Fetal Exposure to Low Levels of the Plasticizer DEHP Predisposes the Adult Male Adrenal Gland for Endocrine Disruption

In utero exposure to endocrine disrupting chemicals (EDCs) may affect adult health. Di-(2-ethylhexyl) phthalate (DEHP) is an EDC widely used in the production of polyvinyl chloride products and an ubiquitous environmental contaminant. We used a rat model system to show that fetal exposure to DEHP decreased levels of major steroid hormones in adulthood and that environmentally-relevant levels of DEHP affected both gene expression and epigenomic loci that were affected by exposure to high levels. In the adrenal gland, we reported that the peroxisome proliferator-activated receptor (PPAR) and cholesterol biosynthesis pathways were sensitive targets of DEHP. We hypothesized that low levels of DEHP exposure insult the endocrine system (a "first hit") and increase its susceptibility to later exposure ("second hit") and subsequent disease. Here, we demonstrate that a second hit in the adult offspring exposed in utero to low levels of DEHP affected serum aldosterone levels. To unveil the first hit influence of early DEHP exposure, we treated in utero DEHP-exposed adult offspring with stressors that targeted the PPAR or cholesterol biosynthesis pathways. Treatment with the PPAR-gamma antagonist T0070907 reduced serum aldosterone compared to animals not exposed to DEHP in utero. Analysis of gene expression in animals that were subjected to both early and late exposure revealed deregulation of genes for the potassium channel Kcnk5 and the retinoid-X receptors (RXR) Rxra and Rxrb, indicating that these entities are linked to endocrine disruption. We propose that early exposure to environmental doses of DEHP predisposes the animal for disease later in life.