Impact of quercetin-3-0-rutinoside on biochemical and reproductive profile of rats prenatally exposed to high fat diet.

Abstract

The increasing prevalence of infertility and obesity over the last few decades have become a major public health challenge among individuals within the reproductive age. Consumption of a high-fat diet (HFD) is a harbinger for many metabolic alterations and diseases including infertility and subfertility. Studies have shown that the reproductive health of an individual can be programmed prior birth since exposure to certain environmental factors especially during intrauterine life play significant roles in transcriptional and epigenetic alterations in pivotal genes. However, understanding the molecular mechanisms linking oxidative stress caused by adverse environmental conditions to intrauterine alterations at critical periods of development might help in the clinical management of diet-induced infertility problems. This study therefore aimed at investigating the impact of maternal HFD consumption on sex-linked differences in the reproductive hormone profiles of diet unexposed offspring and examined the therapeutic potential of 150 mg/kg Quercetin-3-O-rutinoside (QR) against the HFD-induced biological changes. Adult female Sprague Dawley rats were randomly divided into two groups and fed either 45% HFD or normal diet (ND) for eight weeks before mating with male rats fed ND. Thereafter, the pregnant rats were divided into four dietary treatment groups: ND, HFD, ND+QR, and HFD+QR. At gestation day 19 (GD19), n=7 animals per group were sacrificed. Blood and tissue samples were collected and stored at -800C for biochemical and molecular analyses. The remaining dams were allowed to litter naturally and sacrificed. The pups were also sacrificed at postnatal day (PND) 21, 28 and 35. Blood and tissue samples were collected and stored for subsequent analyses. Using standard laboratory procedures, we measured oxidative changes in the liver, placenta and brain tissues by assessing levels of malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), catalase and nitric oxide (NO). Concentrations of hypothalamic gonadotropin releasing hormone (GnRH), serum luteinizing hormone (LH), testicular testosterone, and brain tumour necrosis factor (TNF-α) and glucagon-like peptide 1 (GLP-1) were assessed via enzyme linked immunosorbent assay (ELISA) technique. HFD-induced transcriptional changes in chemerin, chemokine-like receptor (CMKLR 1), TNF-α, GLP-1, interleukin-1 (IL-1β) and nuclear factor kappa B (NFκB) in the hypothalamic and testicular tissues were assessed by reverse transcriptase polymerase chain reaction (RT-PCR). After eight weeks of maternal HFD consumption, lipogram test indicated decreased plasma total cholesterol (TC) level, hypertriglyceridemia and increased low-density lipoprotein (LDL) levels. Our findings also showed that offspring of HFD-fed dams had delayed fur appearance and lower body weight compared to those from the control (ND) dams. These morphological changes were accompanied by elevated MDA levels in placenta, liver and brain tissues of HFD-fed dams and their diet-naïve offspring. Furthermore, there was evidence of hepatic nitrosative stress, time-dependent and sex-linked differences in hepatic SOD and brain GSH levels in the offspring. Also, hypothalamic GnRH and serum LH levels were significantly reduced at PND 28 and 35 in the offspring. Moreover, testicular testosterone was decreased at PND 35 in offspring of HFD-fed dams. Upregulation of chemerin, TNF-α, IL-1β mRNA transcripts in the hypothalamic-gonadal axis of male offspring indicates possible HFD-induced tissue inflammation and consequences for dysregulated steroidogenic and/or reproductive functions. Elevated brain GLP-1 may be linked to activated bioenergetic and homeostatic responses to HFD-induced oxidative stress. Overall, maternal HFD exposure led to induced oxidative stress, low-grade tissue inflammation and decreased levels of gonadotropins and androgens in their diet naïve offspring, whereas QR has little or no significant effects on these parameters.