Endocrine: Testes - Adverse Effects
(Perfluorinated chemicals)

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Testes Adverse Effects
PFOS - PFOA Index Page

• Due to length, we are presenting this effect as a separate section for PFOS and PFOA. The study of the adverse effects of PFOS-PFOA chemicals is in its infancy and we anticipate that more effects will be presented and published over the next several years. Most of the animal studies (as of early 2004) have been performed by the major producers of PFOS-PFOA (3M and DuPont).

• Click here to return to the same section for fluorine & organofluorine pesticides.

This is not an exhaustive list. The review of data was performed in 2003 to early 2004. When time allows more information will be added,

Abstract: The objectives of the present work were to study the effects of certain peroxisome proliferators on xenobiotic-metabolizing enzyme activities in the testes of normal and hypothyroid rats, i.e. phenol sulfotransferases (pST), phenol UDP-glucuronosyl transferases (pUDPGT), glutathione transferases (GST), catalase, epoxide hydrolase (EH), glutathione peroxidase (GPX) and NAD(P)H quinone oxidoreductase (QR). Adult male rats (normal and hypothyroid) were treated for 10 days with clofibrate (0.5%), perfluorooctanoic acid (0.5%, PFOA), acetylsalisylic acid (1%, ASA) and di(2-ethylhexyl)phthalate (2%, DEHP) in their diet. The results show that treatment of normal rats with peroxisome proliferators dramatically affects the activities of xenobiotic-metabolizing enzymes (40-60% reduction). The highest effects are seen in catalase activity (50-60% with PFOA and ASA), pUDPGT (55% with PFOA), pST (55% with PFOA) and QR (50% with DEHP). These effects are not seen or are weaker after induction of hypothyroidism. Taken together, it is concluded that different classes of peroxisome proliferators have different effects on rat testicular xenobiotic-metabolizing enzymes.
Ref: 1997. Chem Biol Interact May 2;104(2-3):131-45. Effects of peroxisome proliferators and/or hypothyroidism on xenobiotic-metabolizing enzymes in rat testis; by Mehrotra K, Morgenstern R, Lundqvist G, Becedas L, Bengtsson Ahlberg M, Georgellis A.

Abstract: Elimination in urine and feces was compared between four perfluorinated fatty acids (PFCAs) with different carbon chain length. In male rats, perfluoroheptanoic acid (PFHA) was rapidly eliminated in urine with the proportion of 92% of the dose being eliminated within 120 h after an intraperitoneal injection. Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) was eliminated in urine with the proportions of 55, 2.0 and 0.2% of the dose, respectively. By contrast, four PFCAs were eliminated in feces with the proportion of less than 5% of the dose within 120 h after an injection. In female rats, the proportions of PFOA and PFNA eliminated in urine within 120 h were 80% and 51% of the dose, respectively, which were significantly higher compared with those in male rats. There was the tendency that PFCA with longer carbon chain length is less eliminated in urine in both male and female rats. Fecal elimination of PFCAs was not different between PFCAs in female rats and comparable to those in male rats. The rates of biliary excretion of PFCAs in male rats were slower than those in female rats. Sex-related difference in urinary elimination of PFOA was abolished when male rats had been castrated. On the contrary, treatment with testosterone suppressed the elimination of PFOA in urine in both castrated male rats and female rats. The effect of testosterone was in a time- and dose-dependent manner. These results suggest that PFCAs are distinguished by their carbon chain length by a renal excretion system, which is regulated by testosterone.
Ref: 2001. Chem Biol Interact Apr 16;134(2):203-16. Comparison of the elimination between perfluorinated fatty acids with different carbon chain length in rats; by Kudo N, Suzuki E, Katakura M, Ohmori K, Noshiro R, Kawashima Y.

