Developmental Programming: Prenatal Bisphenol A Induces Non-Monotonic Changes in Epigenetic Modulators in Metabolic Tissues of Female Sheep

Abstract

Developmental exposure to endocrine disruptor bisphenol A (BPA) is associated \\with metabolic defects during adulthood in the female sheep. These are characterized by peripheral insulin resistance and increase in negative mediators of insulin sensitivity such as oxidative stress in metabolic tissues, lipotoxicity in liver and muscle and adipocyte hypertrophy in visceral (VAT) and subcutaneous (SAT) adipose tissue. Conceivably, developmental impact of BPA on regulators of insulin sensitivity involves changes in epigenetic machinery and mediated via changes in expression of enzymes that induce covalent modifications of DNA and histone. To determine the impact of prenatal BPA exposure on epigenetic enzymes [DNA methyltransferases (DNMT), histone deacetylases (HDAC), histone acetyl transferase EP300, histone methylases (SUV39H1, SMYD3 and EZH2) and histone demethylase KDM1A], metabolic tissues (liver, muscle, VAT and SAT) were collected from 21-month-old female offspring born to mothers treated with 0, 0.05, 0.5, or 5 mg/kg/day of BPA from days 30-90 of gestation. Data were analyzed by Cohen’s effect size analysis and large magnitude differences (Cohens d>0.8) discussed. In liver, prenatal BPA induced: 1) a decrease in DNMT1 and 3B at all doses and DNMT3A at the highest dose, 2) a decrease in histone deacetylase HDAC3 as opposed to increase in acetylase EP300 at the highest dose, 3) a decrease in SUV39H1 at the two higher doses, and 4) an increase in EZH2 only with 0.5 mg dose. The prenatal BPA-induced changes in muscle include: 1) increases in expression of DNMTs and EP300 at all doses, 2) an increase in SUV39H1 at 0.5 mg dose and EZH2 at 0.05 and 0.5 mg doses, and 3) decreases in SMYD3 at the lowest dose and KDM1A with 0.05 and 5 mg doses. Prenatal BPA treatment also induced depot-specific changes at the adipose tissue level. In the VAT prenatal BPA induced: 1) increases in expression of all DNMTs examined 2) increases in HDAC2 at all doses except HDAC3 only at 0.05 and 0.5mg dose and 3) increases in histone acetylase EP300 at all doses. In SAT BPA induced: 1) decrease in DNMT3A at 0.5mg and increase at 5 mg, 2) decreases in HDAC1 and HDAC2 at the lowest dose, 3) an increase in HDAC3 at the medium dose, and 4) a decrease in EP300 at the lowest dose. Contrasting changes in histone methylation modifying enzymes were also evident between VAT and SAT manifested as increases in SUV39H1 at the two higher doses and SMYD3 at all three doses in the VAT as opposed to decrease in SUV39H1 and SMYD3 at 0.05 and 0.5 mg doses and EZH2 and KDM1A at the lowest dose in the SAT. These findings indicating developmental exposure to BPA induces non-monotonic dose responses in epigenetic modifying enzymes are consistent with the premise that changes in epigenetic machinery underlie the metabolic disruptions induced by prenatal BPA treatment likely accounting for the tissue specific changes in insulin sensitivity. (support by R01-ES-016541)