Increased reproductive success in the white American mink (Neovison vison) with chronic dietary β-sitosterol supplement

Animal Reproduction Science 119 (2010) 287–292

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Increased reproductive success in the white American mink (Neovison vison) with chronic dietary ␤-sitosterol supplement Petteri Nieminen a,b,c,∗ , Ilpo Pölönen d , Anne-Mari Mustonen b a b c d

University of Oulu, Faculty of Medicine, Institute of Biomedicine, Department of Anatomy and Cell Biology, P.O. Box 5000, FI-90014 Oulu, Finland University of Joensuu, Faculty of Biosciences, P.O. Box 111, FI-80101 Joensuu, Finland University of Kuopio, Faculty of Medicine, Department of Anatomy, P.O. Box 1627, FI-70211 Kuopio, Finland HAMK University of Applied Sciences, Wahreninkatu 11, FI-30100 Forssa, Finland

a r t i c l e

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Article history: Received 4 August 2009 Received in revised form 14 January 2010 Accepted 18 January 2010 Available online 25 January 2010 Keywords: American mink Neovison vison Phytosterol Reproduction ␤-Sitosterol

a b s t r a c t ␤-Sitosterol is a weakly estrogenic phytosterol used in functional foods to lower elevated serum cholesterol concentrations. It has been reported to cause reproductive disturbances in fish and lower the sperm count of rodents but, in contrast, there were indications of enhanced reproduction in a preliminary study on the brown American mink (Neovison vison). In the present experiment the effects of chronic dietary ␤-sitosterol exposure on the reproduction of the American mink were evaluated with a large number of experimental animals. Male and female finnwhite mink (n = 200) – a previously uninvestigated color type with lower reproductive success compared to brown mink – were exposed to 50 mg ␤sitosterol kg−1 d−1 for 10 months and compared with 200 control animals. After 3 months in November, 15 males per group were sacrificed and their biochemical variables determined. The serum glucose and high-density lipoprotein cholesterol concentrations were lower in the ␤-sitosterol-exposed group, while other effects were minor. The females were mated with the top-rated males (4–5:1) in March and their reproductive performance was determined. The reproductive success increased in the ␤-sitosterol group with significantly fewer barren females and a higher number of successfully reproducing females than in the control group, which supports previous studies on brown mink and voles indicating that ␤-sitosterol could be used to enhance the reproductive performance of these mammals. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Plant sterols or phytosterols (PS) are plant-derived compounds analogous to animal cholesterol (Chol) with crucial functions in plant plasma membranes (Roche et al., 2008). PS, such as ␤-sitosterol, have Chol-lowering properties by competitively displacing Chol from micelles and decreasing the absorption of Chol and possibly some other lipid-soluble substances from the intestine (Ikeda et al.,

∗ Corresponding author at: University of Joensuu, Faculty of Biosciences, P.O. Box 111, FI-80101 Joensuu, Finland. Tel.: +358 13 2513576; fax: +358 13 2513590. E-mail address: petteri.nieminen@uef.fi (P. Nieminen). 0378-4320/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.anireprosci.2010.01.008

1988; Brufau et al., 2008). The consumption of PS to treat hypercholesterolemia (Drexel et al., 1981; Mattson et al., 1982; Jones et al., 2000) and as a potential prophylactic against cancers (Awad and Fink, 2000) has focused attention on the possible risks of chronic PS consumption. PS are also potential endocrine disruptors that can affect reproduction due to accumulation in gonads and similarities in structure to sex steroids (Moghadasian, 2000). The effects of PS on the reproduction of vertebrates have been inconsistent (Malini and Vanithakumari, 1991; MacLatchy and Van Der Kraak, 1995; Mellanen et al., 1996; Baker et al., 1999; Nieminen et al., 2004; Ryökkynen et al., 2005a). In a preliminary study, brown male American mink (Neovison vison) had higher plasma testosterone concentrations before the mating season and females had an

