Perfluorooctanesulfonic acid modulates barrier function and systemic T cell homeostasis during intestinal inflammation

The intestinal epithelium is continuously exposed to deleterious environmental factors which might cause aberrant immune responses leading to inflammatory disorders. However, what environmental factors might contribute to disease are yet poorly understood. Here, to overcome the lack of in vivo models suitable for screening of environmental factors we used zebrafish reporters of intestinal inflammation. Using zebrafish, we interrogated the immunomodulatory effects of polyfluoroalkyl substances (PFAS), which have been positively associated with ulcerative colitis incidence. Exposure with perfluorooctanesulfonic acid (PFOS) during TNBS-induced inflammation enhances the expression of proinflammatory cytokines as well as neutrophil recruitment to the intestine of zebrafish larvae, which was validated in TNBS-induced colitis mice models. Moreover, PFOS exposure in mice undergoing colitis resulted in neutrophil-dependent increased intestinal permeability and enhanced PFOS translocation into circulation. Finally, this was associated with a neutrophil dependent expansion of systemic CD4+ T cells. Thus, our results indicate that PFOS worsens inflammation-induced intestinal damage with disruption of T cell homeostasis beyond the gut and provides a novel in vivo toolbox to screen for pollutants affecting intestinal homeostasis.

Perfluoroalkyl and polyfluoroalkyl substance exposure and association with sex hormone concentrations: results from the NHANES 2015–2016

Background There is increasing global concern regarding the health impacts of perfluoroalkyl and polyfluoroalkyl substances (PFAS), which are emerging environmental endocrine disruptors. Results from previous epidemiological studies on the associations between PFAS exposure and sex hormone levels are inconsistent. Objective We examined the associations between serum PFAS compounds (PFDeA, PFHxS, PFNA, PFOA, PFOS) and sex hormones, including total testosterone (TT), free testosterone (FT), estradiol (E), and serum hormone binding globulin (SHBG). Results After adjusting for potential confounders, PFDeA, PFOS, and PFHxS exposures were significantly associated with increased serum testosterone concentrations in males. PFDeA, PFOA, and PFOS exposures were positively correlated with FT levels in 20–49-year-old women, while PFOS exposure was negatively associated with TT levels in 12–19-year-old girls. PFAS exposure was negatively associated with estradiol levels including: PFDeA in all females, PFHxS, PFNA, PFOS, and PFOA in 12–19-year-old girls, PFNA in women above 50 years, and PFOA in 12–19-year-old boys, while PFDeA and PFOS exposures were positively associated with estradiol levels in these boys. n-PFOS exposure was positively associated with SHBG levels in men older than 20 and in all females. Conclusions Using a large cohort of males and females aged from 12 to 80, we found that PFAS exposure appears to disrupt sex hormones in a sex-, age-, and compound-specific manner. Future work is warranted to clarify the causality and mechanisms involved.

Associations among perfluorooctanesulfonic/perfluorooctanoic acid levels, nuclear receptor gene polymorphisms, and lipid levels in pregnant women in the Hokkaido study

The effect of interactions between perfluorooctanesulfonic (PFOS)/perfluorooctanoic acid (PFOA) levels and nuclear receptor genotypes on fatty acid (FA) levels, including those of triglycerides, is not clear understood. Therefore, in the present study, we aimed to analyse the association of PFOS/PFOA levels and single-nucleotide polymorphisms (SNPs) in nuclear receptors with FA levels in pregnant women. We analysed 504 mothers in a birth cohort between 2002 and 2005 in Japan. Serum PFOS/PFOA and FA levels were measured using liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Maternal genotypes in PPARA (rs1800234; rs135561), PPARG (rs3856806), PPARGC1A (rs2970847; rs8192678), PPARD (rs1053049; rs2267668), CAR (rs2307424; rs2501873), LXRA (rs2279238) and LXRB (rs1405655; rs2303044; rs4802703) were analysed. When gene-environment interaction was considered, PFOS exposure (log10 scale) decreased palmitic, palmitoleic, and oleic acid levels (log10 scale), with the observed β in the range of − 0.452 to − 0.244; PPARGC1A (rs8192678) and PPARD (rs1053049; rs2267668) genotypes decreased triglyceride, palmitic, palmitoleic, and oleic acid levels, with the observed β in the range of − 0.266 to − 0.176. Interactions between PFOS exposure and SNPs were significant for palmitic acid (Pint = 0.004 to 0.017). In conclusion, the interactions between maternal PFOS levels and PPARGC1A or PPARD may modify maternal FA levels.

