Effects of perfluorobutane sulfonate and perfluorooctane sulfonate on lipid homeostasis in mouse liver☆
Graphical abstract
Introduction
Perfluorobutane sulfonate (PFBS) is a short-chain per- and polyfluoroalkyl substances (PFASs). Since perfluorooctane sulfonate (PFOS) was phased out under the facilitation of the Stockholm Convention on Persistent Organic Pollutants (POPs) in 2009, PFBS was widely produced and used as an alternative for PFOS (Tang et al., 2020). However, the large-scale manufacture and application have turned PFBS into an emerging environmental contaminant of international interest (Annunziato et al., 2022). Generally, PFBS is detected in surface water (Sun et al., 2018), groundwater (Bertanza et al., 2020), and piped drinking water (Schwanz et al., 2016) at levels ranging from tens to hundreds of ng/L. However, PFBS can reach μg/L in waters influenced by discharge of industrial and municipal wastewater. For example, PFBS levels as high as 8.0 μg/L were recently detected in Tangxun Lake of Hubei Province, China (Chen et al., 2020), and 21.2 μg/L PFBS were also determined in groundwater under a fluorochemical industrial park (Bao et al., 2019). Apparently, humans are threatened by PFBS exposure by the intake of contaminated water. In fact, PFBS has already been detected in human populations with an increasing trend (Glynn et al., 2012). Thus, the impact of PFBS on human health is becoming an urgent issue to be explored.
Unlike extensively researched PFOS, a small number of studies have reported the adverse effects of PFBS on mammals. It was reported that an increase in liver weight and hepatocellular hypertrophy were found in rats exposed to 300 and 1000 mg/kg/day PFBS for 10 weeks (Lieder et al., 2009). The exposure of 300 mg/kg body weight PFBS for 24 h induced the elevated expression of several genes targeted for PPARα, PPARy, and PXR in mouse livers (Lau et al., 2020). Other evidence showed that the exposure of adult female mice to PFBS (200 mg/kg/day) for 14 days decreased the total triiodothyronine and thyroxine levels in serum (Cao et al., 2020). In vitro studies showed that 10–200 μM PFBS treatment for 6 days increased the adipogenesis of 3T3-L1 adipocytes (Qi et al., 2018). Exposure to 200 μM PFBS increased the lipogenesis gene expression in HepG2 human hepatoma (Qi et al., 2020). Although these studies revealed that high-dose PFBS exposure could cause hepatoxicity, endocrine disruption, changes in gene expressions, and lipid homeostasis, adverse effects of PFBS at environmentally relevant concentrations on mammals are still unclear.
Several currently reported toxicities of PFBS are related to hepatic lipid homeostasis, which has also been shown to play a vital role in the toxicity of PFOS (Wang et al., 2020a; Zeng et al., 2019b). Lipids are an important class of small molecules present in organisms, which are involved in various biological processes, including membrane architecture, energy homeostasis, inflammation, cellular signaling, and transduction of cellular events (Van Meulebroek et al., 2017). Dysregulation of lipid homeostasis has been reported to be associated with various diseases including cancer, diabetes, atherosclerosis, multiple sclerosis, neurodegenerative diseases and so on (Teo et al., 2015). Thus, the deep analysis of lipid alterations may yield valuable insights into human health risks induced by PFBS exposure. However, the global lipid changes induced by PFBS exposure in mammals were still less understood. The emerging lipidomics aims to obtain a more comprehensive characterization of lipid behavior in a biotic sample, which provides a powerful tool for solving the above question (Van Meulebroek et al., 2017).
Here, we hypothesize that adverse effects on mouse livers after low-dose PFBS exposure might not be apparent at the phenotypic level, and more sensitive endpoints such as the global lipid profiles could be an informative tool to investigate the toxicity. To better understand this toxicity induced by PFBS exposure, PFBS and PFOS were simultaneously exposed to mice for comparative study. The histological and biochemical analyses were used to characterize toxicity in liver at phenotypic levels. Then, the MS-based untargeted lipidomics was used to comprehensively analyze lipid homeostasis. This study provides reference data for health risk assessment caused by PFBS exposure at environmentally relevant concentrations.
Section snippets
Animals treatment
Specific pathogen-free adult C57BL/6 mice (body weight of 25–26 g) were provided by Shanghai SLAC Laboratory Animal Company (Shanghai, China). Only male mice were selected to avoid metabolic disorders caused by female physiological changes. Mice were housed in stainless-steel cages under standard conditions (temperature, 24 ± 0.5 °C; humidity, 50 ± 5%; light/dark cycle, 12 h/12 h). After acclimation for two weeks, the mice were randomly assigned into four groups. One group was the control group
Accumulation of PFBS and PFOS in liver
Actual average PFBS concentrations in drinking water were maintained at 8.24 ± 0.06 and 418.81 ± 24.83 μg/L in the 10 μg/L and 500 μg/L PFBS exposure groups, respectively. And the PFOS concentration in drinking water was 446.64 ± 14.73 μg/L in the 500 μg/L PFOS exposure group. Deviations between nominal and actual concentrations were <20%. Data on the daily water intake of each group are shown in Table S1. After exposure to 10 μg/L and 500 μg/L PFBS for 28 days, PFBS levels in the livers were
Conclusions
This study systematically compared the bioaccumulation, toxicity, and mechanisms of PFBS and PFOS at low-dose exposure. Our results suggested that PFOS is easier to accumulate in mouse livers than its substitute PFBS, which could be the most important contributor to the difference in toxicity of strength at the same exposure concentration. Combined using the phenotypic analysis and lipidomics, this study revealed that PFBS exposure caused toxicity on mouse liver by inhibiting antioxidant enzyme
Author contributions statement
Ling Chen: Conceptualization, Methodology, Software, Investigation, Data curation, Writing – original draft. Yafeng Liu: Methodology, Investigation, Data curation. Hongxin Mu: Methodology, Investigation, Data curation. Huan Li: Methodology, Writing – review & editing. Su Liu: Investigation, Writing – review & editing. Mengyuan Zhu: Writing – review & editing. Yuanqing Bu: Writing - review & editing. Bing Wu: Conceptualization, Writing – review & editing, Supervision, Funding acquisition.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This study was supported by the Natural Science Foundation of Jiangsu Province (BK20200011), and the Fundamental Research Funds for the Central Universities (021114380170), the Research Program of State Key Laboratory of Pollution Control and Resource Reuse (PCRR-ZZ-202104), and the Excellent Research Program of Nanjing University (ZYJH005).
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This paper has been recommended for acceptance by Jiayin Dai.