Abstract: Ammonium perfluorooctanoate is a potent synthetic surfactant used in industrial applications. It rapidly dissociates in biologic media to perfluorooctanoate [CF3(CF2)6CO2-], which is the anion of perfluorooctanoic acid [PFOA, CF3(CF2)6COOH]. PFOA is a peroxisome proliferator known to increase the incidence of hepatic, pancreas and Leydig cell adenomas in rats. The pancreas acinar cell adenomas may be the consequence of a mild but sustained increase of cholecystokinin as a result of hepatic cholestasis. Although no significant clinical hepatic toxicity was observed, PFOA was reported to have modulated hepatic responses to obesity and alcohol consumption among production workers. To further assess these hypotheses, we examined medical surveillance data of male workers involved in ammonium perfluorooctanoate production in 1993 (n=111), 1995 (n=80) and 1997 (n=74). Serum PFOA was measured by high-performance liquid chromatography mass spectrometry methods. Plasma cholecystokinin was measured (only in 1997) by the use of direct radioimmunoassay. Serum biochemical tests included hepatic enzymes, cholesterol and lipoproteins. Serum PFOA levels, by year, were: 1993 (mean 5.0 ppm, SD 12.2, median 1.1 ppm, range 0.0-80.0 ppm); 1995 (mean 6.8 ppm, SD 16.0, median 1.2 ppm, range 0.0-114.1 ppm); and 1997 (mean 6.4 ppm, SD 14.3, median 1.3 ppm, range 0.1-81.3 ppm). Cholecystokinin values (mean 28.5 pg/ml, SD 17.1, median 22.7 pg/ml, range 8.8-86.7 pg/ml) approximated the assay's reference range (up to 80 pg/ml) for a 12 hour fast and were negatively, not positively, associated with employees' serum PFOA levels. Our findings continue to suggest there is no significant clinical hepatic toxicity associated with PFOA levels as measured in this workforce. Unlike a previously reported observation, PFOA did not appear to modulate hepatic responses to either obesity or alcohol consumption. Limitations of these findings include:
1) the cross-sectional design as only 17 subjects were common for the three surveillance years;
2) the voluntary participation that ranged between 50 and 70 percent; and
3) the few subjects with serum levels > or = 10 ppm.
Ref: 2000. Drug Chem Toxicol Nov;23(4):603-20. Plasma cholecystokinin and hepatic enzymes, cholesterol and lipoproteins in ammonium perfluorooctanoate production workers; by Olsen GW, Burris JM, Burlew MM, Mandel JH. Medical Department, 3M Company, St. Paul, MN 55144-1000, USA.

"So far, five different pathways have been identified that might explain how PFOA causes cancer and other types of toxicity. These include mitochondrial toxicity; cell membrane disruption that results in decreased cell communication; peroxisome proliferation; increased levels of estrogen and decreased levels of testosterone; and decreased thyroid hormone levels."
Ref: Environmental Working Group.
2003 report: PFCs: a family of chemicals that contaminate the planet. Part 4: PFC Health Concerns

Human Health... In a mortality study, which followed workers for 37 years, mortality risks for most of the cancer types and non-malignant causes were not elevated. However, a statistically significant risk of death from bladder cancer was reported. Three male employees in the cohort died of bladder cancer (0.12 expected), and all of them had been employed at the plant for more than 20 years. All of them had also worked in high exposure jobs for at least 5 years. In order to screen for morbidity outcomes, an “episode of care” analysis was undertaken for employees who had worked at the plant between 1993 and 1998. Many different types of cancer and other non-malignant conditions were examined. Increased risks were not reported for most of the conditions or did not reach statistical significance. However, an increased risk of episodes was reported for neoplasms of the male reproductive system, the overall category of cancers and benign growths, and neoplasms of the gastrointestinal tract. These risk ratios were highest in employees with the highest and longest exposures to fluorochemicals.
Ref: November 21, 2002 report:
Hazard Assessment of Perfluorooctane sulfonate (PFOS) and its salts. Organisation for Economic Co-operation and Development. ENV/JM/RD(2002)17/FINAL.

Abstract: Response of rat kidney to the challenges by perfluorooctanoic acid (PFOA) was studied using microsomal 1-acyglycerophosphocholine (1-acyl-GPC) acyltransferase as a parameter. Marked induction of the enzyme was brought about in kidney of male rats, whereas the induction in kidney of female rats was far less pronounced. The sex-related difference in the response of kidney to PFOA was much more marked than those seen with p-chlorophenoxyisobutyric acid (clofibric acid) or 2,2'-(decamethy-lenedithio)diethanol (tiadenol). Hormonal manipulations revealed that the sex-related difference in the response of kidney to PFOA was strongly dependent on the state of gonadal hormones of rats. Even after a prolonged administration of PFOA for up to 26 weeks, this sex-related difference was still evident. Induction of peroxisomal beta-oxidation was brought about concurrently with microsomal 1-acyl-GPC acyltransferase and a high correlation was confirmed between the inductions of these two parameters.
Ref: 1991. Biochem Pharmacol Oct 24;42(10):1921-6. Induction by perfluorooctanoic acid of microsomal 1-acylglycerophosphocholine acyltransferase in rat kidney. Sex-related difference; by Kawashima Y, Matsunaga T, Uy-Yu N, Kozuka H.

