Food and Chemical Toxicology 126 (2019) 262–276 Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox Review Effects of zearalenone and its derivatives on the synthesis and secretion of mammalian sex steroid hormones: A review T Wanglong Zhenga,b,c,d, Nannan Fenga,c,d, Yin Wangb, Lance Nollb, Shiwei Xub, Xuming Liub, Nanyan Lub, Hui Zoua,c,d, Jianhong Gua,c,d, Yan Yuana,c,d, Xuezhong Liua,c,d, Guoqiang Zhua,c,d, ∗∗∗ ∗∗ ∗ Jianchun Biana,c,d, , Jianfa Baib, , Zongping Liua,c,d, a College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China b Kansas State Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, Unites States c Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, China d Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China ARTICLE INFO ABSTRACT Keywords: Zearalenone (ZEA), a non-steroidal estrogen mycotoxin produced by several species of Fusarium fungi, can be Zearalenone metabolized into many other derivatives by microorganisms, plants, animals and humans. It can affect mam- Steroid sex hormones malian reproductive capability by impacting the synthesis and secretion of sex hormones, including testosterone, Steroidogenesis estradiol and progesterone. This review summarizes the mechanisms in which ZEA and its derivatives disturb the Leydig cell synthesis and secretion of sex steroid hormones. Because of its structural analogy to estrogen, ZEA and its Granulosa cell derivatives can exert a variety of estrogen-like effects and engage in estrogen negative feedback regulation, which can result in mediating the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the pituitary gland. ZEA and its derivatives can ultimately reduce the number of Leydig cells and granulosa cells by inducing oxidative stress, endoplasmic reticulum (ER) stress, cell cycle arrest, cell apoptosis, and cell regeneration delay. Additionally, they can disrupt the mitochondrial structure and influence mi- tochondrial functions through overproduction of reactive oxygen species (ROS) and aberrant autophagy sig- naling ways. Finally, ZEA and its derivatives can disturb the expressions and activities of the related steroido- genic enzymes through cross talking between membrane and nuclear estrogen receptors. 1. Introduction these contaminated cereal commodities may have contributed to the worldwide dispersal of ZEA (Zinedine et al., 2007). Several studies Zearalenone (ZEA), also known as F-2 mycotoxin, is a non-steroidal carried out in Europe and in transcontinental countries, reported the estrogen mycotoxin produced by several species of Fusarium fungi high incidence of ZEA in cereals and in animal feeding stuffs(Miraglia (Stanciu et al., 2018; Tatay et al., 2016). These fungi can contaminate et al., 2009). The impact of climate on ZEA occurs through multiple cereal grains, including maize, wheat, sorghum, barley, and oats, and pathways. Changes in air and water temperatures, weather-related produce ZEA in the field and farm or during harvest and storage at a changes, and extreme events can shift the seasonal and geographic low temperature and high humidity (Ali and Degen, 2018; Dellafiora occurrence of fungi contaminants (Castro-Ibanez et al., 2015; Wu et al., et al., 2017). ZEA are not only dangerous for the public health, but they 2011). The world's largest agri-food exporters include countries such as also deteriorate the marketable quality of the contaminated products, Brazil and Argentina and parts of Asia including China and India are causing tremendous economic losses (Reddy et al., 2018). The in- identified as hot spots for impacts of climate change (Ray et al., 2012). cidence and extent of ZEA contamination is strictly related to geo- Studies have suggested that there are two main routes for human graphic and climate as well as cultivation, harvesting, stocking, and and animal exposure to ZEA and its derivatives (Bertero et al., 2018; transport conditions (Miraglia et al., 2009). The international trade of Yang et al., 2018a). The first is consuming cereal grains and their ∗ Corresponding author. College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China. ∗∗ Corresponding author. Kansas State Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, Unites States. ∗∗∗ Corresponding author. College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China. E-mail addresses: [email protected] (J. Bian), [email protected] (J. Bai), [email protected] (Z. Liu). https://doi.org/10.1016/j.fct.2019.02.031 Received 27 November 2018; Received in revised form 17 February 2019; Accepted 20 February 2019 