Maternal Exposure to Bisphenol A Combined with High-Fat Diet-Induced Programmed Hypertension in Adult Male Rat Offspring: Effects of Resveratrol

Abstract

Maternal exposure to endocrine disrupting chemicals (EDCs) and a high-fat intake may induce the developmental programming of hypertension in adult offspring. Bisphenol A (BPA) is one of the most commonly environmental EDCs. As the nitric oxide (NO) and aryl hydrocarbon receptor (AHR) signaling pathways both contribute to the pathogenesis of hypertension, we evaluated whether resveratrol, an antioxidant and an AHR antagonist, can prevent hypertension programmed by a maternal BPA and HF diet. Sixteen-week-old male rat offspring were assigned to six groups (n = 8 per group): Control, HF (D12331, Research Diets), BPA (50 μg/kg/day), HF + BPA, BPA + R (resveratrol 50mg/L in drinking water throughout pregnancy and lactation), and HF + BPA + R. Maternal BPA exposure exacerbated hypertension programmed by HF consumption in adult male offspring, which was protected by maternal resveratrol therapy. The BPA and HF diet synergistically induced oxidative stress in offspring kidneys, which resveratrol treatment prevented. We observed that HF + BPA-induced programmed hypertension was associated with a decreased NO bioavailability, increased oxidative stress, and an activated AHR signaling pathway. The beneficial effects of resveratrol are relevant to restoring NO bioavailability, reducing oxidative stress, and antagonizing the AHR signaling pathway. Our results cast a new light on resveratrol as a reprogramming strategy to protect against hypertension programmed by combined BPA and HF exposure, but this strategy has yet to be translated into clinical applications.

Keywords: aryl hydrocarbon receptor; asymmetric dimethylarginine; bisphenol A; developmental origins of health and disease (DOHaD); high-fat diet; hypertension; nitric oxide; oxidative stress.

Figure 1

Effects of maternal high-fat diet (HF), bisphenol A (BPA), and resveratrol (R) on systolic blood pressure (SBP) measured in male offspring at 3, 4, 8, 12 and 16 weeks of age. n = 7–8/group; * p < 0.05 versus control; # p < 0.05 versus HF; † p < 0.05 versus BPA; ‡ p < 0.05 versus HF + BPA; $ p < 0.05 versus BPA + R.

Figure 2

Representative Western blots (A) show the endothelial NO synthase (eNOS) (~150 kDa), the neuronal NO synthase (nNOS) (~160 kDa), PRMT1 (~42 kDa), DDAH-1 (~34 kDa), and DDAH-2 (~30 kDa) bands in the offspring kidneys at 16 weeks of age. Relative abundance of renal cortical (B) eNOS, (C) nNOS, (D) PRMT1, (E) DDAH1, and (F) DDAH2. n = 7–8/group; * p < 0.05 versus control; # p < 0.05 versus HF; † p < 0.05 versus BPA; ‡ p < 0.05 versus HF + BPA.

Figure 3

Effects of maternal high-fat diet (HF), bisphenol A (BPA), and resveratrol (R) on (A) renal DDAH activity and (B) urinary NO₂⁻ levels in male offspring at 16 weeks of age. n = 7–8/group; * p < 0.05 versus control; # p < 0.05 versus HF; † p < 0.05 versus BPA; ‡ p < 0.05 versus HF + BPA.

Figure 4

(A) Light micrographs illustrating immunostaining for 8-hydroxydeoxyguanosine (8-OHdG) in the kidney in male offspring at 16 weeks of age. Bar = 50 μm. (B) Quantitative analysis of 8-OHdG-positive cells per microscopic field (×400). n = 5/group; * p <0.05 versus control; # p <0.05 versus HF; † p < 0.05 versus BPA; ‡ p < 0.05 versus HF + BPA.

Figure 5

Effects of maternal high-fat diet (HF), bisphenol A (BPA), and resveratrol (R) on (A) the aryl hydrocarbon receptor (AHR) protein level and (B) mRNA expression of AHR target genes, including Ahrr, Cyp1a1, and Arnt in male offspring kidneys at 16 weeks of age. n = 7–8/group; * p < 0.05 versus control; # p < 0.05 versus HF; † p < 0.05 versus BPA; ‡ p < 0.05 versus HF + BPA; $ p < 0.05 versus BPA + R.