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The Carcinogenic And Estrogenic Effects Of PUFA

Discussion in 'Scientific Studies' started by haidut, Jan 23, 2018.

  1. haidut

    haidut Member

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    Yet another study, which I decided to post because it is one of the few studies that directly points the finger at PUFA (and linoleic acid in particular - the nemesis of user @Travis) as the cause of breast, colon, prostate and other cancers. It also provides evidence for greatly increase serum estrogen levels in organisms fed even normal-fat diet with a significant PUFA content. Combined with the study I posted on PUFA promoting cortisol synthesis, I think the picture on how "essential" PUFA is becomes rather complete.

    Dietary polyunsaturated fatty acids and cancers of the breast and colorectum: emerging evidence for their role as risk modifiers | Carcinogenesis | Oxford Academic
    "...Tannenbaum and Silverstone demonstrated that a high fat diet stimulates mammary tumour development in mice when compared with a low fat diet ( 13). In further studies, the effect was shown to be independent of caloric intake and the response to fat was non-linear, reaching a plateau. Subsequent studies have shown that many steps in the tumourigenic process, including initiation, promotion, latency, growth and metastasis, can be influenced by dietary fat. Within the last few decades, studies in rodents have shown that large amounts of dietary fat increase the incidence of cancers of the breast, colon and prostate. Moreover, diets that contain high levels of the ω-6 fatty acid linoleic acid enhance tumourigenesis. Thus, the essential linoleic acid appears to be pivotal in tumour induction and metastasis, whereas high levels of fats such as olive oil, which are rich in oleic acid (monounsaturated, ω-9) and fish oil (polyunsaturated, ω-3) do not promote tumour development in animal models and even have protective effects."

    "...Fay et al. conducted a meta-analysis of data on mammary tumour incidence extracted from 97 reports of experiments involving over 12 800 mice and rats to study the effects of saturated and monounsaturated fats and ω-6 PUFAs and ω-3 PUFAs ( 14 ). The results indicated that ω-6 PUFAs have a strong and saturated fats a weaker tumour-enhancing effect, whereas the ω-3 PUFAs have a small, statistically non-significant protective effect; monounsaturated fats had no significant effect. ω-6 PUFAs had a stronger tumour-enhancing effect when they represented <4% of total calories, but the effect was still stronger than that of saturated fat when they represented >4% of the caloric intake."

    "...Hilakivi-Clarke et al. tested the hypothesis that consumption of a high fat diet during gestation increases the incidence of carcinogen-induced mammary tumours in rats. Pregnant or virgin female Sprague–Dawley rats that had previously been treated with 7,12-dimethylbenz[ a ]anthracene were assigned to an isocaloric diet containing either 16 (low fat) or 43% calories from fat (high fat) throughout gestation ( 15 ). The fat source was corn oil, which is rich in ω-6 PUFAs (primarily linoleic acid). On gestation day 19, the serum oestradiol levels were ~2-fold higher in rats fed the high fat diet than in those fed the low fat diet and the number of rats developing mammary tumours was significantly higher (40% tumour-bearing animals) in the group given the high fat diet than in those given the low fat diet (10%). Thus, consumption of a high ω-6 PUFA diet during gestation increased the risk of developing carcinogen-induced mammary tumours, possibly by increasing the concentration of circulating oestrogens. These data raise the possibility that human breast cancer might be prevented by dietary manipulation during pregnancy, which has not been addressed in epidemiological studies."

    "...Hilakivi-Clarke et al. also tested the hypothesis that feeding pregnant rats a high fat diet would increase both circulating 17α-oestradiol concentrations in the dams and the risk of developing carcinogen-induced mammary tumours among their female offspring ( 16 ). Isocaloric diets in which 12–16% (low fat) or 43–46% (high fat) of the calories were derived from corn oil (primarily the ω-6 PUFA linoleic acid) were fed throughout gestation. The plasma concentrations of 17α-oestradiol were significantly higher in pregnant females fed the high fat diet. The female offspring of these rats were fed laboratory chow from birth onwards. When they were exposed to 7,12-dimethylbenz[ a]anthracene, they had a significantly higher mammary tumour incidence (60 versus 30%) and a shorter latency for tumour appearance than the offspring of dams on the low fat diet; they also showed onset of puberty at a younger age and their mammary glands contained significantly higher numbers of the epithelial structures that are the targets for malignant transformation. (The term acceleration mass was used in the past for a very early onset of puberty and growth of breast tissue, hypothesized to be due to high protein intake.) If these findings can be extrapolated to humans, they may explain the link between diet and breast cancer risk, indicating that exposure in utero to a diet rich in ω-6 PUFAs and/or oestrogenic stimuli may affect breast cancer risk later in life."