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increasing trend in litter size due to dietary ␤-sitosterol at 50 mg kg−1 d−1 (Ryökkynen et al., 2005b). Due to the small sample size (n = 10 per group), a comprehensive study was launched on two color types with a different reproductive outcome: the whelping result of white mink is lower than that of brown mink (data provided by Finnish Fur Breeders’ Association, 2008). The first of these two experiments yielded no differences in the reproductive performance between the exposed and control brown mink (Nieminen et al., 2008). The present data are from the second study that investigated if the previous results on the effects of chronic dietary PS supplement on reproduction (Ryökkynen et al., 2005b) could be observed in the finnwhite color type with a high number of experimental animals. The specific aims were to investigate the general health of adults and the growth of their kits and to determine if ␤-sitosterol could be used as an agent to increase the reproductive performance of some fur-producing carnivores. 2. Materials and methods The experimental animals chosen for the study were juvenile American mink (finnwhite color type; 200 males and 200 females) of the Mannikarin Turkis Oy fur farm (Kalajoki, Finland; 64.339787◦ N, 23.976478◦ E) born in May 2005. The animals were assigned randomly into two study groups as follows: (i) the control group receiving a standard fur animal feed (metabolizable energy 15.2–19.5 MJ kg dry matter−1 , protein 26.8–47.6%, fat 33.5–57.9%, carbohydrates 12.9–25.3%, Kalajoen Jäähdyttämö Ltd., Kalajoki) according to regular farming practices and (ii) the ␤sitosterol-exposed group receiving 50 mg ␤-sitosterol (S-5753, Sigma–Aldrich Co., St. Louis, MO) kg body mass (BM)−1 d−1 carefully mixed with the same feed. The animals were housed as described in Nieminen et al. (2008). Water or ice was available ad lib. The experiment was approved by the Animal Care and Use Committee of the University of Joensuu. On August 23rd 2005 and regularly thereafter (Nieminen et al., 2008) the BM of the animals were measured to calculate and adjust the ␤-sitosterol dose. The feeding experiment began on September 1st 2005 and was terminated in July 2006, when all kits produced by the experimental mink had attained the age of 7 weeks. On November 21st 2005, 15 male mink from both experimental groups were euthanized during the pelting time as outlined in Nieminen et al. (2008) in order to obtain blood for biochemical analyses. The selection of the males was based on the standard criteria to improve the breeding stock of the farm: the smallest males with the lowest fur quality were pelted and their BM and lengths determined, while the other males were kept as potential breeders. Blood samples were obtained, processed and analyzed for hemoglobin and clinical chemistry variables and the carcasses were stored and processed as described previously (Nieminen et al., 2008). Between March 8th and 26th 2006 each top-rated male was mated with 4–5 females avoiding inbreeding. Due to the selection, the numbers of individuals chosen for mating were as follows: control group, 20 males and 95 females;

and 50 mg kg−1 d−1 group, 21 males and 97 females. All females were mated twice with the same male to ensure the fertilization of as many females and ova as possible. The number of kits in each litter was counted on the 1st, 7th, and 21st d after delivery and the sex and BM of the offspring were determined on the 7th and 21st d. The whelping results of the females were divided into four categories as follows: 0 = failed to mate, 1 = mated but barren, 2 = gave birth to kits but lost all of them, 3 = had surviving kits 7 weeks after delivery. The average duration of gestation and the time interval between fertilization and implantation were estimated by determining the average date between the two matings and the date of delivery. The estimated duration of time from mating to delivery was the sum of d between mating and ovulation (approx. 2 d; Sundqvist et al., 1988) plus the preimplantation period in d, and the relatively constant postimplantation period (28–30 d; Concannon et al., 1980). Thus, the length of the preimplantation gestation (d) was calculated as follows: [(date of delivery − date of mating) − 2 − 29]. Comparisons between the experimental groups were performed with the Student’s t-test or, in the case of nonparametric variables, with the Mann–Whitney U-test. Differences in the time-series (BM data and number of kits) were analyzed with the repeated measures analysis of variance and the Duncan’s post hoc test. The 2 test and the binomial test were used to analyze the distribution of the females in the reproduction categories (0–3). Correlations were calculated with the Spearman correlation coefficient (rs ). All analyses were performed with the SPSS-program (v. 15.0, SPSS Inc., Chicago, IL). The p value <0.05 was considered statistically significant. The results are presented as the mean ± standard error of the mean (SE). 3. Results and discussion Most of the mink remained healthy during the study. A few adults and kits died but no obvious causes of death could be verified at necropsies and there were no differences in mortality between the experimental groups. Likewise there were no significant differences in the BM changes in the time-series. The absolute and relative liver masses were higher and the serum high-density lipoprotein Chol (HDL-Chol) and glucose concentrations lower in the male mink due to PS (Tables 1 and 2). There were no differences according to the treatment in the absolute and relative masses of the other organs (kidneys, spleen, heart ventricles, testes, thyroids) or adipose tisTable 1 The effects of the 3-month exposure to ␤-sitosterol on the body mass (BM), body length, body mass index and absolute and relative masses of the liver of the male mink (mean ± SE). ␤-Sitosterol dose

