zearalenone and Puberty--Precocious

Zearalenone (ZEN) is a non-steroidal mycoestrogen that widely contaminates agricultural products. ZEN and its derivatives share similar molecular mechanisms and activity with estrogens and interact with ERα and ERβ leading to changes in the reproductive system in both animals and humans. The reduced form of ZEN, α-ZEA ralenol, has been used as an anabolic agent for animals and also proposed as hormonal replacement therapy in postmenopausal women. Furthermore, both zearelanol ZEN and derivatives have been patented as oral contraceptives. ZEN has been widely used in the United States since 1969 to improve fattening rates in cattle by increasing growth rate and feed conversion efficiency. Evidence of human harm from this practice is provided by observations of central precocious puberty. As a result, this practice has been banned by the European Union. As ZEN has been associated with breast enlargement in humans, it has been included in many bust-enhancing dietary supplements but epidemiological evidence is lacking with regard to breast cancer risk. Extensive work with human breast cancer cell lines has shown estrogenic stimulation in those possessing ER but a reduction in DMBA-induced breast cancers in rodents given ZEN. Protein disulfide isomerase provides a molecular biomarker of dietary exposure to ZEN and its derivatives allowing the detection and control of harmful food intake. The interaction of ZEN with anti-estrogens, anticancer agents and antioxidants requires further investigation.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Breast Neoplasms; Cattle; Cell Line, Tumor; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Estrogens, Non-Steroidal; Female; Food Contamination; Growth Substances; Hormone Replacement Therapy; Humans; Inactivation, Metabolic; Puberty, Precocious; Receptors, Estrogen; Zearalenone; Zeranol

Since the 1970s, there has been a worldwide scientific discussion on the potential health consequences of human exposure to endocrine disrupters: many environmentally persistent compounds are oestrogen agonists and/or androgen antagonists. Thus, they can dysregulate the hypothalamic-pituitary-gonadal axis potentially affecting human puberty timing. Zearalenone (ZEA) is a non-steroidal mycotoxin produced by Fusarium species on several grains. Despite its low acute toxicity and carcinogenicity, ZEA exhibits oestrogenic and anabolic properties in several animal species. ZEA food contamination is caused either by direct contamination of grains, fruits and their based-products or by 'carry-over' of mycotoxins in animal tissues, milk and eggs after intake of contaminated feedstuff. In addition, zeranol (alpha-ZAL), a resorcyl lactone derived from ZEA, has been widely used in the USA as a growth promoter to improve fattening rates in cattle. From 1978 to 1984, a great epidemic of premature thelarche and precocious puberty occurred in Puerto Rico. To explain this condition, it was suggested that dairy and meat products could be contaminated with anabolic oestrogens such as ZEA or alpha-ZAL. Subsequently, worldwide other groups have also reported causative associations between oestrogenic mycotoxins and development of early thelarche and/or precocious puberty in exposed children. In addition to animal data, epidemiological studies strongly support the hypothesis that human pubertal development may be induced by foetal/early or prepubertal exposure to oestrogenic compounds. Indeed, ZEA and its metabolites are able to adopt molecular conformation, which sufficiently resembles 17beta-oestradiol to allow it to bind to oestrogen receptors (ERs) in target cells exerting oestrogenic (agonist) actions. In this view, oestrogenic mycotoxins are suspected as triggering factor for precocious pubertal development at least in prepubertal exposed girls.

Topics: Animals; Cattle; Child; Environmental Exposure; Estrogens; Female; Food Contamination; Humans; Hypothalamus; Male; Puberty; Puberty, Precocious; Zearalenone; Zeranol

Topics: Animal Feed; Animals; Cattle; Cattle Diseases; Chickens; Child; Eggs; Female; Food Analysis; Foodborne Diseases; Fusarium; Humans; Infertility; Male; Meat; Milk; Mycotoxins; Poultry Diseases; Puberty, Precocious; Resorcinols; Swine; Swine Diseases; Vaginal Diseases; Zearalenone; Zeranol

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.

