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Abstract: Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are surface active fluorochemicals that, due to their exceptional stability to degradation, are persistent in the environment. Both PFOA and PFOS are eliminated slowly in humans, with geometric mean serum elimination half-lives estimated at 3.5 and 4.8 years, respectively. The biological activity of PFOA and PFOS in rodents is attributed primarily to transactivation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARA), which is an important regulator of lipid and carbohydrate metabolism. However, there are significant species-specific differences in the response to PFOA and PFOS exposure; non-rodent species, including humans, are refractory to several but not all of these effects. Many of the metabolic effects have been attributed to the activation of PPARA; however, recent studies using PPARα knockout mice demonstrate residual PPARA-independent effects, some of which may involve the activation of alternate nuclear receptors, including NR1I2 (PXR), NR1I3 (CAR), NR1H3 (LXRA), and NR1H4 (FXR). The objective of this investigation was to characterize the activation of multiple nuclear receptors and modulation of metabolic pathways associated with exposure to PFOA and PFOS, and to compare and contrast the effects between rat and human primary liver cells using quantitative reverse transcription PCR (RT-qPCR). Our results demonstrate that multiple nuclear receptors participate in the metabolic response to PFOA and PFOS exposure resulting in a substantial shift from carbohydrate metabolism to fatty acid oxidation and hepatic triglyceride accumulation in rat liver cells. This shift in intermediary metabolism was more pronounced for PFOA than PFOS. Furthermore, while there is some similarity in the activation of metabolic pathways between rat and humans, particularly in PPARA regulated responses; the changes in primary human cells were more subtle and possibly reflect an adaptive metabolic response rather than an overt metabolic regulation observed in rodents. [Copyright &y& Elsevier]

Abstract: The relationship between age and plasma concentration of perfluorooctanoate (PFOA) in young rats was investigated. The study was conducted in two phases in which male and female rats between 3 and 8 weeks of age were administered the ammonium salt of PFOA (APFO) by single oral gavage at either 10 or 30mg/kg. In Phase I, APFO was administered at a dose of 10mg/kg body weight to 27-, 34-, 38-, 48-, and 55-day-old male and female rats. Plasma was collected 24h after the dose. In Phase II, APFO doses of either 10 or 30mg/kg body weight were given to groups of 23-, 30-, and 32-day-old male and female rats, and plasma was collected at 2 and 24h after the dose (separate groups), and urine was collected for 24h. PFOA concentrations were measured by LC/MS/MS. In Phase I, plasma concentrations of PFOA were not dependent on age for rats 5 weeks of age and older; however, in 4-week-old rats, male plasma PFOA concentrations were 5–6 times lower than during weeks 5–8, and female plasma PFOA concentrations were 2.5–4 times higher than subsequent weeks. In Phase II, plasma samples collected 2h post-dosing indicated no significant difference in the PFOA uptake by age in females; although, in males, plasma PFOA concentrations were significantly less in 32-day-old rats, approximating one-half of the values observed at 23 and 30 days of age. Plasma samples collected 24h after dosing from 3- to 5-week-old rats indicated a slightly but significantly higher male plasma concentration at 30 and 32 days of age as compared to 23 days of age for the 30mg/kg dose group only. Significantly lower (approximately 10-fold) plasma PFOA concentrations occurred in 32-day-old females as compared with 23- and 30-day-old females at both 2 and 24h after the dose. Although statistically significant changes in urine PFOA concentrations did not occur between age and dose groups within sex, urine PFOA concentrations generally supported plasma elimination. At 23 days of age, the ratio of male to female plasma PFOA concentrations was approximately 2–3:1 compared to approximately 30:1 at 32 days of age. An unexplainable inconsistency in PFOA plasma concentrations for both sexes was noted when comparing Phase I values for 27-day-old rats to Phase II values for 23- and 30-day-old rats. The Phase I values for the 27-day-old rats of both sexes were five to six times lower than Phase II values for the 23- and 30-day-old rats. However, Phase I values for 34-day-old rats were comparable to Phase II values for 32-day-old rats. Despite this anomaly between the 23-, 27-, and 30-day-old rat values, there is strong evidence that age-dependent changes in the elimination of PFOA develop in female rats between 3 and 5 weeks of age, with a consistent marked difference occurring after 30 days of age. [Copyright &y& Elsevier]

Examines the distribution of organic fluorochemicals in drinking and surface water. Versatility of compounds in industrial and commercial applications; Assessment of fluorochemical distribution in localized geography; Administration of high performance liquid chromatography for solid-phase extraction.