Control

BM (kg) Body length (cm) Body mass index (kg (m3 )−1 ) Liver mass (g) Liver mass (%BM)

2.8 47 29.0 61.0 2.2

*

± ± ± ± ±

50 mg kg−1 d−1 0.08 1.6 1.90 4.18* 0.15*

2.8 44 32.6 71.5 2.5

± ± ± ± ±

0.09 0.4 1.14 2.78* 0.04*

Statistically significant difference from the controls (p < 0.05).

P. Nieminen et al. / Animal Reproduction Science 119 (2010) 287–292 Table 2 The effects of the 3-month exposure to ␤-sitosterol on the blood hemoglobin and serum clinical chemistry of the male mink (mean ± SE). ␤-Sitosterol dose

Control

Hemoglobin (g l−1 ) Glucose (mmol l−1 ) Insulin (␮U ml−1 ) Triacylglycerols (mmol l−1 ) Total cholesterol (mmol l−1 ) LDL-cholesterol (mmol l−1 ) HDL-cholesterol (mmol l−1 ) Urea (mmol l−1 ) Creatinine (␮mol l−1 ) Urea/creatinine ratio Total protein (g l−1 ) Alanine aminotransferase (U l−1 ) Aspartate aminotransferase (U l−1 )

193.7 12.6 37.6 1.6 4.6 0.5 4.1 4.9 100.0 49.4 75.8 114.6 145.4

± ± ± ± ± ± ± ± ± ± ± ± ±

50 mg kg−1 d−1 5.28 1.48* 2.87 0.06 0.12 0.03 0.12* 0.54 4.86 6.41 1.56 19.93 28.57

192.3 8.2 39.9 1.5 4.8 0.5 3.8 5.2 92.3 61.6 79.7 120.0 121.8

± ± ± ± ± ± ± ± ± ± ± ± ±

3.39 0.85* 3.32 0.05 0.10 0.03 0.09* 0.43 5.62 7.57 2.42 14.09 26.76

LDL: low-density lipoprotein, and HDL: high-density lipoprotein. * Statistically significant difference from the controls (p < 0.05).

sues (omental, mesenteric, retroperitoneal). The reduction in the glucose levels would be judged beneficial from the viewpoint of clinical medicine, and a recent study has, in fact, suggested that particular PS could have anti-diabetic properties (Tanaka et al., 2006). Lactating mink dams are prone to nursing sickness, a disease with similarities, such as hyperglycemia, to type 2 diabetes (Rouvinen-Watt, 2003). Thus, based on these data, PS could have potential as a nutritional supplement in the mink. On the contrary, the decreased HDL-Chol level could be considered deleterious from the human perspective (Ambrose et al., 2006). However, it is not surprising that the well-documented effects of decreased Chol uptake and plasma total Chol concentrations due to ␤-sitosterol consumption (Drexel et al., 1981; Moghadasian, 2000) would be targeted at HDL-Chol as, opposed to humans, HDL is the principle carrier of circulating Chol in mustelids (Cryer and Sawyerr, 1978; Nieminen et al., 2002). Generally, the results of the variables of clinical chemistry indicate that PS for 3 months did not have any harmful effects on the overall health of white mink judged by, e.g., the liver and kidney function tests. The PS-exposed male mink had a higher number of kits per mated female than the control males (Table 3). The number of barren females was lower and the number of successfully reproduced females higher in the PS group (Table 4) and the number of kits was higher when Table 3 The effects of ␤-sitosterol exposure on the reproductive parameters of the male mink (mean ± SE). ␤-Sitosterol dose Number of males used for mating/group Number of mated females/male Total number of kits/male Total number of male kits/male Number of kits per mated female/male Number of male kits per mated female/male *

Control

50 mg kg−1 d−1

20

21

4.6 ± 0.29

4.5 ± 0.36

14.6 ± 1.75

19.2 ± 1.98

7.0 ± 0.99

9.8 ± 1.10

3.1 ± 0.32*

4.3 ± 0.27*

1.4 ± 0.17*

2.1 ± 0.16*

Statistically significant difference from the controls (p < 0.05).

