Responses of the Liver to Perfluorinated Fatty Acids with Different Carbon Chain Length in Male and Female Mice:In Relation to Induction of Hepatomegaly, Peroxisomal .BETA.-Oxidation and Microsomal 1-Acylglycerophosphocholine Acyltransferase

Abstract

Perfluorinated fatty acids (PFCAs), straight chain fatty acid analogues of which all aliphatic hydrogens are substituted with fluorine are primarily used as industrial materials, because of their surfactant properties, and their chemical and thermal stability. 1) Of PFCAs, perfluorooctanoic acid (PFOA) was the most widely used as a reactive intermediate in the industrial synthesis of fluoroacrylic esters, and its salts are used as processing aids in the production of fluoropolymer and fluoroelastmers and in other surfactant use. Since PFOA does not undergo biotransformation 2) and accumulates in the environment, [3][4][5] PFOA is found in the serum of not only occupationally exposed workers, 6) but also general populations. 7,8) In this respect, most efforts have been made to study biological and hazardous effects of PFOA in particular, 9) so that toxicological information pertaining to PFCAs is limited largely to PFOA.The previous studies showed that administration of PFOA markedly induced peroxisomal b-oxidation in the liver of male rats, whereas the induction was observed in female rats to an extremely less extent. 10,11) The subsequent study using rats as experimental animals showed that a sex-related difference in the induction by perfluorononanonic acid (PFNA) and perfluoroheptanoic acid (PFHA) was significant whereas the extent was not so striking as that by PFOA and that perfluorodecanoic acid (PFDA) markedly induced peroxisomal b-oxidation without sex-related difference.12) When compared the potency to induce peroxisomal b-oxidation by among PFHA, PFOA, PFNA and PFDA in the liver of male rats, the potency of the induction has been shown to be in the order of PFHAϽPFOAϽPFNAՅPFDA.12) On the basis of the findings from in vitro experiments employing rat hepatocytes, it is likely that the extent of the induction of peroxisomal b-oxidation by PFCAs depends on only concentration of PFCA molecules rather than the difference in their perfluoroalkyl chain length.12,13) Differed from the case of rats, the administration of PFOA to female mice has been shown to markedly induce peroxisomal b-oxidation in the liver to the extent comparable to that of male mice. 11,14) However, no explanation has been made for the mechanism responsible for this observation. Moreover, little information is available about biological effect of PFCAs other than PFOA in the liver of mice. These facts stimulate our interest in studying the response of the liver to PFCAs with different perfluoroalkyl chain lengths.The specific goals of the present study are to ascertain (i) whether there exists perfluoroalkyl chain length-related difference in response of the liver of mice to PFCAs employing inductions of hepatomegaly, peroxisomal b-oxidation and microsomal 1-acylglycerophosphocholine (1-acyl-GPC) acyltransferase as parameters; (ii) the reason why there is no difference in the response of hepatic peroxisomal b-oxidation to PFOA in male and female mice; and (iii) whether there is sex-related difference in the response of hepatic peroxisomal ...

Repeated dose and reproductive/developmental toxicity of perfluorooctadecanoic acid in rats

“…Such hepatic effects of PFAAs are considered to be exerted via the peroxisome proliferator-activated receptor alpha (PPARα), but other mechanisms have also been suggested . Kudo et al (2006) reported that intraperitoneal administration of PFAAs with six-to nine-carbon length increased the liver weight and hepatic peroxisomal β-oxidation activity in mice, and the potency was in the order of perfluorononanonic acid (PFNA; C9) PFOA (C8) > perfluoroheptanoic acid (PFHpA; C7) > perfluorohexanoic acid (PFHxA; C6). In the other study, PFOA (C8) and perfluorodecanoic acid (PFDeA; C10) considerably increased the liver weight, and hepatic peroxisomal palmitoyl-and lauroyl-CoA oxidase activities, but the responses to perfluorobutanoic acid (PFBA; C4) were lower and perfluoroacetic acid (C2) was inactive in male mice fed a diet containing PFAAs (Permadi et al, 1993).…”

“…Data on the toxic properties of other PFAAs are limited, but they have been studied in recent years (Chengelis et al, 2009;Das et al, 2008;Fang et al, 2008;Lieder et al, 2009aLieder et al, , 2009bMertens et al, 2010;Shi et al, 2007;Stump et al, 2008;van Otterdijk 2007avan Otterdijk , 2007bZhang et al, 2008). Available data indicate that PFAAs with a longer carbon chain are eliminated more slowly from the body Ohmori et al, 2003), and their toxic potency increases by lengthening the carbon chain (Kudo et al, 2000(Kudo et al, , 2006Permadi et al, 1992). Since the bioaccumulation potential of PFAAs also increases depending on their carbon number (Martin et al, 2003), long-chain PFAAs may cause serious environmental and/or human health concerns in the future.…”

Effects of Perfluorinated Fatty Acids with Different Carbon Chain Length on Fatty Acid Profiles of Hepatic Lipids in Mice

“…24) Our previous studies showed that, although a striking difference exists in the effects of PFCAs on the liver when they are estimated by the induction of AOX as a parameter, the induction of AOX by PFCAs depends on only the number of PFCA molecules, but not the difference in their perfluoroalkyl chain length with regard to the difference in the extent of the induction. [22][23][24] These findings suggest that PFCAs with a perfluoroalkyl chain of 6-10 carbons have almost the same potency as a ligand for peroxisome proliferator-activated receptor (PPAR)a in the liver of rats, 22,24) since AOX is considered to be induced by peroxisome proliferators through the activation of PPARa.25) Our previous study demonstrated that the treatment of male rats with PFOA evidently changed the acyl composition of hepatic phospholipids and that the changes were, in part, elucidated by the induction of stearoyl-CoA desaturase (SCD) by PFOA.26) To date, however, little informa- …”

“…19,20) PFOA was shown to be accumulated in the liver of rats and mice and to cause hepatomegaly, 21) induction of enzymes including peroxisomal acyl-CoA oxidase (AOX) in particular [22][23][24] and accumulation of TG. 24) Our previous studies showed that, although a striking difference exists in the effects of PFCAs on the liver when they are estimated by the induction of AOX as a parameter, the induction of AOX by PFCAs depends on only the number of PFCA molecules, but not the difference in their perfluoroalkyl chain length with regard to the difference in the extent of the induction.…”

C6-Perfluorinated Compounds: The New Greaseproofing Agents in Food Packaging

“…Supporting this finding, recent studies observed that the potency of PFHxA at the human peroxisome-proliferator activated receptor (PPAR)α, activation of which is associated with decreased blood lipid levels, is approximately half the potency of PFOA in the human hepatocellular carcinoma cell line HepG2 [42•] and approximately six-fold less potent than PFOA in both mouse and human PPARα in transiently transfected COS cells [43•]. Additionally, the decreased retention of PFHxA in the liver compared with the longer-chained compounds such as PFOA greatly decreases its potency to induce hepatic peroxisomal proliferation in vivo [44]. Concomitant with these findings, there was also no association of PFHxA serum levels (0.03 ng/ml median) with blood lipids in a Chinese population [45•].…”