Persistent alterations in immune cell populations and function from a single dose of perfluorononanoic acid (PFNA) in C57Bl/6 mice

Abstract

Perfluorononanoic acid (PFNA) is a perfluoroalkyl substance (PFAS) that is structurally related to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Whereas PFOA and PFOS are known immunotoxicants, PFNA is less well characterized. Our previous study showed that PFNA has immunomodulatory effects on leukocyte populations and immune function. The present studies sought to determine whether, and to what degree, the immune system recovered 28 days after PFNA exposure. None of the parameters measured had fully recovered. A few parameters had partially recovered, including decreased spleen size and the decreased ratio of the CD4+/CD8+ double-positive population in thymus. The majority of effects of PFNA remained unchanged 28 days after exposure, including decreased proportion of intact thymocytes (as determined by FSC vs SSC), alterations in the ratios of immune cell populations in spleen and the CD4+, CD8+ and double-negative populations in thymus. Notably, PFNA markedly increased the TNFα response to LPS in vivo, and no recovery was evident 28 days after exposure. The effect of PFNA on CD4+ T cells, CD8+ T cells and CD19+ cells was more pronounced in females. The current study demonstrates that a single high dose exposure to PFNA (e.g. as might occur accidentally in an occupational setting) has long-lasting effects on the immune system.

Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances and childhood atopic dermatitis: a prospective birth cohort study

“…Wielsøe et al exposed human hepatoma cell line (HepG2) with PFHxS, PFOA, PFOS and PFNA for 24 h and found a dose-dependent increase in DNA damage and increased ROS generation [ 34 ]. PFNA was also found to have immunomodulatory effects on leukocyte populations and immune function, including decreased spleen size and a decreased ratio of CD4+/CD8+ double-positive population in thymus of mice [ 35 ].…”

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days

“…PFNA, a 9-carbon PFAS, induced splenic atrophy and altered immune cell populations in C57BL/6 mice at 0.1 mmol PFNA/kg, but with a 31-38% decrease in body weight for both male and female mice, relative to control (Rockwell et al 2013(Rockwell et al , 2017. Published reports demonstrated the pharmacokinetics of PFOA and PFOS were dependent on the magnitude and frequency of dosing (Lou et al 2009) and on the species (Rodriguez et al 2009;Chang et al 2016).…”

“…Similarly, a single exposure to 0.1 mmol PFNA/kg (% 46 mg/kg) resulted in hepatomegaly in C57Bl/6 mice (Rockwell et al 2013). Heptatic histopathological and biological damage (immunological and non-immunological) have been observed following exposure to a variety of PFAS compounds in research animals, including peroxisome proliferation and activation of PPARa, peroxisomal b-oxidation, and liver tumors (DeWitt et al 2009;Foreman et al 2009;Qazi et al 2010;DeWitt et al 2012;OHAT 2016;Rockwell et al 2017). However, with its resident lymphocyte and Kupffer cell populations, the liver is also a sensitive immune organ, capable of generating acute-phase proteins and cytokines, and engaging in phagocytosis, host resistance, and antigen recognition, processing, and presentation (Sheth and Bankey 2001;Racanelli and Rehermann 2006).…”

“…Immune cell phenotype determination in the spleen is a reliable indicator of immunotoxicity in mice, with a concordance rate of 83% (Luster et al 1992;FDA 2002). At 5.0 mg PFDA/kg/week, spleen weight, total spleen cells, the total numbers of Ig þ , NK þ , and B-cells (Qazi et al 2009) in C57BL/6 mice exposed to PFOA or PFOS at subacute toxicity levels, of alterations in the proportions and numbers of T-cells, B-cells, immature T-cells, and phagocytes in spleen and thymus of C57BL/6 mice exposed to 0.1 mmol PFNA/kg (Rockwell et al 2013(Rockwell et al , 2017, and of splenic atrophy following exposure to PFOS (C ¼ 8), PFOA (C ¼ 8), PNFA (C ¼ 9), or PFDA (C ¼ 10) (Harris et al 1989;Qazi et al 2009;Rockwell et al 2013Rockwell et al , 2017. No significant changes were observed in splenic leukocyte sub-populations in PFDA-exposed HSD rats.…”

Perfluoroalkyl Substances Increase Susceptibility of Northern Leopard Frog Tadpoles to Trematode Infection

“…Although PFAS exposure is associated with a broad range of adverse effects (e.g., delayed development, endocrine disruption), their effects on the immune system are particularly concerning because of the potential to increase infectious disease risk (Ankley et al 2004; Hoover et al 2017). In mice, both the innate and adaptive immune systems are affected by exposure to PFAS (Yang et al 2000; Dewitt et al 2009; Qazi et al 2009; Rockwell et al 2017). For instance, independent exposures to high concentrations of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoate acid (PFOA) decreased the total number of circulating white blood cells and lymphocytes (Qazi et al 2009).…”