title: Reproductive toxicity and thyroid effects in Sprague Dawley rats exposed to low doses of ethylenethiourea.
abstract: Ethylenethiourea (ETU) is the common metabolite of the widely used ethylenebisdithiocarbamate fungicides. It is identified as Endocrine Disruptor given its ability to interfere with thyroid hormone biosynthesis by inhibiting thyroid peroxidase activity. As far as we know, no studies have been performed to assess potential effects of ETU exposure at low dose levels, i.e. below the established LOAEL and NOAEL, during critical phases of development. Therefore, the aim of the present study was to verify the short- and long-term effects on thyroid function, reproduction and development of oral exposure to ETU levels comparable to and lower than LOAEL/NOAEL in rats. Sixty dams were treated daily by gavage during pregnancy and lactation with 0, 0.1, 0.3, 1.0 mg/kg bw per day of ETU. F1 generation was similarly treated from weaning to sexual maturity. Thyroid biomarkers were analyzed in dams and in offspring. Reproductive biomarkers were analyzed in F1 rats. For the first time this study has demonstrated reproductive toxicity and hypothyroidism at a lower than LOAEL dose exposure in pregnant dams and F1 generation. Our data suggest that even low doses of ETU can interfere with thyroid homeostasis and reproductive hormone profile if exposure starts in critical stages of development.
authors.affiliation: Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy. francesca.maranghi@iss.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Maranghi
authors.forename: Simona
authors.initials: S
authors.lastname: De Angelis
authors.forename: Roberta
authors.initials: R
authors.lastname: Tassinari
authors.forename: Flavia
authors.initials: F
authors.lastname: Chiarotti
authors.forename: Stefano
authors.initials: S
authors.lastname: Lorenzetti
authors.forename: Gabriele
authors.initials: G
authors.lastname: Moracci
authors.forename: Daniele
authors.initials: D
authors.lastname: Marcoccia
authors.forename: Enzo
authors.initials: E
authors.lastname: Gilardi
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Virgilio
authors.forename: Agostino
authors.initials: A
authors.lastname: Eusepi
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Antonella
authors.initials: A
authors.lastname: Olivieri
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D003409:Congenital Hypothyroidism / Q000139:chemically induced / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000633:toxicity*; D045166:Estradiol Congeners / Q000097:blood; D005031:Ethylenethiourea / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005659:Fungicides, Industrial / Q000378:metabolism / Q000633:toxicity; D007037:Hypothyroidism / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007247:Infertility, Female / Q000097:blood / Q000139:chemically induced*; D007248:Infertility, Male / Q000097:blood / Q000139:chemically induced*; D007774:Lactation; D008297:Male; D010573:Pesticide Residues / Q000633:toxicity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D045165:Testosterone Congeners / Q000097:blood; D013961:Thyroid Gland / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D052244:Endocrine Disruptors; D045166:Estradiol Congeners; D005659:Fungicides, Industrial; D010573:Pesticide Residues; D045165:Testosterone Congeners; D005031:Ethylenethiourea
keywords: 17β-estradiol; ANOVA; CTRL; DHT; E2; EDs; ETU; Endocrine Disruptors; GD; H–E; LOAEL; Low Observed Adverse Effect Level; Low doses; NOAEL; No Observed Adverse Effect Level; PAC; PND; Pregnancy; Reproductive toxicity; SD; Susceptible life stages; T; T3; T4; THs; TSH; Thyroid; analysis of variance; body weight; bw; controls; dihydrotestosteron; ethylenethiourea; gestational day; haematoxylin–eosin; post-natal day; pregnancy adverse outcomes; standard deviation; testosterone; thyroid hormones; thyroid stimulating hormone; thyroxine; triiodothyronine