoptosis of epidermal basal cells and intradermal infiltration of mast cells and fibroblasts (Albarenque et al., 2000). Increased TNF-α mRNA expression may play an important part in T-2-caused apoptosis in epidermal cells (Albarenque et al., 2001a). Enhanced expression of c-fos and c-jun may be associated with epidermal apoptosis induced by topical application of T-2 (0.5 μg/μL) (Albarenque et al., 2001b). The activation of MMP9/2 and MAPK pathways mediated T-2 (2.97, 5.94 and 11.88 mg/kg BW)-induced skin inflammation and cutaneous damage in Swiss albino mice (Agrawal et al., 2012b). T-2 induced human skin-fibroblast Hs68 cell necrosis accompanied by increased concentration of released cytokeratin 18 (Janik-Karpinska et al., 2022). In summary, TGF-β1, TNF-α, c-fos and c-jun, MMP and p38 MAPK and cytokeratin 18 may be the potential targets of T-2 dermal toxicity.

Where T-2 (1.2 mg/kg BW) exposure affects the protein composition and quality of shrimp muscle, arginine kinase (spot 27) was particularly responsive to T-2 and could potentially be used as a biomarker protein for T-2 intoxication by shrimp (Huang et al., 2020).

3. Conclusions and perspectives

The long-term consumption of T-2-contaminated food and feed can cause gastrointestinal toxicity, immunotoxicity, hepatotoxicity, reproductive toxicity, neurotoxicity, nephrotoxicity, cardiotoxicity, skeletal toxicity, muscular toxicity, and dermal toxicity in humans and animals. Thus, the application of protective agents to reduce the organ toxicity of T-2 is of particular importance. Evidence from available studies has demonstrated that BA, selenium/SeMet and T-2 adsorbents effectively alleviated the majority of organ toxicity caused by T-2 (Fig. 4). Protective agents alleviated toxicity primarily through antioxidant, anti-inflammatory, or anti-apoptotic pathways or by reducing toxin uptake in organs. Although different strategies of protective agents have been developed for T-2, further validation of their utility and safety in animal production is needed.

Fig. 4.

Protective agents of organ toxicity under T-2 exposure. Arg = arginine; ASS = aqueous soap solution; BA = betulinic acid; CA = cholic acid; CC-2 = N,N′-dichloro-bis (2,4,6-trichlorophenyl) urea; CMA = compound mycotoxin adsorbent; EGM = esterified glucomannan; FWGE = fermented wheat germ extract; GTP = green tea powder; HSCAS = hydrated sodium calcium aluminosilicate; Meth = methylprednisolone; NAC = N-acetylcysteine; PG300 = polyethylene glycol 300; Que = quercetin; QSM = quince seed mucilage; RA = rosmarinic acid; RES = resveratrol; Se = selenium; SeMet = selenomethionine; TSP = topical skin protectant; VC = vitamin C; VE = vitamin E; YCWE = yeast cell wall extract.

In addition to the protective agents, inhibition or activation of T-2 toxicity targets can also help mitigate toxicity to an extent. However, the detoxifying effects of toxicity targets need to be validated in vivo and in vitro. The multi-component protectants may protect against T-2 toxicity more comprehensively. The development of antagonists of T-2 toxicity in the future, based on one target or multiple targets, is also an alternative strategy.

Biotransformation and degradation by bacteria and yeast leaves neither toxic residues nor any undesirable by-products. Therefore, microbial biotransformation of T-2 to non-toxic or less toxic metabolites has been recognized as a promising approach. Researchers have now found that bacterial enzyme ZenA hydrolyzes zearalenone, and sodium metabisulfite inactivates deoxynivalenol by sulfonation (Danicke et al., 2023). Curtobacterium sp. (Ueno et al., 1983), Blastobacter sp. (Beeton and Bull, 1989), and Lactobacillus plantarum (Cserháti et al., 2013) could 100% degrade T-2. Deeper mining of bacterial enzymes or compounds that degrade T-2 from these microorganisms is also necessary. In addition, proper processing of T-2 contaminated animal feed has some positive effects on reducing the toxicity of T-2.

Notably, ferroptosis could mediate T-2-induced cell toxicity by increasing ROS levels, whereas NAC significantly blocked ferroptosis under T-2 exposure (Wang et al., 2021). T-2 exposure resulted in decreased expression of GPX4, (a key negative regulatory protein of ferroptosis), accompanied by degeneration of articular cartilage in rats (Sun et al., 2021). Therefore, exploring the role of ferroptosis in T-2 organ toxicity would provide another new detoxification strategy.

Author contributions

Pengju Wang: Topic selection, Outline, Figures, and Writing – original draft. Qinghua Wu: Outline of figures and tables, and Writing – review & editing. Lv-hui Sun: Outline of figures and tables, and Writing – review & editing. Xu Wang: Outline of figures and tables, and Writing – review & editing. Aimei Liu: Writing – review & editing, Supervision, and Funding acquisition.

Declaration of competing interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, and there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the content of this paper.