Mechanisms of Extrahepatic Tumor Induction by Peroxisome Proliferators in Male CD Rats

Abstract

Wyeth-14,643 (WY) and ammonium perfluorooctanoate (C8) belong to a diverse class of compounds which have been shown to produce hepatic peroxisome proliferation in rodents. From previous work, WY, but not C8, has been shown to produce hepatocellular carcinoma in rats, while C8 has been shown to produce Leydig cell adenomas. In addition, based on a review of bioassay data a relationship appears to exist between peroxisome-proliferating compounds and Leydig cell adenoma and pancreatic acinar cell hyperplasia/adenocarcinoma formation. To further investigate the relationship between peroxisome-proliferating compounds and hepatic, Leydig cell, and pancreatic acinar cell tumorigenesis, a 2-year feeding study in male CD rats was initiated to test the hypothesis that peroxisome proliferating compounds induce a tumor triad (liver, Leydig cell, pancreatic acinar cell), and to examine the potential mechanism for the Leydig cell tumors. The study was conducted using 50 ppm WY and 300 ppm C8. The concentration of WY in the diet was decreased to 25 ppm on test day 301 due to increased mortality. In addition to the ad libitum control, a second control was pair-fed to the C8 group. Interim sacrifices were performed at 1- or 3-month intervals. Peroxisome proliferation measured by beta-oxidation activity and cell proliferation were measured in the liver and testis at all time points and in the pancreas beginning at the 9-month time point (cell proliferation only). Serum hormone concentrations (estradiol, testosterone, LH, FSH, and prolactin) were also measured at each time point. Increased relative liver weights and hepatic beta-oxidation activity were observed in both the WY- and C8-treated rats at all time points. In contrast, hepatic cell proliferation was significantly increased only in the WY-treated group. Neither WY nor C8 significantly altered the rate of Leydig cell beta-oxidation or Leydig cell proliferation when compared to the control groups. Moreover, the basal rate of beta-oxidation in Leydig cells was approximately 20 times less than the rate of hepatic beta-oxidation. There were no biologically meaningful differences in serum testosterone, FSH, prolactin, or LH concentrations in the WY- and C8-treated rats when compared to their respective controls. There were, however, significant increases in serum estradiol concentrations in the WY- and C8-treated rats at 1, 3, 6, 9, 15, 18, and 21 months. At 12 months, only the C8-treated rats had elevated serum estradiol concentrations when compared to the pair-fed control. Histopathological evaluation revealed compound-related increases in liver, Leydig cell, and pancreatic acinar cell tumors in both WY- and C8-treated rats. The data support the hypothesis that the peroxisome-proliferating compounds induce the previously described tumor triad. In addition, both C8 and WY produced a sustained increase in serum estradiol concentrations that correlated with the potency of the 2 compounds to induce Leydig cell tumors (i.e., WY caused a more consistent sustained increase in serum e...

In utero exposure to perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) did not increase body weight or intestinal tumorigenesis in multiple intestinal neoplasia (Min/+) mice

“…We examined whether PFOA and PFOS affected intestinal tumorigenesis in the sensitive Min/+ mouse model, since adenomas in liver, testicular Leydig cells and pancreatic acinar cells were reported in male Sprague-Dawley and CD (only highest dose) rats after 2 year exposure to 0, 30 or 300 mg PFOA/kg diet, equal to mean daily doses of approximately 0, 1.5 and 15 mg/kg (Biegel et al, 2001;Butenhoff et al, 2012b). Originally reported significant increase in mammary lesions was comparable with controls and non-significant upon pathological reevaluation (Butenhoff et al, 2012b).…”

“…Negative outcome in many in vitro and in vivo tests at gene and/or chromosome level indicated that PFOA is not genotoxic (EFSA, 2008). Thus, cancers detected after exposure to PFOA in liver, Leydig cells in testis and pancreas appears to be induced by non-genotoxic mechanisms, probably involving 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 30 peroxisome proliferation and activation of the peroxisome proliferator-activated receptor alpha (PPARα) and disturbance of the endocrine system (Biegel et al, 2001;EFSA, 2008;Klaunig et al, 2012).…”

“…Hepatocellular adenomas, testicular Leydig cell adenomas and pancreatic acinar cell adenomas have been reported in rats after exposure to PFOA in the diet for 2 years (Biegel et al, 2001;Butenhoff et al, 2012b). A 2-year study of PFOS given in the diet to rats reported hepatocellular and thyroid follicular cell adenomas and mammary fibroadenomas/adenomas (Butenhoff et al 2012a).…”

Effects of fluorotelomer alcohol 8:2 FTOH on steroidogenesis in H295R cells: Targeting the cAMP signalling cascade

“…Recently, some PFCs have been shown to have potential endocrinedisruptive activities in vertebrates. For example, perfluorooctanoic acid (PFOA) lowered concentrations of testosterone and cholesterol in serum in rats (Biegel et al, 2001;Martin et al, 2007), and modified the mRNA expression of genes associated with cholesterol biosynthesis and steroid metabolism in fetal mouse liver (Rosen et al, 2007). Exposure to perfluorodecanoic acid (PFDA) decreased circulating concentrations of testosterone and dihydrotestosterone in male rats (Bookstaff et al, 1990).…”

Excretion of PFOA and PFOS in Male Rats During a Subchronic Exposure

“…PFOA and PFOS caused reductions in body weight, decreases in weight gain rate, and interference in lipid metabolism in rats (Lau et al 2007;Luebker et al 2002). The liver is considered the primary target organ for both acute and chronic exposure of the above two fluorochemicals, and their hepatotoxicity in rodents has been extensively studied, which mainly includes increased liver weight, induction of hepatocellular hypertrophy and lipid vacuolation, increased incidence of hepatocellular adenoma, and hypocholesterolemia (Biegel et al 2001;Butenhoff et al 2002;Seacat et al 2003). Additionally, the potential neurotoxicity, genotoxicity, molecular toxicity, and reproductive and developmental toxicities of PFOA and PFOS were demonstrated in recent toxicological studies (Austin et al 2003;Guruge et al 2006;Kennedy et al 2004;Lau et al 2004;Ren et al 2008).…”