Induction of apoptosis and CYP4A1 expression in Sprague-Dawley rats exposed to low doses of perfluorooctane sulfonate

Abstract

-In previous studies, perfluorooctane sulfonate (PFOS), an environmental organic compound, was reported to cause hepatotoxicity and hypolipidemia in rodents. However, the low dose toxicity of PFOS and the toxic mechanisms involved remain to be determined. To clarify the low dose toxicity and action mechanism in the target organ toxicity, Sprague-Dawley (SD) rats were orally administered with PFOS at the doses of 0, 1.25, 5, 10 mg/kg/day for 28 days. As a result, no death or abnormal symptoms were observed in all groups. The significant loss of mean body weight was observed in female rats treated with 10 mg/kg PFOS and the relative liver weight of 10 mg/kg PFOS-treated group was significantly greater compared to control. Histopathological examination revealed that fatty change was evident in the liver of male rats treated with PFOS (5 and 10 mg/kg) and hypertrophy and cellular swellings in females at the dose of 10 mg/kg, which showed different pattern of pathological lesions. In addition, we demonstrated the expression induction of hepatic caspase-3 and cytochrome P450 4A1 (CYP4A1) related with apoptosis and lipid metabolism, respectively. This study suggested that no-observed-adverseeffect level (NOAEL) of PFOS was 1.25 mg/kg in 28-day repeated toxicity study and, however, the toxic response showed gender differences. The possible toxic mechanism of PFOS was the induction of apoptosis and altering lipid metabolism which resulted in hepatotoxicity.

Mechanism of perfluorooctanesulfonate (PFOS)-induced apoptosis in the immunocyte

“…These results were consistent with similar observations in previous studies evaluating PFOS, perfluoroctanic acid (PFOA), and perfluorinated insecticide N-ethy1-perfluorooctane sulfonamide (N-EtPFOSA) (PedenAdams et al, 2008;Qazi et al, 2009;Kim et al, 2011;Zheng et al, 2011;Elcombe et al, 2012). For example, a recent study by Elcombe et al (2012) evaluated PFOSinduced liver-related effects in male Sprague Dawley rats; following a 7-day dietary exposure to K+PFOS at 20 or 100 ppm, there was a significantly increased liver weight.…”

“…For example, a recent study by Elcombe et al (2012) evaluated PFOSinduced liver-related effects in male Sprague Dawley rats; following a 7-day dietary exposure to K+PFOS at 20 or 100 ppm, there was a significantly increased liver weight. Kim et al (2011) also obtained similar results at comparable doses in Sprague-Dawley rats. Those studies also indicated that the increased liver weight might be partially associated with reductions in body weight, since body weight and food intake significantly decreased at higher doses of PFOS.…”

“…However, there is still a lack of understanding of the toxicokinetics and mode(s)/mechanism(s) of immunotoxic action of PFOS. During the last decade, at the cellular level, PFOS has been shown to induce different biochemical changes, several of which are typically associated with apoptosis (Liu et al, 2007;Chen et al, 2011;Kim et al, 2011). Therefore, PFOS toxicity is thought to be caused, in part, by the induction of apoptosis.…”

Enhanced cytotoxicity of pentachlorophenol by perfluorooctane sulfonate or perfluorooctanoic acid in HepG2 cells

“…Previous studies showed that the expression of CYPs could be up-regulated by PFOS or PFOA in tested animals (Andersen et al, 2008;Cheng and Klaassen, 2008;Liu et al, 2009a;Kim et al, 2011;Nordén et al, 2012). This induction of CYPs in mice liver by PFOA was demonstrated through activation of PPAR and other transcription factors (Cheng and Klaassen, 2008).…”

Initial study on the possible mechanisms involved in the effects of high doses of perfluorooctane sulfonate (PFOS) on prolactin secretion

“…However, other animals such as rats are less sensitive than monkey to PFOS exposure. In fact, the no-observedeadverse-effect level (NOAEL) of PFOS in SpragueeDawley rats orally treated with this xenobiotic, is 1.25 mg/ kg b.w./day in 28-day repeated toxicity studies (Kim et al, 2011). Moreover, the lowest-observed-adverse-effect-level (LOAEL) of PFOS is 1.5 mg/kg b.w./day in adult male rats treated with the chemical in the diet for 4 weeks (Seacat et al, 2003).…”