289

Table 4 The effects of ␤-sitosterol exposure on the reproductive parameters of the female mink (mean ± SE). ␤-Sitosterol dose

Control

50 mg kg−1 d−1

Number of all females/group Number of unmated females/group Unmated females (%) Number of mated females/group Mated females (%) Number of barren females/group Barren females (%) Number of females with lost litters/group Females with lost litters (%) Number of successfully reproduced females/group Successfully reproduced females (%) Time of parturition from May 1st (=0) (d)

95

97

3

2

3.2 92

2.1 95

96.8 24*

97.9 11*

25.3 4

11.3 2

4.2

2.1

64*

82*

67.4

84.5

6.6 ± 0.51

6.6 ± 0.37

*

Statistically significant difference from the controls (p < 0.05).

calculated per all experimental females or per all mated females in an experimental group (Table 5). The sex ratio of the kits did not differ between the groups, but the BM of the male kits were slightly lower in the PS-exposed group on the 7th postnatal d (Table 6). While the results of the present study cannot give an exact answer to the mechanism behind the increased reproductive probability, some explanations can be suggested from the observations of this study and previous experiments. As both males and females were exposed, the effects could be targeted at either gender. It can be hypothesized that PS could exert their influence on mink reproduction as follows: (1) sperm count and/or quality, (2) ovulation and the number of ova released, (3) duration of diapause and blastocyst survival, (4) success of implantation and (5) the postimplantation gestation. Previous data on the effects of PS on male mink reproduction are scarce (Ryökkynen et al., 2005b) and, thus, the results of the present study have to be compared with data on other mammalian species, where the effects of ␤-sitosterol on the male reproductive system have been equivocal. In some cases, plasma and testicular testosterone levels increased with dietary PS (Nieminen et al., 2002, 2004; Oshima and Gu, 2003). On the other hand, ␤-sitosterol reduced the sperm count of rodents (Malini and Vanithakumari, 1991), while brown male mink showed increased plasma testosterone concentrations due to PS in January before the mating season with unchanged sperm count and quality in March (Ryökkynen et al., 2005b). ␤Sitosterol can accumulate in testes and be converted into sex steroids (Subbiah and Kuksis, 1973, 1975), which could hypothetically explain the increased plasma testosterone concentrations. Thus, the possibility of enhanced reproduction triggered by improved sperm quantity or quality is not excluded by the results of this study.

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Table 5 The effects of ␤-sitosterol exposure on the litter size of the female mink (mean ± SE). ␤-Sitosterol dose

Control

50 mg kg−1 d−1

Number of kits at 1 d of age/all females Number of kits at 7 d of age/all females Number of kits at 21 d of age/all females Number of male kits at 21 d of age/all females Number of kits at 1 d of age/mated females Number of kits at 7 d of age/mated females Number of kits at 21 d of age/mated females Number of male kits at 21 d of age/mated females Number of kits at 1 d of age/delivered females Number of kits at 7 d of age/delivered females Number of kits at 21 d of age/delivered females Number of male kits at 21 d of age/delivered females Number of kits at 1 d of age/successfully reproduced females Number of kits at 7 d of age/successfully reproduced females Number of kits at 21 d of age/successfully reproduced females Number of male kits at 21 d of age/successfully reproduced females

3.2 ± 0.31*

4.3 ± 0.26*

3.1 ± 0.28*

4.2 ± 0.26*

3.1 ± 0.28*

4.2 ± 0.26*

1.5 ± 0.17*

2.2 ± 0.16*

3.3 ± 0.32*

4.4 ± 0.26*

3.2 ± 0.28*

4.3 ± 0.26*

3.2 ± 0.28*

4.2 ± 0.26*

1.6 ± 0.17*

2.2 ± 0.16*

4.7 ± 0.29

5.0 ± 0.22

4.4 ± 0.26

4.9 ± 0.23

4.3 ± 0.27

4.8 ± 0.23

2.1 ± 0.19

2.5 ± 0.16

4.7 ± 0.29

5.0 ± 0.22

4.4 ± 0.26

4.9 ± 0.23

4.3 ± 0.27

4.8 ± 0.23

2.1 ± 0.19

2.5 ± 0.16

*

Statistically significant difference from the controls (p < 0.05).