Available online 27 February 2019 0278-6915/ © 2019 Elsevier Ltd. All rights reserved. W. Zheng, et al. Food and Chemical Toxicology 126 (2019) 262–276 Abbreviations miRNAs that microRNAs MMP mitochondrial membrane potential 17β-HSD 17 beta-hydroxysteroid dehydrogenase mtDNA mitochondrial DNA 3β-HSD 3 beta-hydroxysteroid dehydrogenase MTT assay 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium 4-PBA 4-phenylbutyrate bromide assay AC adenylate cyclase NUR77 nerve growth factor IB ASK-1 apoptosis signal-regulating kinase 1 P450SCC P450 side-chain cleavage enzyme ATM ataxia telangiectasia mutated PAC phosphofurin acidic cluster CAT catalase PDE cyclic nucleotide phosphodiesterase CDK2 cyclin dependent kinase 2 PI3K phosphatidylinositol-4,5-bisphosphate 3-kinase CHOP transcriptional factor C/EBP homologous protein PITX-1 pituitary homeobox-1 CYP11A1 cytochrome P450 family 11 subfamily A member 1 PKA protein kinase A Cyp11a1 cholesterol side cleavage enzyme Prxs peroxiredoxins CYP17 cytochrome P450 family 17 ROS reactive oxygen species EDS ethane dimethane sulfonate SF1 steroidogenic factor 1 EGF epidermal growth factor SOD superoxide dismutases ER stress endoplasmic reticulum stress StAR steroidogenic acute regulatory protein EREs estrogen response elements TRX1 and TRX2 thioredoxin isoforms ERO1 endoplasmic reticulum oxidoreductin 1 ZAN Zearalanone ERs nuclear estrogen receptors ZAN-14-glu Zearalanone-14-Glucuronide FAD Flavin adenine dinucleotide ZAN-16-glu Zearalanone-16-Glucuronide FAS Fas cell surface death receptor ZEA zearalenone FASL FAS ligand ZEA-14-glu zearalenone-14-Glucuronide FSH follicle-stimulating hormone ZEA-14-sulfate Zearalenone-14-sulfate GADD45A growth arrest and DNA damage-inducible protein ZEA-16-glu zearalenone-16-Glucuronide gadd45 alpha ZEA-16-sulfate Zearalenone-O-14-sulate GPR30 G protein-coupled receptor 30 ZEA-O-14-glu zearalenone-O-14-Glucuronide GPXs glutathione peroxidases ZEA-O-16-glu zearalenone-O-16-Glucuronide GR glutathione reductase α-ZAL α-zearalanol GSH Glutathione α-ZAL-14-glu α-zearalanol-14-Glucuronide GSSG glutathione disulfide α-ZAL-16-glu α-zearalanol-16-Glucuronide GST glutathione S-transferase α-ZEL α-zearalenol HB-EGF heparin bound epidermal growth factor α-ZEL-14-glu α-zearalenol-14-Glucuronide HCG human chorionic gonadotropin α-ZEL-16-glu α-zearalenol-16-Glucuronide HSD11B1 hydroxysteroid 11-beta dehydrogenase 1 β-ZAL β-zearalanol IGF-1 insulin like growth factor 1 β-ZAL-14-glu β-zearalanol-14-Glucuronide JNK c-Jun amino terminal kinase β-ZAL-16-glu β-zearalanol-16-Glucuronide LH luteinizing hormone β-ZEL β-zearalenol LHX3 LIM class of homeodomain protein-3 β-ZEL-14-glu β-zearalenol-14-Glucuronide MAPK mitogen activated protein kinase β-ZEL-16-glu β-zearalenol-16-Glucuronide derived products that are contaminated with ZEA or toxigenic fungi production, spermatozoal mass motility of spermatozoal morphology of (Zheng et al., 2018d). The second is consuming animal-derived food, adult ram (Milano et al., 1991). A field outbreak of ZEA mycotoxicosis including meat, eggs, and milk, which was derived from animals that in horses was associated with corn screenings containing approximately were already contaminated by ZEA or were injected with its derivatives 2.6 mg/kg of ZEA and the concentration of the toxin recorded in to promote growth (Belhassen et al., 2015; Jeong et al., 2010; Mauro naturally contaminated oats does not have a significant effect on the et al., 2018). The adverse effects of ZEA have been widely investigated release of reproductive hormones, cycle length or uterine histology in in human, farm animals, poultry, birds and companion animals such as mares (Aurich et al., 2006). pig, ovine, bovine, horse, chicken, birds, dogs and cats (Blajet-Kosicka Accumulating evidence has suggested that exposure to ZEA can et al., 2014; Minervini and Dell'Aquila, 2008). Among these animals, impair the reproductive capacity and disturb the production and de- pigs are the most susceptible species to the toxicity of ZEA, gilts being velopment of sperm and oocytes in humans and animals (Adibnia et al., the most sensitive, and poultry, horse, birds are lower susceptible 2016; Takagi et al., 2008; Yang et al., 2018c; Yousef et al., 2017). species (Malekinejad et al., 2006b; Olsen et al., 1987). The oestrogenic Several studies have also shown that ZEA can not only disrupt puberty syndrome in swine affects primarily the reproductive tract and mam- and the estrous cycle, but also could affect early pregnancy events in- mary gland, and in more sensitive