Perfluorooctane Sulfonate Exposure Induces Cardiovascular Dysfunction in Female Rats: Role of Ovaries

Abstract

Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental pollutants frequently detected in drinking water worldwide. Reports linking PFAS exposure to cardiovascular disease have increased significantly in recent years. Furthermore, women appear to be more susceptible to the adverse effects of PFAS. However, the potential role of ovaries in the increased vulnerability of females to PFAS-related health effects remains unknown. In this study, we investigated the impact of perfluorooctane sulfonate (PFOS), a prominent PFAS, on the cardiovascular function in female rats with intact ovaries and ovariectomized (OVX) females. Bilateral OVX or sham surgeries were performed in 8-week-old female SD rats. Following recovery from surgeries, the rats were given drinking water containing 50 μg/mL of PFOS for 3 weeks. Control groups received PFOS-free water. PFOS exposure significantly reduced body weight but increased blood pressure similarly in both intact and OVX rats. Echocardiography analysis revealed that PFOS exposure decreased cardiac output, end-systolic volume, and end-diastolic volume in intact but not OVX rats. Vascular function studies demonstrated that PFOS equally reduced endothelium-dependent and -independent relaxation responses in intact and OVX rats. The endothelium-independent contractile responses were more pronounced in both intact and OVX rats. eNOS protein levels were similarly decreased in both intact and OVX rats. In conclusion, PFOS affects cardiac function through hormone-dependent mechanisms, while vascular function is impaired independent of ovarian status, indicating an intricate interplay between PFOS exposure, ovarian status, and cardiovascular function.

Keywords: Cardiovascular Dysfunction; Endothelial Dysfunction; Environmental Pollutants; Nitric Oxide Synthase; Ovariectomy; Perfluorooctane sulfonate (PFOS); Vascular Reactivity.

Figure 1.

Effect of PFOS on body weight and blood pressure response. In the 8-week-old female SD rats, bilateral ovariectomy (OVX) or sham surgeries were performed. After recovery, rats were divided into four groups, i.e., intact ovaries control, PFOS-exposed, OVX control, and PFOS-exposed. Rats received drinking water containing 50 μg/mL PFOS for three weeks, while control groups received PFOS-free water. (A) Percent body weight gain and (B) blood pressure changes each week. (C) Percent body weight gain and (D) Blood pressure at the end of 3 weeks. Data are means ± SEM of 6 rats per group. *p ≤ 0.05 compared to their respective vehicle control groups.

Figure 2.

Effect of PFOS on endothelium-denuded mesenteric artery contractility in intact and OVX females. Mesenteric artery rings were obtained from vehicle (veh) or PFOS exposed intact and OVX females. Vascular contractile responses were taken to (A) KCl (80 mM), and to cumulative additions of (B) phenylephrine (PE) and (C) thromboxane analogue (U46619). * p ≤ 0.05 compared to their respective vehicle control groups. Data are means ± SEM of 6 rats per group.

Figure 3.

Effect of PFOS on mesenteric artery relaxation responses in intact and OVX females. Mesenteric artery rings were obtained from vehicle (veh), or PFOS exposed intact and OVX females. (A) Endothelium-dependent relaxation. Mesenteric arterial rings were precontracted with PE and examined for relaxation to ACh. (B) Endothelium-independent relaxation. Mesenteric arterial rings were precontracted with PE and examined for relaxation to cumulative additions of SNP. * p ≤ 0.05 compared to their respective vehicle control groups. Data are means ± SEM of 6 rats per group.

Figure 4.

Effect of PFOS on mesenteric arterial eNOS mRNA and protein levels in intact and OVX females. (A) eNOS mRNA expression was measured using real-time reverse transcriptase PCR and normalized relative to GAPDH levels. (B) eNOS protein was measured by Western blotting. Representative blots are shown at the top and densitometric values are shown at the bottom. * p ≤ 50.05 compared to their respective vehicle control groups.

Figure 5.

Effect of PFOS on echocardiography parameters in intact and OVX females. Heart rate, stroke volume, ejection fraction, fractional shortening, cardiac output, end-systolic volume, and end-diastolic volume parameters were evaluated from at least 3 adjacent cardiac cycles and expressed as mean values. Data are means ± SEM of 6 rats per group. *p ≤ 0.05 compared to their respective vehicle control group.

Figure 6.

Effect of PFOS on left ventricular wall thickness in intact and OVX females. Left ventricular wall thickness were measured following hematoxylin and eosin staining and quantified using ImageJ software. Data are means ± SEM of 6 rats per group.