However, as PS did not affect the sperm count or quality of male mink in the previous study, while the number of kits was slightly increased (Ryökkynen et al., 2005b), the effects of PS could be targeted at females. It was previously observed that the tissue distribution of ␤-sitosterol shows accumulation in ovaries (Moghadasian, 2000; Sanders et al., 2000) suggesting that they could be a target of PS action on reproduction. In the mammalian reproductive cycle the luteinizing hormone surge caused by the positive feedback between estradiol and the hypophysis triggers ovulation (Despopoulos and Silbernagl, 1986). In female mink, ovulation is induced by copulation (Joergensen, 1985; Sundqvist et al., 1988) and females can ovulate several times during a mating season giving birth to kits from two different ovuTable 6 The effects of ␤-sitosterol exposure on the body mass (BM) and sex ratio of the mink kits (mean ± SE). ␤-Sitosterol dose

Control

BM of female kits at 7 d of age (g) BM of male kits at 7 d of age (g) BM of female kits at 21 d of age (g) BM of male kits at 21 d of age (g) Sex ratio at 21 d of age (% male kits)

29.8 32.2 124.3 124.0 47

*

± ± ± ± ±

50 mg kg−1 d−1 0.67 0.60* 1.93 2.02 3.5

29.7 29.8 124.1 125.9 53

± ± ± ± ±

Statistically significant difference from the controls (p < 0.05).

0.60 0.60* 1.87 1.99 2.9

lations (Sundqvist et al., 1988). PS caused previously lower plasma estradiol and higher follicle-stimulating hormone levels or increased estradiol concentrations in carnivores (Nieminen et al., 2002, 2003). Also in rodents, ␤-sitosterolenriched drinking water increased estradiol concentrations (Oshima and Gu, 2003). Higher estradiol secretion around ovulation could hypothetically explain the increased litter size and the decreased percentage of barren females in the PS mink. The mink has delayed implantation for up to 49 d post coitum (Sundqvist et al., 1988). As a result, the gestation time is highly variable between 38 and 75 d (Lagerkvist et al., 1992; Tauson, 1992), while the length of the postimplantation period is relatively constant (Concannon et al., 1980). Litter size is positively correlated with late fertilization and a short gestation period (Lagerkvist, 1992). Also in the present study, the negative correlation (rs = −0.187, p < 0.05) between the number of kits and the estimated duration of preimplantation gestation supports this view. The implantation is regulated by photoperiod and prolactin is required to initiate the luteal progesterone secretion, which is crucial for implantation (Sundqvist et al., 1988). ␤-Sitosterol-rich plant supplements can increase progesterone concentrations of rodents (Oshima and Gu, 2003) and while the specific effects of ␤-sitosterol on prolactin secretion are not known, some other phytoestrogens stimulate prolactin secretion (Stahl et al., 1998; Romanowicz et al., 2004). It is thus possible that ␤-sitosterol treatment could advance or promote implantation and be responsible for the observed decrease in the number of barren females. As the estimated total duration of gestation (51 ± 0.5 d) and time interval between fertilization and implantation (22 ± 0.5 d) were, however, equal in both experimental groups, it is unlikely that the time point of mating and the duration of delayed implantation would explain the observed enhancing effects of PS on reproduction, while it is possible that more embryos could have implanted in the exposed females. During gestation, the plasma estradiol levels of female mink are relatively low (Pilbeam et al., 1979), while increases can be observed around implantation (Lagerkvist et al., 1992) and towards delivery (Tauson, 1992). High concentrations of exogenous estrogens can cause reabsorption of offspring in female mink (Pilbeam et al., 1979) but it cannot be stated if the same would occur with endogenous hormones. Yet, if the effects of PS on mink reproduction were targeted at this stage, deleterious effects could be more probable than the observed enhancement of reproductive performance, as estrogen-like effects would be a potential outcome of PS exposure (Moghadasian, 2000) with impaired survival of embryos. In contrast, the hypothetical increase of progesterone levels that could be induced by PS (Oshima and Gu, 2003) would be probably beneficial during late gestation. Some studies indicate reproductive alterations in vertebrates (Malini and Vanithakumari, 1991; MacLatchy and Van Der Kraak, 1995; Nakari and Erkomaa, 2003) due to possible endocrine disruption caused by PS (Juberg, 2000), but also a study reporting increased probability of reproduction in PS-exposed Microtus voles exists (Nieminen et al., 2004). In accordance with Nieminen et al. (2004), no

