Hepatic Mitochondrial Alteration in CD-1 Mice Associated with Prenatal Exposures to Low Doses of Perfluorooctanoic Acid (PFOA)

Abstract

Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3 and 1 mg/kg of PFOA from gestation days (GD) 1 through 17. On postnatal day (PND) 21, histopathologic changes in the livers of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND 91 in an apparent dose-dependent response. Transmission electron microscopy (TEM) of selected liver sections from PND 91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. Within hypertrophied hepatocytes, mitochondria were not only increased in number, but also exhibited altered morphologies suggestive of increased and/or uncontrolled fission and fusion reactions. These findings suggest that peroxisome proliferation is not a component of PFOA-induced hepatic toxicity in animals that are prenatally exposed to low doses of PFOA.

Environmental perfluoroalkyl acid exposures are associated with liver disease characterized by apoptosis and altered serum adipocytokines

“…The current data support the presence of apoptosis in the absence of additional inflammation with PFAA exposures. When considering data from other studies that used rodent, fish and human cell line models to demonstrate the actual presence of fatty infiltration of liver cells following PFAS exposure and mechanisms thereof, (Fai Tse et al, 2016;Peng et al, 2013;Quist et al, 2015;Wang et al, 2013), our data possibly support a role for PFAAs in the initiation stage of NAFLD, or steatosis.…”

Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase

“…Curiously, compared to WT hepatocytes, the TrxR1/Gsr-, Trx1/Gsr-, and Trx1/TrxR1/Gsr-null hepatocytes also showed a significantly increased abundance of coarse electron-dense bodies (DBs) surrounded by one or more distinct layers of membrane (yellow arrows in Figure 4A and quantified in Figure 4B ), as well as coarse electron-dense formations within some mitochondria (yellow asterisks in Figure 4A ). The identities of these structures and their relationship to each other are uncertain, although they might reflect mitochondrial fission and mitophagic activities ( Khraiwesh et al, 2013 ; Quist et al, 2015 ).…”

Prenatal Exposure to Perfluoroalkyl Substances Associated With Increased Susceptibility to Liver Injury in Children

“…In line with our findings, animal studies have shown that prenatal exposure to PFOA and PFOS causes hepatocellular injury and fatty liver in the offspring. ( 14,15 ) Previous human cross‐sectional studies have also shown positive associations of plasma or serum concentration of PFAS, including PFOS, PFOA, and PFNA, with liver enzymes levels in U.S adolescents and adults in NHANES, ( 19,43 ) adult populations from Sweden, ( 20 ) and U.S communities drinking PFAS‐contaminated water. ( 17,18 ) In a previous U.S. study involving children with physician‐diagnosed NAFLD, we showed that plasma PFOS and PFHxS levels were associated with increased risk for NASH.…”