title: Prepubertal exposure to an oestrogenic mycotoxin zearalenone induces central precocious puberty in immature female rats through the mechanism of premature activation of hypothalamic kisspeptin-GPR54 signaling.
abstract: Sporadic epidemics and several researches in rodents indicated that zearalenone (ZEA) and its metabolites, the prevailing oestrogenic mycotoxins in foodstuffs, were a triggering factor for true precocious puberty development in girls. Nevertheless, the neuroendocrine mechanism through which ZEA mycoestrogens advance puberty onset is not fully understood. To elucidate this issue, hypothalamic kisspeptin-G-protein coupled receptor-54 (GPR54) signaling pathway that regulates the onset of puberty was focused on in the present study. Immature female SD rats were given a daily intragastric administration of corn oil (vehicle control), 50 μg/kg body weight (bw) of 17β-estradiol (E2, positive control), and 3 doses (0.2, 1 and 5 mg/kg bw) of ZEA for consecutive 5 days starting from postnatal day 15, respectively. Puberty onset was evaluated by detecting the physiological and hormonal responses, and hypothalamic kisspeptin-GPR54 pathway was determined to reveal the neuroendocrine mechanism. As the markers of puberty onset, vaginal opening was significantly accelerated and uterine weight was increased in both E2 and 5 mg/kg ZEA groups. Serum levels of follicle stimulating hormone, luteinizing hormone and estradiol were also markedly elevated by E2 and 5 mg/kg ZEA, which is compatible with the changes in peripheral reproductive organs. The mRNA and protein expressions of hypothalamic gonadotropin-releasing hormone (GnRH) were both obviously elevated by E2 and 5 mg/kg ZEA. GnRH expression changes occurred in parallel with increased expressions of hypothalamic Kiss1 and its receptor GPR54 at both mRNA and protein levels. Most of these changes were also noted in 1 mg/kg ZEA group, but none in 0.2 mg/kg group. Therefore, within the context of this study, the No Observed Adverse Effect Level (NOAEL) for ZEA in terms of oestrogenic activity and puberty-promoting effect in immature female rats was considered to be 0.2 mg/kg bw per day, and the Lowest Observed Adverse Effect Level (LOAEL) was 1 mg/kg bw per day. In conclusion, prepubertal exposure to dietary relevant levels of ZEA induced central precocious puberty in female rats by premature activation of hypothalamic kisspeptin-GPR54-GnRH signaling pathway, followed by the stimulation of gonadotropins release at an earlier age, resulting in the advancement of vaginal opening and enlargement of uterus at periphery.
authors: Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20 Dongdajie Street, Fengtai District, Beijing 100071, PR China.
authors: Rong
authors: R
authors: Yang
authors: Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20 Dongdajie Street, Fengtai District, Beijing 100071, PR China. Electronic address: wangyimei2006@126.com.
authors: Yi-Mei
authors: YM
authors: Wang
authors: Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20 Dongdajie Street, Fengtai District, Beijing 100071, PR China.
authors: Li
authors: L
authors: Zhang
authors: Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20 Dongdajie Street, Fengtai District, Beijing 100071, PR China.
authors: Zeng-Ming
authors: ZM
authors: Zhao
authors: Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20 Dongdajie Street, Fengtai District, Beijing 100071, PR China.
authors: Jun
authors: J
authors: Zhao
authors: Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20 Dongdajie Street, Fengtai District, Beijing 100071, PR China. Electronic address: pengsq@hotmail.com.
authors: Shuang-Qing
authors: SQ
authors: Peng
mesh_terms: D000818:Animals; D004967:Estrogens / Q000633:toxicity*; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D006728:Hormones / Q000097:blood; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D059648:Kisspeptins / Q000378:metabolism*; D008297:Male; D009183:Mycotoxins / Q000633:toxicity*; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011629:Puberty, Precocious / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism; D012741:Sexual Maturation / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D015025:Zearalenone / Q000633:toxicity*
chemical_list: D004967:Estrogens; D006728:Hormones; C492247:Kiss1r protein, rat; D059648:Kisspeptins; D009183:Mycotoxins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D015025:Zearalenone
keywords: GnRH; Hypothalamus; Kisspeptin; Precocious puberty; Zearalenone