Neonatal xenoestrogen exposure alters growth hormone-dependent liver proteins and genes in adult female rats.

The hypothalamic-growth hormone (GH)-liver axis represents a new concept in endocrine regulation of drug toxicity. Preponderant sex differences are found in liver gene expression, mostly dependent on the sexually dimorphic pattern of GH secretion which is set during the neonatal period by gonadal steroids. We tested if GH-dependent sexually dimorphic liver enzymes and proteins was perturbed by neonatal Bisphenol A (BPA) treatment in female rats. Female rats were sc injected with BPA (50 or 500 μg/50 μl) or castor oil vehicle from postnatal day 1 to 10. At five months serum prolactin, pituitary GH, and serum and liver insulin growth factor-I (IGF-I) were measured by RIA. Major urinary proteins (MUPs) were determined by electrophoresis. Liver Cyp2c11, Cyp2c12, Adh1, Hnf6, and Prlr mRNA levels were determined by real time PCR. Pituitary GH content and liver IGF-I concentration were increased by neonatal BPA treatment, indicating partial masculinization of the GH axis in treated females. GH-dependent female predominant liver enzyme genes (Cyp2c12 and Adh1) and a transcription factor (Hnf6) were downregulated or defeminized, while there were no changes in a male predominant gene (Cyp2c11) or protein (MUP). Our findings indicate that perinatal exposure to BPA may compromise the sexually dimorphic capacity of the liver to metabolize drugs and steroids.