Prochloraz: an imidazole fungicide with multiple mechanisms of action.
Prochloraz is an imidazole fungicide that is widely used in Europe, Australia, Asia and South America within gardening and agriculture. Screening studies have shown that prochloraz elicits multiple mechanisms of action in vitro, as it antagonizes the androgen and the oestrogen receptor, agonizes the Ah receptor and inhibits aromatase activity. In vivo prochloraz acts as an antiandrogen in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions in the prostate and increasing luteinizing hormone levels. In order to investigate the developmental effects of prochloraz, pregnant Wistar dams were dosed perinatally with 30 mg/kg prochloraz. Results showed that prochloraz significantly reduced plasma and testicular testosterone levels in gestational day 21 male foetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. In male pups a significant increase in nipple retention was found, and the weight of the bulbourethral glands was decreased. Behavioural studies showed that the activity level and sweet preference of adult males were significantly increased, indicating that exposure during gestation and lactation causes permanent effects in adulthood. Overall, these results indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis. Thus, a novel endocrine disruptor has been identified that is mechanistically interesting as it elicits dual mechanisms of action and acts as an antiandrogen both by blocking the androgen receptor and by inhibiting fetal steroidogenesis. That a fungicide with such effects is so widely used is a cause for concern, and its use should be reduced, thereby minimizing the risk of human exposure.
Vinggaard
Anne Marie
AM
Department of Toxicology and Risk Assessment, Danish Institute for Food and Veterinary Research, Søborg, Denmark. amv@dfvf.dk
Hass
Ulla
U
Dalgaard
Majken
M
Andersen
Helle Raun
HR
Bonefeld-Jørgensen
Eva
E
Christiansen
Sofie
S
Laier
Peter
P
Poulsen
Mette Erecius
ME
D000726:Androgen Antagonists / Q000633:toxicity*; D059002:Androgen Receptor Antagonists; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D052244:Endocrine Disruptors / Q000633:toxicity*; D005262:Feminization / Q000139:chemically induced; D005659:Fungicides, Industrial / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000633:toxicity*; D008297:Male; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics; D012098:Reproduction / Q000187:drug effects; D013737:Testis / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D052244:Endocrine Disruptors; D005659:Fungicides, Industrial; D007093:Imidazoles; D011944:Receptors, Androgen; C045362:prochloraz