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The model of the prepubertal ovariectomized lamb was selected as a sensitive model to characterize the estrogenic effects of bisphenol A (BPA) on the hypothalamo-pituitary axis (HPA). In a first experiment, the disrupting effect of BPA and of 17-beta estradiol (E2), administered as a constant 54-h iv infusion, on luteinizing hormone (LH) pulsatility was quantified. The results showed that the inhibitory effect of BPA and E2 on LH secretion appeared to follow a dual mechanism: a rapid (about 1 h) suppressive effect for high exposure and an effect observed with a period of latency (about 48 h) probably of genomic origin and observed for lower E2 and BPA levels. For E2, the disrupting dose was 0.14 microg/(kg x d), corresponding to a plasma concentration of 2 pg/ml; for BPA, the lowest observed disrupting plasma concentration was 38 ng/ml, a value only 10-fold higher than the human plasma concentration routinely reported in biomonitoring surveys. In a second experiment, we showed that after 7 weeks of BPA treatment, there was no BPA accumulation and no evidence of an alteration in the HPA responsiveness to BPA. Finally, our results showed that directly considering plasma concentrations, the ratio of the BPA disrupting plasma concentration in lambs over the observed human plasma concentration is only 10, whereas if the dose is considered, it could be concluded that the BPA disrupting dose in lamb is conservatively 50-fold higher than the currently recommended Tolerable Daily Intake of 50 microg/(kg x d).

Estrogenicity of Bisphenol A: A Concentration-Effect Relationship on Luteinizing Hormone Secretion in a Sensitive Model of Prepubertal Lamb