    "...High intake of the ω-6 PUFAs linoleic acid and arachidonic acid inhibits the detoxification of oestrogens by 2-hydroxylation ( 70 ) and increases 16α-hydroxylation, resulting in metabolites that can undergo redox cycling and generate hydroxyl radicals. Whether ω-6 PUFAs also enhance the formation of 4-hydroxylated oestrogens is not known.
    Increased activity of oestradiol 4-hydroxylase in target tissues of oestrogens may play an important role in the development of oestradiol-induced tumourigenesis ( 69 ). A high degree of activity is expressed in the kidneys of male Syrian hamsters, the uterus of CD-1 mice and the pituitary gland of rats, which are susceptible to oestrogen-induced cancer. Each of these target organs contains a very high concentration of endogenous catecholamines, which may significantly inhibit catechol- O -methyltransferase-catalysed O -methylation of 4- and 2-hydroxyoestradiol in vivo . Moreover, catechol- O -methyltransferase-catalysed O -methylation of 4-hydroxyoestradiol is inhibited by 2-hydroxy-17α-oestradiol, whereas the O -methylation of 2-hydroxy-17β-oestradiol is not inhibited by 4-hydroxy-17α-oestradiol. Therefore, it is likely that 4-hydroxy-17β-oestradiol accumulates in these target organs because of inhibition of its O -methylation and also because of its rapid formation. Furthermore, greater oestradiol 4-hydroxylase activity has been observed in human breast cancer tissue than in normal breast tissue ( 70 ) and 4-hydroxyoestradiol appears to be the most abundant oestrogen metabolite in human breast cancer tissue. Studies are needed to confirm these findings.
    Several attempts have been made to characterize CYP isoforms with high oestradiol 4-hydroxylase activity in oestrogen target tissues ( 69 ). In human breast cancer cells and uterine myoma, oestradiol 4-hydroxylation is catalysed predominantly by CYP1B1. The expression of its mRNA is regulated by multiple endogenous factors, including cAMP, and by lipid-soluble xenobiotics. It will be important to characterize the selective expression and differential regulation of CYP1B1 and other CYP isoforms with oestradiol 2- and 4-hydroxylase activity in different cell types in human breast and the effects of various fatty acids. Human biomarkers should now be used to investigate whether 4-hydroxyoestradiol can mediate oxidative damage to cellular macromolecules via free radicals and can trigger lipid peroxidation of ω-6 PUFAs in breast tissue (Figure 3 ). The potent mitogenic effects of 17α-oestradiol and its locally formed, hormonally active 4-hydroxylated metabolite in breast epithelium may stimulate the growth of initiated (DNA-damaged) cells, which is thought to be a necessary event in the development of oestrogen-associated cancers."
     
  2. Travis

    Travis Member

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    Ton's of data exemplifying the general trend. Many people speak of the ω−6/ω−3 ratio, but I think perhaps 18:2/18:0 ratio could be more important. This here is a very good article:

    Dubnov, Gal. "Omega-6/omega-3 fatty acid ratio: the Israeli paradox." Omega-6/Omega-3 Essential Fatty Acid Ratio: The Scientific Evidence. Vol. 92. Karger Publishers (2003)

    I don't usually explicitly state that 'you should read this particular article,' but some articles are so well‐written that I try to get people to read them. This is one of those articles, and it explains the 'Israeli Paradox:' a term invented to call attention to the fact that despite having a high unsaturated fatty acid diet, the Israeli's don't have lower mortality . . . so not really a paradox at all, but merely echos of Ancel Keys. This is in fact exactly what you'd expect from reading Ray Peat articles; the only 'paradox' apparent is why they don't die sooner from so much falafel: or deep‐fried chickpea balls fried in sunflower, corn, and/or cottonseed oil.

    '...chickpea is rich in nutritionally important unsaturated fatty acids such as linoleic and oleic acids.' ―Jukanti

    Apparently dozens of websites didn't get the memo, and are still under the impression that the Isreali diet is 'one of the world's healthiest diets.' True: they do eat vegetables, but they also douse their food with ω−6 linoleic acid.