Title: COMBINED ORAL (GAVAGE) FERTILITY, DEVELOPMENTAL AND PERINATAL/POSTNATAL REPRODUCTION TOXICITY STUDY OF PFOS IN RATS – ARGUS RESEARCH LABORATORIES STUDY NUMBER: 6295.9, 1999. Year study performed: 1999 Species/Strain: Sprague Dawley rats. Sex (males/females/both): Both. Number of animals per dose: 35. Route of administration: Gavage. Dosing regimen (list all with units): Five groups of 35 rats per sex per dose group were administered PFOS by gavage for six weeks prior to and during mating. Treatment in male rats continued until one day before sacrifice (approximately 22 days total); female rats were treated throughout gestation, parturition, and lactation. Doses: 0, 0.1, 0.4, 1.6, and 3.2 mg/kg/day. Premating exposure period for males/females (P and F1, if appropriate): Six weeks for P; Nine and a half weeks for F1... Terminal body weights were also significantly reduced in the 1.6 and 3.2 mg/kg/day dose groups. Signs of reproductive toxicity in the F0 generation males were seen at the highest dose group of 3.2 mg/kg/day and included significant reductions in the absolute weights of the seminal vesicles (with fluid) and the prostate. A significant increase in the number of males with brown liver at 3.2 mg/kg/day dose group was also reported...
Ref: November 21, 2002 report:
Hazard Assessment of Perfluorooctane sulfonate (PFOS) and its salts. Organisation for Economic Co-operation and Development. ENV/JM/RD(2002)17/FINAL.

-- In a second prenatal developmental toxicity study, groups of 25 pregnant Sprague-Dawley rats were administered 0, 1, 5, and 10 mg/kg/day PFOS in corn oil by gavage on gestation days (GD) 6-15 (Wetzel, 1983). Sexually mature Sprague-Dawley rats, one per sex per cage, were paired until confirmation of mating or until two weeks had elapsed. Mating was confirmed by daily vaginal examinations for the presence and viability of sperm or the presence of a copulatory plug. The day of confirmation of mating was designated as day 0 of gestation. Doses were adjusted according to the most recently recorded body weight measurements... Statistically significant increases in the incidences in the number of litters containing fetuses with visceral anomalies, delayed ossification, and skeletal variations were observed in the high dose group of 10 mg/kg/day. These included external and visceral anomalies of the cleft palate, subcutaneous edema, and cryptorchism as well as delays in skeletal ossification of the skull, pectoral girdle, rib cage, vertebral column, pelvic girdle, and limbs. Skeletal variations in the ribs and sternebrae were also observed. Under the conditions of the study, a NOAEL of 1 mg/kg/day and a LOAEL of 5 mg/kg/day for developmental toxicity were indicated.
Ref: November 21, 2002 report: Hazard Assessment of Perfluorooctane sulfonate (PFOS) and its salts. Organisation for Economic Co-operation and Development. ENV/JM/RD(2002)17/FINAL.

• Note from FAN:
Cryptorchism: failure of one or both testes to move into the scrotum as the male fetus develops