ROS-Triggered Autophagy Is Involved in PFOS-Induced Apoptosis of Human Embryo Liver L-02 Cells

The liver is the primary target organ for perfluorooctane sulphonate (PFOS), a recently discovered persistent organic pollutant. However, the mechanisms mediating hepatotoxicity remain unclear. Herein, we explored the relationship between reactive oxygen species (ROS) and autophagy and apoptosis induced by PFOS in L-02 cells, which are incubated with different concentrations of PFOS (0, 50, 100, 150, 200, or 250 μmol/L) for 24 or 48 hrs at 37°C. The results indicated that PFOS exposure decreased cell activities, enhanced ROS levels in a concentration-dependent manner, decreased mitochondrial membrane potential (MMP), and induced autophagy and apoptosis. Compared with the control, 200 μmol/L PFOS increased ROS levels; enhanced the expression of Bax, cleaved-caspase-3, and LC3-II; induced autophagy; decreased MMP; and lowered Bcl-2, p62, and Bcl-2/Bax ratio. The antioxidant N-acetyl cysteine (NAC) protected MMP against PFOS-induced changes and diminished apoptosis and autophagy. Compared with 200 μmol/L PFOS treatment, NAC pretreatment reversed the increase in ROS, Bax, and cleaved-caspase-3 protein caused by PFOS, lowered the apoptosis rate increased by PFOS, and increased the levels of MMP and Bcl-2/Bax ratio decreased by PFOS. The autophagy inhibitor 3-methyladenine and chloroquine decreased apoptosis and cleaved-caspase-3 protein level and increased the Bcl-2/Bax ratio. In summary, our results suggest that ROS-triggered autophagy is involved in PFOS-induced apoptosis in L-02 cells.

Perfluoroalkyl and Polyfluoroalkyl substance exposure and association with sex hormone concentrations: Results from the NHANES 2015 -2016

Background: There is increasing global concern regarding the health impacts of perfluoroalkyl and polyfluoroalkyl substances (PFAS), which are emerging environmental endocrine disruptors. Results from previous epidemiological studies on the associations between PFAS exposure and sex hormone levels are inconsistent.Objective: We examined the associations between serum PFAS compounds (PFDeA, PFHxS, PFNA, PFOA, PFOS) and sex hormones, including total testosterone (TT), free testosterone (FT), estrogen (E), and serum hormone binding globulin (SHBG).Results: After adjusting for potential confounders, PFDeA, PFOS, and PFHxS exposures were significantly associated with increased serum testosterone concentrations in males. PFDeA, PFOA, and PFOS exposures were positively correlated with FT levels in 20-49 years old women while PFOS exposure was negatively associated with TT levels in 12-19 years old girls. PFAS exposure was negatively associated with estradiol levels including: PFDeA in all females, PFHxS, PFNA, PFOS, and PFOA in 12-19 years old girls, PFNA in women above 50 years old, and PFOA in 12-19 years old boys while PFDeA and PFOS exposures were positively associated with estradiol levels in these boys. n-PFOS exposure was positively associated with SHBG levels in men older than 20 and in all females.Conclusions: Using a large cohort of males and females aged from 12-80, we found that PFAS exposure appears to disrupt sex hormones in a gender-, age-, and compound-specific manner. Future work is warranted to clarify the causality and mechanisms involved.