WINDOWS OF DI-2-ETHYLHEXYL PHTHALATE (DEHP) SUSCEPTIBILITY: IMPLICATIONS FOR PLACENTA PHYSIOLOGY, EPIGENETICS, AND LONG-TERM METABOLIC OUTCOMES

Environmental exposure to endocrine disrupting chemicals (EDCs) during critical periods of development is associated with an increased risk of metabolic diseases, including hepatic steatosis and obesity. Di-2-ethylhexyl-phthalate (DEHP) is an EDC strongly associated with these adult metabolic abnormalities. The exact molecular mechanisms linking these adverse metabolic outcomes with prenatal DEHP exposure, however, remain unknown. In addition, DEHP developmental windows of susceptibility to DHEP are unknown yet have important public health implications. The overall objective of this dissertation was to use a mouse system to model human exposure and identify these windows and uncover novel mechanisms underlying DEHP exposure-induced metabolic outcomes in adult offspring. This dissertation presents a novel exposure model that describes the role of preconception exposure window, low DEHP doses, western diet (WD) challenge, epigenetics, and the placenta in understanding environmental exposures. In Chapter 2, we report that developmental DEHP exposure combined with a WD post-weaning does not cause overt DEHP-induced metabolic outcomes beyond what is normally observed with a WD. In contrast, Chapter 3 reports that preconception-gestation-lactation DEHP exposure window alters metabolic pathways in the adult female liver associated with oxidative stress and mitochondrial dysfunction resulting in hepatic steatosis. Fewer metabolic alterations in male offspring were observed and they were uniquely found in DEHP preconception exposure window. Finally, in Chapter 4, we describe sex-specific induced alterations in fetal weight that may be partially due to impaired placenta vasculature and/or changes in global and gene-specific DNA methylation. Collectively, this work demonstrates that metabolic changes in adult offspring exposed periconceptionally to DHEP depends on the timing of exposure, dose, and sex. Most importantly, this work reveals novel DEHP-induced modes of action and windows of susceptibility that can inform DEHP regulations and risk assessments.