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reproductive risks seemed to be present due to PS consumption in the present experiment as observed also in brown mink (Nieminen et al., 2008). In this previously published dose-response study, PS did not increase the litter size or influence the number of barren females. The average litter size was 5.5–5.8 kits per mated female 21 d after delivery, higher than the values of the PS-treated female mink of the present experiment (4.2 kits), while the control finnwhite mink had significantly smaller litters (3.2 kits). The average litter size of all white color types was 3.6–4.6 kits per mated female in Finland on June 1st in 1993–2008, on the same level as in the PS-treated females of the present study but lower than in brown mink (4.4–5.0; data provided by the Finnish Fur Breeders’ Association, 2008). It seems that PS were able to decrease the proportion of barren females of finnwhite mink (25% in the control group, 11% in the exposed group) closer to the average of brown mink (6–12%; Nieminen et al., 2008). 4. Conclusions In conclusion, ␤-sitosterol caused no adverse health effects on adult mink or on the development of their offspring and it seems possible that ␤-sitosterol supplements could decrease the proportion of barren females in farming of the finnwhite color type, which usually has a lower whelping result than the wild-type mink. Acknowledgements We wish to thank Katja Ikonen, Maija Määttänen, Jenna Toivanen, Maija Lahti, Kari Manninen and the staff at the Mannikarin Turkis Oy fur farm for technical aid and the Finnish Fur Breeders’ Association for financial support. References Ambrose, M.S., DeNofrio, D., Kuvin, J.T., Pandian, N.G., Karas, R.H., Patel, A.R., 2006. Low levels of high-density lipoprotein cholesterol are associated with vascular remodeling in cardiac transplant recipients. Transplant. Proc. 38, 3016–3020. Awad, A.B., Fink, C.S., 2000. Phytosterols as anticancer dietary components: evidence and mechanism of action. J. Nutr. 130, 2127–2130. Baker, V.A., Hepburn, P.A., Kennedy, S.J., Jones, P.A., Lea, L.J., Sumpter, J.P., Ashby, J., 1999. Safety evaluation of phytosterol esters. Part 1. Assessment of oestrogenicity using a combination of in vivo and in vitro assays. Food Chem. Toxicol. 37, 13–22. Brufau, G., Canela, M.A., Rafecas, M., 2008. Phytosterols: physiologic and metabolic aspects related to cholesterol-lowering properties. Nutr. Res. 28, 217–225. Concannon, P., Pilbeam, T., Travis, H., 1980. Advanced implantation in mink (Mustela vison) treated with medroxyprogesterone acetate during early embryonic diapause. J. Reprod. Fertil. 58, 1–6. Cryer, A., Sawyerr, A.M., 1978. A comparison of the composition and apolipoprotein content of the lipoproteins isolated from human and ferret (Mustela putorius furo L.) serum. Comp. Biochem. Physiol. 61B, 151–159. Despopoulos, A., Silbernagl, S., 1986. Color Atlas of Physiology, 3rd ed. Georg Thieme Verlag, Stuttgart. Drexel, H., Breier, C., Lisch, H.-J., Sailer, S., 1981. Lowering plasma cholesterol with beta-sitosterol and diet. Lancet 317, 1157. Ikeda, I., Tanaka, K., Sugano, M., Vahouny, G.V., Gallo, L.L., 1988. Inhibition of cholesterol absorption in rats by plant sterols. J. Lipid Res. 29, 1573–1582. Joergensen, G., 1985. Mink Production. Scientifur, Hilleroed.

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