Perinatal exposure to the fungicide prochloraz feminizes the male rat offspring.
Prochloraz is a commonly used fungicide that has shown multiple mechanisms of action in vitro. It antagonizes the androgen and the estrogen receptors, agonizes the Ah receptor, and inhibits aromatase activity. In vivo prochloraz acts antiandrogenically in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions, and increasing luteinizing hormone (LH) levels. The purpose of this study was to investigate reproductive toxic effects after exposure during gestation and lactation to prochloraz alone and a mixture of five pesticides (deltamethrin, methiocarb, prochloraz, simazine, and tribenuron-methyl). Prochloraz (30 mg/kg/day) or the mixture (20 mg/kg/day) was dosed to pregnant Wistar dams from gestational day (GD) 7 until postnatal day (PND) 16. Some dams were taken for cesarean section at GD 21, and others were allowed to give birth. Results showed that prochloraz and the mixture significantly reduced plasma and testicular testosterone levels in GD 21 male fetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. Chemical analysis of the rat breast milk showed that prochloraz was transferred to the milk. In males a significant increase of nipple retention was found, and the bulbourethral gland weight was decreased, whereas other reproductive organs were unaffected. In addition cytochrome P450 (CYP)1A activities in livers were induced by prochloraz, possibly as a result of Ah receptor activation. Behavioral studies showed that the activity level and sweet preference of adult males were significantly increased. Overall these results strongly indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis.
Vinggaard
Anne Marie
AM
Department of Toxicology and Risk Assessment, Danish Institute for Food and Veterinary Research, DK-2860 Søborg, Denmark. amv@dfvf.dk
Christiansen
Sofie
S
Laier
Peter
P
Poulsen
Mette Erecius
ME
Breinholt
Vibeke
V
Jarfelt
Kirsten
K
Jacobsen
Helene
H
Dalgaard
Majken
M
Nellemann
Christine
C
Hass
Ulla
U
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects; D002585:Cesarean Section; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005262:Feminization / Q000139:chemically induced*; D005518:Food Preferences / Q000187:drug effects; D005659:Fungicides, Industrial / Q000633:toxicity*; D005837:Genitalia, Male / Q000187:drug effects / Q000254:growth & development; D012739:Gonadal Steroid Hormones / Q000097:blood; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D007093:Imidazoles / Q000633:toxicity*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008892:Milk / Q000737:chemistry; D009043:Motor Activity / Q000187:drug effects; D009558:Nipples / Q000187:drug effects / Q000254:growth & development; D009929:Organ Size / Q000187:drug effects; D010988:Play and Playthings; D051381:Rats; D017208:Rats, Wistar; D012661:Semen / Q000166:cytology / Q000187:drug effects; D012741:Sexual Maturation / Q000187:drug effects; D013649:Taste / Q000187:drug effects
D005659:Fungicides, Industrial; D012739:Gonadal Steroid Hormones; D007093:Imidazoles; D003577:Cytochrome P-450 Enzyme System; C045362:prochloraz