Resveratrol Butyrate Ester Supplementation Blunts the Development of Offspring Hypertension in a Maternal Di-2-ethylhexyl Phthalate Exposure Rat Model

Abstract

Resveratrol (REV) is a plant polyphenol with a plethora of beneficial properties. We previously enhanced the efficacy of REV via esterification of REV with butyrate to form resveratrol butyrate ester (RBE). Compared with REV, RBE exhibits higher bioavailability and better antioxidant effects. Hypertension can originate in early life because of maternal toxic chemical exposure. This study aims to examine the effectiveness of RBE in the protection of offspring hypertension induced by maternal di-2-ethylhexylphthalate (DEHP) exposure and to explore the underlying mechanisms. DEHP (10 mg/kg/day) was used as oral gavage to pregnant rats during gestation and lactation. The control group received the vehicle. Three groups of DEHP-exposed dams received REV (6.67 mg/kg/day), or low-dose (3.33 mg/kg/day) or high-dose (6.67 mg/kg/day) RBE in drinking water during gestation and lactation. Perinatal DEHP exposure resulted in hypertension and bodyweight gain in adult male offspring, which was prevented by high-dose RBE. REV supplementation attenuated DEHP exposure-induced increases in blood pressure but not bodyweight. High-dose RBE decreased renal oxidative damage, increased plasma butyrate concentrations, and altered short chain fatty acid receptor (SCFA) expression. Low-dose RBE treatment reduced downstream mediators of the acryl hydrocarbon receptor (AHR) signaling pathway. Moreover, DEHP exposure, REV and RBE treatment differentially shaped the offspring’s gut microbiota. In particular, high-dose RBE increased the abundance of the genus Duncaniella. The beneficial effects of RBE treatment were related to reducing oxidative damage, increasing plasma butyrate concentrations, downregulating SCFA receptor expression, antagonizing AHR signaling, and altering the gut microbiota. This study provides the first evidence of RBE as a novel plant polyphenol bioproduct targeting the oxidative stress and gut microbiota to protect against maternal DEHP exposure-primed offspring hypertension.