Bisphenol-A imprinting of GH-dependent sexually dimorphic liver proteins and genes in female rats.

RAMIREZ, M.C.; BOURGUIGNON N; BONAVENTURA MM; LUX LANTOS V; LIBERTUN C; BEC¨²-VILLALOBOS, D

Houston

Congreso; ENDO 2012; 2012

The Endocrine Society

Bisphenol-A imprinting of GH-dependent sexually dimorphic liver proteins and genes in female rats. M. Cecilia Ramirez*; Nadia Bourguignon*; Mar¨ªa Marta Bonaventura, Victoria Lux-Lantos,  Carlos Libertun and Damasia Becu-Villalobos. *contributed equally IBYME-CONICET, Buenos Aires, Argentina   Bisphenol A (BPA) is a known endocrine disruptor that is prevalent in our environment. As an estrogenic chemical, it has potential adverse effects on animals and humans exposed during embryonic developmental stage. In a previous work we demonstrated organizational effects of neonatal steroids on the GHRH-GH axis, and sexually dimorphic GH-dependent liver enzymes in females. While most studies on the effect of neonatal exposure to BPA have concentrated on the disruption of the reproductive axis, we test the hypothesis that GH imprinting of sexually dimorphic liver enzymes is also perturbed by neonatal BPA in female rats. On postnatal days 1-10, female pups received a daily sc. injection of BPA in castor oil 50 ¦Ìg/50 ¦ÌL (BPA50); 500 ¦Ìg/50 ¦ÌL (BPA500) or vehicle. Males were injected with castor oil. Rats were studied at 4 months of age. Serum IGF-I levels were not modified by neonatal BPA treatment, but pituitary GH concentration was higher in males compared to females (P=0.039) and not different from BPA treated females (P=0.11 and 0.46 males vs. BPA500 and 50, respectively).  Liver IGF-I content, a downstream target of GH, was also higher in males compared to females (P=0.039), but not to BPA500 and 50 females (P=0.987 and P=0.259, respectively). We confirmed male specific liver expression of CYP2C11 mRNA levels, with a male/female ratio of 353. BPA treatment did not masculinize its expression in females. CYP2C12 mRNA was expressed predominantly in female rat livers (female/male ratio was 53). Neonatal BPA treatment induced a partial defeminization of this gene in female livers, as BPA50 and 500 females had significant different CYP2C12 mRNA levels from both males and females (P<0.05, BPA50 and 500 vs. females and males). Female predominant genes (HNF-6 and ADH1) were also defeminized; while a male predominant liver protein (MUP) was not masculinized in females by neonatal BPA. We demonstrate that even though body weight, and serum IGF-I levels were not modified by neonatal BPA, pituitary GH content, and liver IGF-I concentration were increased, indicating partial masculinization of the GH axis. These changes produced a long-lasting defeminization of GH-dependent female predominant liver enzymes and transcription factors. Therefore, our findings should alert to the potential consequences of the in utero exposure to the endocrine disruptor as it may compromise liver metabolic enzymes, and modify therapeutic efficacy of drugs or susceptibility to systemic toxicity.