3.5 Reproductive Toxicity Studies in Animals. York (2002) conducted an oral two-generation reproductive toxicity study of APFO, which is summarized below. Although this preliminary risk assessment focuses on developmental toxicity, the summary below of the two generation reproductive toxicity study includes all endpoints. Five groups of 30 Sprague-Dawley rats per sex per dose group were administered APFO by gavage at doses of 0,1,3,10, and 30 mg/kg/day six weeks prior to and during mating. Treatment of the F0 male rats continued until mating was confirmed,and treatment of the F0 female rats continued throughout gestation, parturition, and lactation....
Parental Males (F0)... At necropsy, statistically significant reductions in terminal body weights were seen at 3,10,and 30 mg/kg/day. Absolute weights of the left and right epididymides, left cauda epididymis, seminal vesicles (with and without fluid), prostate, left and right adrenals, spleen, and thymus were also significantly reduced at 30 mg/kg/day.
The absolute weight of the seminal vesicles without fluid was significantly reduced in the 10 mg/kg/day dose group... No treatment-related effects were seen at necropsy or upon microscopic examination of the reproductive organs, with the exception of increased thickness and prominence of the zona glomerulosa and vacuolation of the cells of the adrenal cortex in the 10 and 30 mg/kg/day dosegroups.
F1 Males ... Statistically significant (p<0.01) delays in sexual maturation (the average day of preputial separation) were observed in high-dose animals versus concurrent controls (52.2 days of age versus 48.5 days of age, respectively)... The ratios of the weights of the seminal vesicles, with and without fluid, liver and left and right kidneys to the terminal body weights were significantly increased in all treated groups. The ratios of the weights of the left testis, with and without the tunica albuginea and the right testis to the terminal body weight, were significantly increased at 3 mg/kg/day and higher. The ratios of the weights of the left epididymis, left cauda epididymis, right epididymis and brain to the terminal body weight significantly increased at 10 mg/kg/day and higher. The ratios of the weight of the seminal vesicles with fluid to the brain weight were increased at 1 mg/kg/day and higher, with statistical significance at 1 and 10 mg/kg/day... The ratios of the left and right testes weight-to-brain weight were increased in the 3 mg/kg/day and higher dosage groups. These ratios were significantly increased at 10 mg/kg/day (right testis only)and 30 mg/kg/day. Histopathologic examination of the reproductive organs was unremarkable; however, treatment-related microscopic changes were observed in the adrenal glands of high-dose animals (cytoplasmic hypertrophy and vacuolation of the cells of the adrenal cortex) and in the liver of animals treated with 3,10,and 30 mg/kg/day (hepatocellular hypertrophy). No other treatment- related effects were reported...
April 10, 2003: Preliminary Risk Assessment of the Developmental Toxicity associated with Exposure to Perfluorooctanoic Acid and its Salts. US EPA Office of Pollution Prevention and Toxics. 63 pages.

Abstract: Perfluorooctanoic acid (PFOA) is an octanoic acid derivative to which all aliphatic hydrocarbons are substituted by fluorine. PFOA and its salts are commercially used in various industrial processes. The chemical is persistent in the environment and does not undergo biotransformation. It was reported that PFOA is found not only in the serum of occupationally exposed workers but also general populations. Recent studies have suggested that the biological half-life of PFOA in humans is 4.37 years based on study of occupationally exposed workers. It is increasingly suspect that PFOA accumulates and affects human health, although the toxicokinetics of PFOA in humans remain unclear. In experimental animals, PFOA seems low in toxicity. PFOA is well-absorbed following oral and inhalation exposure, and to a lesser extent following dermal exposure. Once absorbed in the body, it distributes predominantly to the liver and plasma, and to a lesser extent the kidney and lungs. PFOA is excreted in both urine and feces. Biological half-life of PFOA is quite different between species and sexes and the difference is due mainly to the difference in renal clearance. In rats, renal clearance of PFOA is regulated by sex hormones, especially testosterone. PFOA is excreted into urine by active tubular secretion, and certain organic anion transporters are though to be responsible for the secretion. Fecal excretion is also important in the elimination of PFOA. There is evidence that PFOA undergoes enterohepatic circulation resulting in reduced amounts of fecal excretion. Elucidation of the mechanisms of transport in biological systems leads to elimination and detoxification of this chemical in the human body.
Ref: J Toxicol Sci. 2003 May;28(2):49-57. Toxicity and toxicokinetics of perfluorooctanoic acid in humans and animals; by Kudo N, Kawashima Y.

Note from FAN:
... The biological half-life (t1/2) of perfluorooctanoic acid (PFOA) in male rats is 70 times longer than that in female rats.
Ref: 2002 Chem Biol Interact Mar 20;139(3):301-16. Sex hormone-regulated renal transport of perfluorooctanoic acid; by Kudo N, Katakura M, Sato Y, Kawashima Y.

Abstract: There is a marked sex difference in the whole-body elimination of perfluorooctanoic acid (PFOA) in rats, with females excreting the perfluorinated acid much more rapidly (half life [t1/2] less than 1 day) than males (t1/2 = 15 days). Our objective was to determine if androgens or estrogens are involved in causing this sex difference in PFOA elimination. Castration of males greatly increased the elimination of [1-14C]PFOA (9.4 mumol/kg, i.p.) in urine, demonstrating that a factor produced by the testis was responsible for the slow elimination of PFOA in male rats. Castration plus 17 beta-estradiol had no further effect on PFOA elimination whereas castration plus testosterone replacement at the physiologic level reduced PFOA elimination to the same level as rats with intact testes. Thus, in male rats, testosterone exerts an inhibitory effect on renal excretion of PFOA. In female rats, neither ovariectomy nor ovariectomy plus testosterone affected the PFOA urinary elimination, demonstrating that the inhibitory effect of testosterone on PFOA renal excretion is a male-specific response. Probenecid decreased the high rate of PFOA renal excretion in castrated males but had no effect on male rats with intact testes. We conclude that testosterone is a key determinant of the sex difference in PFOA elimination in rats.
Ref: 1992. J Biochem Toxicol Spring;7(1):31-6. Renal excretion of perfluorooctanoic acid in male rats: inhibitory effect of testosterone; by Vanden Heuvel JP, Davis JW 2nd, Sommers R, Peterson RE.

