The objective of the present study was to review the existing data on the mechanisms involved in the endocrine disrupting activity of mancozeb (MCZ) in its main targets, including thyroid and gonads, as well as other endocrine tissues that may be potentially affected by MCZ. MCZ exposure was shown to interfere with thyroid functioning through impairment of thyroid hormone synthesis due to inhibition of sodium-iodine symporter (NIS) and thyroid peroxidase (TPO) activity, as well as thyroglobulin expression. Direct thyrotoxic effect may also contribute to thyroid pathology upon MCZ exposure. Gonadal effects of MCZ involve inhibition of sex steroid synthesis due to inhibition of P450scc (CYP11A1), as well as 3β-HSD and 17β-HSD. In parallel with altered hormone synthesis, MCZ was shown to down-regulate androgen and estrogen receptor signaling. Taken together, these gonad-specific effects result in development of both male and female reproductive dysfunction. In parallel with clearly estimated targets for MCZ endocrine disturbing activity, namely thyroid and gonads, other endocrine tissues may be also involved. Specifically, the fungicide was shown to affect cortisol synthesis that may be mediated by modulation of CYP11B1 activity. Moreover, MCZ exposure was shown to interfere with PPARγ signaling, being a key regulator of adipogenesis. The existing data also propose that endocrine-disrupting effects of MCZ exposure may be mediated by modulation of hypothalamus-pituitary-target axis. It is proposed that MCZ neurotoxicity may at least partially affect central mechanisms of endocrine system functioning. However, further studies are required to unravel the mechanisms of MCZ endocrine disrupting activity and overall toxicity.
Ovo istraživanje je imalo za cilj da pruži pregled postojećih podataka o mehanizmima uključenim u delovanje mankozeba (MCZ) kao endokrinog ometača u ciljnim organima, u koja se ubrajaju štitna i polne žlezde, kao i u ostalim endokrinim tkivima na koja potencijalno može uticati MCZ. Pokazalo se da izloženost mankozebu remeti rad štitne žlezde tako što ometa sintezu tiroidnih hormona inhibirajući aktivnost natrijum-jodid simportera (NIS) i tiroidne perioksidaze (TPO), kao i ekspresiju tiroglobulina. Neposredno tirotoksično dejstvo takođe može doprineti razvoju tiroidne patologije pri izlaganju mankozebu. Delovanje mankozeba na polne žlezde uključuje inhibiciju sinteze polnih steroida usled inhibicije P450scc (CYP11A1), kao i 3β-HSD i 17β-HSD. Uporedo sa promenama u sintezi hormona, pokazalo se da MCZ snižava slanje signala androgenih i estrogenih receptora. Ovi efekti koji se odnose na polne žlezde zajedno dovode do pojave reproduktivne disfunkcije kako kod muškaraca, tako i kod žena. Pored jasno utvrđenih ciljnih organa na koja MCZ deluje kao endokrini ometač, mogu biti pogođena i druga endokrina tkiva. Konkretno, pokazalo se da ovaj fungicid utiče na sintezu kortizola, moguće posredstvom modulacije aktivnosti CYP11B1. Pored toga, utvrđeno je da izloženost mankozebu remeti signale PPARγ, koji su ključni regulator adipogeneze. Postojeći podaci takođe ukazuju na to da do posledica izloženosti mankozebu može doći posredstvom modulacije ose hipotalamus-hipofiza-ciljni organ. Navodi se da je moguće da neurotoksičnost mankozeba makar delimično utiče na centralne mehanizme rada endokrinog sistema. Ipak, neophodna su dalja istraživanja kako bi se razjasnili ne samo mehanizmi delovanja mankozeba kao endokrinog ometača već i njegova toksičnost uopšte.
Keywords: adipose tissue; adrenal; mancozeb; ovary; testes; thyroid.