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PRENATAL EXPOSURE TO THE FUNGICIDE PROCHLORAZ ALTERS THE ONSET OF PARTURITION IN THE DAM AND SEXUAL DIFFERENTIATION IN MALE RAT OFFSPRING
Citation:
Noriega, N C., J S. Ostby, C R. Lambright, V S. Wilson, AND L E. Gray Jr. PRENATAL EXPOSURE TO THE FUNGICIDE PROCHLORAZ ALTERS THE ONSET OF PARTURITION IN THE DAM AND SEXUAL DIFFERENTIATION IN MALE RAT OFFSPRING. Presented at Society of Toxicology, Salt Lake City, UT, March 09 - 13, 2003.
Description:
Prenatal Exposure to the Fungicide Prochloraz alters the onset of Parturition in
the Dam and Sexual Differentiation in Male Rat Offspring.
N. Noriega1; E. Gray1; J. Ostby1; C. Lambright1; V. Wilson1
1. RTD, NHEERL, ORD, USEPA, RTP, NC, USA;
Prochloraz (PZ) is an imidazole fungicide reported to inhibit aromatase, as well as
estrogen and androgen receptor mediated activities in vitro. Our laboratory
demonstrated that PZ exposure from gestational day (GD) 14-18 decreased
testosterone while increasing progesterone in fetal rat testes. Thus, PZ is
interesting in that it may alter endocrine function through diverse mechanisms. We
examined mechanisms of PZ action in vitro and conducted a preliminary study to
investigate effects of gestational exposure on Sprague-Dawley dams and their
offspring. In vitro, PZ displayed anti-androgenic activity in MDA-kb2 cells
containing endogenous androgen receptor (AR) and stably transfected with a
MMTV-luc reporter. Treatment above 1M caused a dose-dependent inhibition of
DHT-induced luc expression, and was cytotoxic at 100M. Prochloraz inhibited
R1881 binding to the rat AR (IC50 approx 60M). Daily PZ administration
(gavage) to pregnant dams from GD 14-18 at doses of 62.5, 125, 250 and 500
mg/kg bodyweight/day inhibited maternal weight gain in the 500 mg/kg group.
Pup delivery was delayed by up to 30 hours in some high-dose treated dams and
some pups were stillborn at 125 mg/kg/d and higher. No pups in the 500 mg/kg
group survived to postnatal day 13. Prenatal PZ treatment reduced anogenital
distance in 2 day old pups by about 8% in the highest dosage group (NS), and
induced female-like areolas in male offspring at frequencies of 33%, 71% and
100% in 62.5, 125 and 250 mg/kg groups, respectively. Some males of the 250
mg/kg treatment group showed phallus abnormalities and delayed preputial
separation. A larger scale follow-up is underway. Our results are consistent with
published in vitro PZ effects, and indicate that PZ displays several forms of
endocrine activity, resulting in delayed parturition and induction of male
reproductive tract malformations. This is an abstract of a proposed presentation
and does not necessarily reflect EPA policy.