Maternal Resveratrol Therapy Protects Male Rat Offspring against Programmed Hypertension Induced by TCDD and Dexamethasone Exposures: Is It Relevant to Aryl Hydrocarbon Receptor?

Abstract

Hypertension can originate from early-life adverse environmental in utero exposure to dexamethasone (DEX) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since DEX and TCDD are related to the aryl hydrocarbon receptor (AHR) signaling pathway, we examined whether resveratrol, an AHR modulator and antioxidant, could prevent programmed hypertension via regulating AHR signaling and oxidative stress. Groups of four-month-old male rat offspring were studied (n = 7–8 per group): control, DEX (0.1 mg/kg i.p. from a gestational age of 16 to 22 days), TCDD (200 ng/kg in four once-weekly oral doses), DEX + TCDD, and DEX + TCDD + R (resveratrol 0.05% in drinking water throughout pregnancy and lactation). Maternal TCDD exposure aggravated prenatal DEX-induced hypertension in adult male offspring, which maternal resveratrol therapy prevented. Maternal TCDD exposure aggravated DEX-induced oxidative damage in offspring kidneys, which was prevented by resveratrol therapy. Maternal resveratrol therapy decreased asymmetric and symmetric dimethylarginine (ADMA and SDMA) levels, thereby preventing combined DEX and TCDD exposure-induced programmed hypertension. Increases in renal Ahrr and Cyp1a1 expression induced by DEX + TCDD exposure were restored by resveratrol therapy. The beneficial effects of resveratrol on DEX + TCDD-induced hypertension relate to reduced renal mRNA expression of Ren, Ace, and Agtr1a expression. Thus, the beneficial effects of resveratrol on DEX + TCDD-induced hypertension include reduction of oxidative stress, restoration of nitric oxide (NO) bioavailability, blockade of the renin–angiotensin system (RAS), and antagonizing AHR signaling pathway.

Maternal Tryptophan Supplementation Protects Adult Rat Offspring against Hypertension Programmed by Maternal Chronic Kidney Disease: Implication of Tryptophan-Metabolizing Microbiome and Aryl Hydrocarbon Receptor

“…The present observations suggest that maternal tryptophan consumption may lead to a myriad of metabolites as endogenous AHR ligands and activate AHR signaling pathway. Although we previously reported that exogenous AHR ligand TCDD induced programmed hypertension together with activation of AHR and its target genes in adult rats [ 10 ], this notion is not supported by the present observations, which showed that tryptophan-derived endogenous AHR ligands activated AHR signaling pathway but had no effect on BP in adult offspring. This discrepancy might be due to high affinity exogenous ligands lead to AHR-associated toxicity, whereas low affinity endogenous levels of activation of AHR have been shown be beneficial [ 37 ].…”

“…We previously reported that prenatal exposure to AHR ligand, like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or bisphenol A, induced programmed hypertension in adult offspring [ 10 , 11 ]. The AHR pathway has been reported to interact with nitric oxide (NO) [ 10 , 11 , 12 ], the renin–angiotensin system (RAS) [ 13 ], and gut microbiota [ 14 ], which are crucial mechanisms underlying hypertension, to affect blood pressure (BP). However, whether the above-mentioned mechanisms interrelate to maternal CKD-induced offspring hypertension and kidney disease of developmental origins remain unclear.…”

Early Origins of Hypertension: Should Prevention Start Before Birth Using Natural Antioxidants?

“…First, cumulative evidence indicates that hypertension, programmed by various early-life insults, are associated with oxidative stress, as reviewed elsewhere [ 5 , 10 ]. These adverse perinatal environmental conditions include maternal caloric restriction [ 30 ], maternal diabetes [ 31 ], maternal nicotine exposure [ 32 ], ethanol consumption [ 33 ], preeclampsia [ 34 ], high-fat diet [ 35 ], high-fructose consumption [ 36 ], high-salt diet [ 37 ], methyl-donor diet [ 38 ], iron deficient diet [ 39 ], zinc deficient diet [ 40 ], magnesium deficient diet [ 41 ], prenatal glucocorticoid exposure [ 42 ], prenatal hypoxia [ 43 ], and exposure to environmental chemicals [ 44 , 45 ]. Second, there are reports that ADMA levels, a NOS inhibitor and ROS inducer, are associated with the elevation of BP in various developmental animal models [ 30 , 31 , 34 ].…”

“…Table 2 indicates reprogramming effects of maternal resveratrol therapy on offspring’s hypertension in rats ranging from 12 to 20 weeks of age [ 44 , 45 , 82 , 83 , 84 ]. However, its long-term effect on offspring outcome remains largely unknown.…”

“…In a maternal combined bisphenol A exposure and high-fat diet model, the protective effects of maternal resveratrol treatment against offspring hypertension are associated with increased NO bioavailability and decreased renal 8-OHdG expression [ 38 ]. Similarly, perinatal resveratrol use can restore the balance between ROS and NO to protect against hypertension in adult offspring born to dams exposed to combined TCDD and dexamethasone administration [ 45 ], high-fructose diet [ 92 ], and L-NAME plus postnatal high-fat diet [ 93 ]. Additionally, the high BP in adult SHRs can also be prevented by resveratrol supplementation in pregnancy and lactation [ 94 ].…”