PARENT SESSION

2L - Immunotoxicity - genotoxicity - ED
Poster Hall
8:30 AM - Wednesday, 30 April 2003
Chair: Hansen, P.D.¹, ¹

(WEP/105) Effects of Polybrominated Diphenylether (PBDE) and PCB on Reproductive Organ and Brain Development and Gene Expression.

Lichtensteiger, Walter¹, Ceccatelli, Raffaella¹, Faass, Oliver¹, Fleischmann, Irčne¹, Ma, Risheng¹, Schlumpf, Margret¹, ¹ Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Zurich, Switzerland

ABSTRACT- PBDE, used as flame retardants, have been found to accumulate in the biosphere, with increasing levels in human milk. In studies on developmental effects of PBDE99 (2,2',4,4',5-pentaBDE) and the PCB mixture, Aroclor1254, we previously reported a delay of female puberty after administration of PBDE99 or Aroclor1254 to time-pregnant Long Evans rats from gestational day 10 to 18, whereas the onset of male puberty was unaffected. Prenatal treatment with PBDE99 (1 or 10 mg/kg/day s.c.) did not influence body weight of adult offspring, whereas Aroclor1254 treatment (10 or 30 mg/kg/day s.c.) resulted in reduced adult female body weight. Reproductive organ weights of adult offspring exhibited different effect patterns for PBDE99 and PCB. After prenatal PBDE99 treatment, weights of ventral and dorsal prostate were increased, that of epididymis decreased, and ovarian weight increased. Levels of estrogen target gene mRNAs were determined in reproductive organs of the same adult offspring by Real Time PCR, with cyclophilin as reference gene. Significant changes were observed for mRNAs encoding for androgen receptor and estrogen receptors alpha and beta in ventral and dorsal prostate, and for progesterone receptor mRNA in uterus of adult, prenatally PBDE99-treated offspring. Additional mRNA species in reproductive organs and mRNA levels in sexually dimorphic brain regions are under investigation for both, PBDE99 and Aroclor 1254. The study will also include an analysis of the responsiveness of target genes to an acute estrogen challenge in adult offspring. Our data indicate that prenatal treatment with PBDE99 can interfere with the development of reproductive organs and induce long term changes in the regulation of estrogen target genes. PBDE99 thus exhibits features of endocrine disruptors, but the effect patterns differ between PBDE and PCB. The basis for these effects remains to be elucidated. In vitro, PBDE99 exhibits very little, if any estrogenic activity (Meerts et al., 2001). Studies on MDA-MB-453-KB2 cells that express the human androgen receptor and are stably transfected with a luciferase reporter plasmid, did not reveal agonistic or antagonistic actions of PBDE99 at the androgen receptor either. (Supported by EU 5th Framework Program, PBDE-NTOX).

Key words: development, polybrominated diphenylether (PBDE), gene expression, PCB