Topics: Animals; Estrogens; Estrous Cycle; Female; Genitalia, Female; Gonadotropin-Releasing Hormone; Hormones; Hypothalamus; Kisspeptins; Male; Mycotoxins; Pituitary Gland; Puberty, Precocious; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Receptors, LHRH; RNA, Messenger; Sexual Maturation; Signal Transduction; Zearalenone

Recently, it was reported that the development of breast tissue and secondary sex characteristics in girls occurred at much younger age and the incidences of premature thelarce (PT) and central idiopathic precocious puberty (ICPP) are increasing. In this context, we wanted to evaluate the mycoestrogen exposure as triggering factor for premature sexual development.. The girls living in Mediterranean region of Turkey were divided in to three groups: control (N.=25; mean age: 6.45 ± 1), PT (N.=28; mean age: 6.86 ± 0.95) and ICPP (N.=25; mean age: 6.97 ± 0.87). Urinary ZEN levels were measured by using ELISA technique and were normalized by urinary creatinine levels. Body Mass Index (BMI) was evaluated and sex hormone levels were also measured.. We found that urinary ZEN was detectable in ~81% of all samples and observed an increase of ~2-fold in PT and a significant increase ~2.8-fold in ICPP group vs. control. We did not find any significant correlations between urinary ZEN levels and BMI and sex hormones in any of the groups.. To our knowledge, this is the first study evaluating urinary ZEN levels in PT and ICPP Turkish patients. We can postulate that ZEN exposure can contribute to the etiology of PT and PP; however further studies on large number of subjects are needed to confirm the present data.

Topics: Body Mass Index; Breast; Case-Control Studies; Child; Child, Preschool; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Female; Humans; Puberty, Precocious; Turkey; Zearalenone

The incidence of idiopathic precocious puberty (IPP) might have an increasing trend. But the causes and risk factors of IPP are unknown. The objective of our study is to evaluate the effects of growth environments and two environmental endocrine disruptors (EDCs), zearalenone (ZEA), and 1,1-dichloro-2,2,bisethylene (p,p'-DDE), on patients with IPP.. Case-control study.. The study consisted of 78 IPP patients at diagnosis and 100 control children matched for age and sex. A questionnaire was designed to collect data on growth environments, and serum ZEA and p,p'-DDE were tested in all subjects. We analyzed data on growth environments, two EDCs, and biological interaction between growth environments and EDCs.. In growth environments, small for gestational age, maternal physical disease during pregnancy, early maternal menarche, early puberty of same-degree relatives, and father's absence in 4- to 6-year olds were risk factors for children with IPP (P<0.05). Serum ZEA concentration, ZEA, and p,p'-DDE-positive rates in the IPP group were significantly higher than those in the control group (P<0.05). There was a biological interaction between growth environments and ZEA (relative excess risk due to interaction =34.562, attributable proportion due to interaction =0.745, synergy index =4.193).. Results suggest possible effects of growth environments and two EDCs on the development of IPP. In addition, growth environments and ZEA have biological interaction that might increase the risk of developing IPP.

Topics: Case-Control Studies; Child; Child, Preschool; Dichlorodiphenyl Dichloroethylene; Endocrine Disruptors; Environmental Pollutants; Female; Humans; Male; Maternal Welfare; Menarche; Premature Birth; Puberty, Precocious; Risk Factors; Socioeconomic Factors; Surveys and Questionnaires; Zearalenone

To test the hypothesis that human puberty timing can be advanced by environmental estrogen exposure.. We analyzed serum mycoestrogen contamination via high-performance liquid chromatography (HPLC) in 32 girls affected by central precocious puberty (CPP) and in 31 healthy female control subjects. All 32 patients received triptorelin (TR) for more than 12 months after diagnosis.. Increased serum levels of zearalenone (ZEA; 933.7 +/- 200.3 pg/mL; 95% CI, 723.5-1143.9) and of its congener alpha-zearalenol (106.5 +/- 1.9 pg/mL; 95% CI, 104.5-108.5) contaminated 6 girls with CPP, who were from a bounded Tuscany area. At diagnosis, ZEA levels correlated with patient height (r = 0.906, P < .05) and weight (r = 0.887, P < .05), but not with bone age. In patients who were mycotoxin-positive, height (F = 4.192; P < .01), weight (F = 3.915; P < .01), and height velocity (F = 2.777, P < .05) were higher than patients who were mycotoxin-negative during 12-months TR treatment. Height correlated with weight both in patients who were mycotoxin-positive (r = 0.986, P < .001) and in patients who were mycotoxin-negative (r = 0.994, P < .001). Body mass index, bone age, and gonadal secretion was not different in patient groups before and during TR treatment (P > .05).. Mycoestrogenic zearalenone is suspected to be a triggering factor for CPP development in girls. Because of its chemical resemblance to some anabolic agents used in animal breeding, ZEA may also represent a growth promoter in exposed patients.

Topics: Case-Control Studies; Child; Cohort Studies; Environmental Exposure; Female; Humans; Italy; Puberty, Precocious; Risk Factors; Zearalenone; Zeranol

Topics: Child; Child, Preschool; Environmental Exposure; Female; Humans; Infant; Male; Maternal-Fetal Exchange; Pregnancy; Puberty, Precocious; Puerto Rico; Resorcinols; Zearalenone