ethylenethiourea and Infertility--Female

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.

Topics: Administration, Oral; Animals; Biomarkers; Congenital Hypothyroidism; Dose-Response Relationship, Drug; Endocrine Disruptors; Estradiol Congeners; Ethylenethiourea; Female; Fungicides, Industrial; Hypothyroidism; Infertility, Female; Infertility, Male; Lactation; Male; Pesticide Residues; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Testosterone Congeners; Thyroid Gland

Genotoxic activation of hydrazine (HZ), two symmetrical dialkylhydrazines, namely, 1,2dimethylhydrazine and 1,2-diethylhydrazine (SDMH and SDEH), thiourea (TU) and ethylene thiourea (ETU) has been evaluated by means of the w/w + somatic assay of Drosophila. Both low bioactivation insecticide-susceptible (IS) and high biotransformation insecticide-resistant (IR) strains were used. The combined application of insecticide-susceptible and insecticide-resistant strains should, in principle, detect somatic cell recombinagens in the Drosophila melanogaster in vivo w/w + assay. The IS strain was more susceptible to toxicity induced by the test chemicals than the IR stocks. Its performance in the biotransformation of the chemicals tested was rather poor. TU was inactive in all strains. With the active compounds, spot frequencies increased approximately linearly with dose for each spot type. SDEH gave a strong positive result in all three female genotypes exposed. HZ, ETU and SDMH were overall weakly positive in the IR strain Haag-79 (HG-R). Interestingly, ETU was clearly positive in the IR Hikone-R (HK-R) strain. A comparison of the recombinagenic potencies between the active and the weakly positive compounds, and among strains, showed pronounced genotype-dependent differences between the low and the high bioactivation strains. The ability of Drosophila to express several procarcinogens in relation to insecticide-resistance after activation catalyzed by CYP450 enzymes is discussed.

Topics: 1,2-Dimethylhydrazine; Animals; Dose-Response Relationship, Drug; Drosophila melanogaster; Ethylenethiourea; Eye Color; Female; Heterozygote; Hydrazines; Infertility, Female; Insecticide Resistance; Mutagenicity Tests; Recombination, Genetic; Thiourea