Abstract: The peroxisome proliferator perfluordecanoic acid (PFDA) has been shown to exert an antiandrogenic effect in vivo by acting directly on the interstitial Leydig cells of the testis. The objective of this study was to examine the in vitro effects of PFDA and identify its site of action in steroidogenesis using as model systems the mouse tumor MA-10 and isolated rat Leydig cells. PFDA inhibited in a time- and dose-dependent manner the hCG-stimulated Leydig cell steroidogenesis. This effect was localized at the level of cholesterol transport into the mitochondria. PFDA did not affect either the total cell protein synthesis or the mitochondrial integrity. Moreover, it did not induce any DNA damage. Morphological studies indicated that PFDA induced lipid accumulation in the cells, probably due to the fact that cholesterol mobilized by hCG did not enter the mitochondria to be used for steroidogenesis. In search of the target of PFDA, we examined its effect on key regulatory mechanisms of steroidogenesis. PFDA did not affect the hCG-induced steroidogenic acute regulatory protein (StAR) levels. However, it was found to inhibit the mitochondrial peripheral-type benzodiazepine receptor (PBR) ligand binding capacity, 18-kDa protein, and messenger RNA (mRNA) levels. Further studies indicated that PFDA did not affect PBR transcription, but it rather accelerated PBR mRNA decay. Taken together, these data suggest that PFDA inhibits the Leydig cell steroidogenesis by affecting PBR mRNA stability, thus inhibiting PBR expression, cholesterol transport into the mitochondria, and the subsequent steroid formation. Moreover, this action of PFDA on PBR mRNA stability indicates a new mechanism of action of peroxisome proliferators distinct from the classic transcription-mediated regulation of target genes.
Ref: 2000. Endocrinology Sep;141(9):3137-48. The peroxisome proliferator perfluorodecanoic acid inhibits the peripheral-type benzodiazepine receptor (PBR) expression and hormone-stimulated mitochondrial cholesterol transport and steroid formation in Leydig cells; by Boujrad N, Vidic B, Gazouli M, Culty M, Papadopoulos V.

Abstract: Effects of perfluorodecanoic acid (PFDA, 20-80 mg/kg, ip) on the androgenic status of sexually mature male rats were investigated 7 days after treatment. PFDA decreased plasma androgen concentrations in a dose-dependent fashion with an ED50 of approximately 30 mg/kg. The highest dose of PFDA decreased plasma testosterone and 5 alpha-dihydrotestosterone concentrations to 12 and 18%, respectively, of ad libitum-fed control (ALC) values. Secondary to the decreased plasma androgen concentrations were dose-related decreases in the weights and epithelial heights of accessory sex organs. Results from pair-fed control (PFC) rats show that hypophagia in PFDA-treated rats was not a major cause of the low plasma androgen concentrations. When rats were castrated and implanted with testosterone-containing capsules, PFDA-treated and ALC rats had similar plasma testosterone concentrations and secondary sex organ weights. Therefore, the androgenic deficiency in intact PFDA-treated rats does not result from increased plasma clearance of androgens. Rather, PFDA must cause the androgenic deficiency by decreasing the secretion of testosterone from the testis. The decrease in testosterone secretion does not appear to result from a decrease in plasma luteinizing hormone (LH) concentrations, because plasma LH concentrations were not significantly altered by PFDA treatment. This finding suggests that PFDA treatment decreases testicular responsiveness to LH stimulation. The observation that PFDA treatment reduced the secretion of testosterone by testes stimulated in vitro with the LH analog human chorionic gonadotropin demonstrates that this is the case. In addition, since plasma LH concentrations did not increase in response to the low plasma androgen concentrations in PFDA-treated rats, we suggest that PFDA disrupts the normal feedback relationship which exists between plasma androgen and LH concentrations.
Ref: 1990. Toxicol Appl Pharmacol Jun 15;104(2):322-33. Androgenic deficiency in male rats treated with perfluorodecanoic acid; by Bookstaff RC, Moore RW, Ingall GB, Peterson RE.

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