    'The Israeli Mediterranean diet contains foods that are extremely healthful, including the sheva minim, or seven species listed in the Torah as being special products of the Land of Israel. The fruits of the sheva minim have been shown to be loaded with antioxidants. The seven species, which are blessed with certain holiness, are wheat, barley, olives, grapes, dates, figs and pomegranates. Depending on the time of year, the fruits of the shivat haminim are ubiquitous in the Shuk.' ―jewishaction.com

    'An extensive study last year that looked at residents of 187 countries found that Israelis have one of the most healthful diets in the world.' ―haaretz.com

    'It incorporates many foods traditionally eaten in Middle Eastern and Mediterranean cuisines, and foods such as falafel, hummus, msabbha, shakshouka, couscous, and za'atar are now widely popular in Israel.' wikipedia.com

    Also notable about the Israelis is that their ω−6/ω−3 ratio is about 22:1, compared to ~4:1 in the Japanese, a longer‐lived population. Perhaps what the Israelis show the world best—besides fractional reserve banking—is that fruits and vegetables offer little protection against massive doses of ω−6.
     
  3. tca300

    tca300 Member

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  4. Kartoffel

    Kartoffel Member

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    @haidut and @Travis , so what do you think about the supposedly protective effect of ω-3 PUFA regarding cancer? I think most of mainstream science is now acknowledging the harmful effects of linoleic acid, but ω-3s are still seen as protective.
     
  5. Travis

    Travis Member

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    They are only protective to the extent that they displace ω−6 linoleic acid on the cell membrane and in the refrigerator. Many unsaturated fatty acids will compete with arachidonic acid—derived only from ω−6 linoleic acid—for cyclooxygense, preventing prostaglandin E₂ formation. These other polyunsaturated fatty acids wouldn't be protective if there wasn't anything to inhibit (i.e. being on a low ω−6 linoleic acid diet) and could be seen as a detriment since they are involved in lipofuscin formation—although free iron and aluminum plays significant roles in this. But as much as DHA and EPA can inhibit prostaglandin formation, they haven't been correlated with lower cancer nearly to the extent that fully‐saturated stearic acid has. And also, when DHA and EPA go through cyclooxygenase they do produce other eicosanoids: eicosapentaenoic acid becomes prostaglandin E₃, a little know prostaglandin with about ¹⁄₄th the activity of prostaglandin E₂. I always try to make the distinction between linoleic acid alone and all other fatty acids because it's the only precursor to arachidonic acid, which in turn is the only precursor to the 2‐series prostaglandins: powerful lipid hormones.
     
  6. Mito

    Mito Member

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    Do you think there is essentially a linear relationship between amount of dietary linoleic acid and the amount of prostaglandin E₂ synthesized in the body? Or is there a saturation point where anything above a given intake will maximize prostaglandin E₂ production?
     
  7. Travis

    Travis Member

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    Since there is (1) only a finite volume available for lipids and (2) that some other fatty acids are cyclooxygenase inhibitors, I think the ratios may matter as well. It is possible to have negligible arachidonic acid, this being replaced by Mead Acid. I would be willing to bet that many coconut, breadfruit, and tuber‐eating islanders had very small amounts of arachidonic acid; the fact that a population can survive an a tropical island lacking in linoleic acid is another proof that it's not essential.
     
  8. Mito

    Mito Member

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    Would that be 18:2/(18:0 + 18:3) or linoleic/(α-linoleic + stearic) or am I missing others?
     
  9. Travis

    Travis Member

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    Fish consumption can reduce cancer, but only to the extent that it antagonizes arachidonic acid (20∶4). This perhaps is not ideal, since the high unsaturation index of the fish fatty acids could promote lipofuscin—but it's hard to say. I just got done reading two Brunk & Terman articles; as of circa 2002, the only things known to influence lipofuscin experimentally had been oxygen, iron, iron chelators, vitamin E, protein inhibitors, and rapamycin (increases autophagy by inhibiting mTOR). The brain is naturally high in unsaturated fatty acids such as DHA (22∶6) and DPA(22∶5), but I haven't yet looked at brain uptake of fatty acids from the blood. You know this happens, to a degree, because DHA crosses the blood–brain barrier after being synthesized in the liver from α-linolenic acid (18∶3‧ω−3). So one of these days we have to see for certain if the rate of lipid transfer across the blood–brain barrier is more‐or‐less constant, or is influenced by diet. Since the most unsaturated fatty acid—DHA (22∶6)—is already routinely transported into the brain, the only way I can imagine that diet could significantly effect lipofuscin formation (besides iron) would be if the rate were increased . . . as if the brain wanted to use fatty acids for β-oxidation and not simply a slow steady-state replacement of membrane lipids. Regardless, both oleic acid and all saturated fatty acids are safe in this regard; this is primarily a question for fish-eaters, or do fish-eaters have more lipofuscin that beefeaters?
     
  10. OP
    haidut

    haidut Member

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    I think you will like this - fish oil produces CVD symptoms in human males.
    Fish oil produces an atherogenic lipid profile in hypertensive men. - PubMed - NCBI
     
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