Increases in a diversity of childhood and adult diseases (eg, autism, behavioral/learning abnormalities, obesity) have been attributed, in part, to programming effects resulting from developmental nutrient and chemical exposures. Bisphenol A (BPA) is a ubiquitous chemical widely used in plastics (e.g., water bottles, food can liners) and paper industries, and significant levels are consistently observed in pregnant women and fetal plasma and amniotic fluid. BPA acts an endocrine disrupter (EDC), and epidemiological studies confirm that EDC exposure during developmental periods may impact stem cell growth and development, and hence the ultimate make-up of organs, cell populations, and cell signaling/function. Consistent with this premise, studies have shown that EDCs alter neurogenesis of adult neural progenitor cells (NPC). Despite the array of EDC-induced cognitive and behavioral effects, there has been scant data of the effects of EDCs on fetal NPC proliferation and differentiation, functions which are critical for brain development. We have confirmed that offspring of both obese, overnourished dams and BPA-exposed control dams develop early onset obesity. Utilizing a model of NPC, we have demonstrated a dose dependent increase in NPC proliferation with increased expression of Hes1 (neuroproliferative factor), whereas in differentiation media, BPA increased Mash1 (proneurogenic factor), Tuj1 and GFAP (neuronal and astrocyte markers), and LSD1 (histone demethylase). We propose that maternal BPA exposure acts additively or synergistically with maternal obesity to alter hypothalamic development, resulting in an increase in appetite versus satiety neurons. Using both NPC neurosphere culture and in vivo/ex vivo rodent studies, this proposal provides a unique opportunity to determine mechanisms of programmed hyperphagia in BPA-exposed offspring which contribute to offspring obesity.

R21ES023112

2013-08-26

2016-08-31