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Mold 103: Zearalanone - Overlap With Ochratoxin A, ME CFS, Long Haul, Diabetes, Low B2, Low NAD, High Estrogen, Low Heme, and IBD

Updated: Jan 13

This article is not medical or healthcare advice. Before starting any health related regimen you should always seek the advice of your Primary Care Physician or an M.D.


Zearalanone {Zen} (produced by the mold Fusarium) is next after Ochratoxin A {OTA}(produced by aspergillus and penicillin) in my mold series of blogs for three reasons. First, i see it often elevated on urine based mycotoxin tests with Ochratoxin A. Second, it is found on the same grains where Ochratoxin A is found. Third, simply, its super nasty given the mouthful of a title for the blog article.


A few of the highlights about this nasty mycotoxin Zen:

 

  1. Causes ferroptosis (un-mitigated cell death leading to large weight loss) by inhibiting gpx4...."ZEA also downregulated the expression of Nrf2, SLC7A11, and GPX4, and .... resulting in the accumulation of lipid peroxides" [15].....

  2. Inhibits glutamate transport and causes NMDA activation, via reduced SLC7A11 transport

  3. Causes copper transport dysregulation [8]

  4. Major endocrin disrupter / high estrogen - closes liver valve - causing herx reactions along with all sorts of health effects from hyper estrogenemia

  5. Activates inflammasome (NLRP3) and is responsible for the maturation and secretion of proinflammatory cytokines IL-1β and IL-18, which play a role in IBD. [19]

  6. Activates cytokines : High IL,4, IL-10, TNFA, INFG; but IL-8 not high [15]

  7. Insulin resistance / blood glucose issues / diabetes from elevated IL10 - Blocks Glut4 (needed for glucose uptake); dysregulated blood glucose. Frequent urination is a sign of insulin resistance and diabetes developing.

  8. Elevated IL-10 also disrupts heme synthesis. Bam!

  9. Leads to metabolic reprogramming as well as an increase, lactic acid production, and NADPH oxidase (NADPH Oxidase= NOX = Super Oxide, and consumes NAD) activity.

  10. High Lactic Acid: High lactic acid decreases the activity of proline oxidase, which catalyzes proline, an amino acid that participates in the biochemical transformation of arginine, a source of nitric oxide (NO). NO plays an important function in the regulation of the intestinal barrier function, and decreased proline metabolism can compromise intestinal integrity and lead to intestinal damage.

  11. Depletes B2: Metabolic reprogramming contributes to alterations in the Krebs cycle, leading to accumulation of succinic acid (requires B2 to be cleared), a decrease in the concentrations of reduced forms of B2/flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NAD), and uncoupling of the respiratory chain. Reactive oxygen species are most dynamically formed in complexes I and III of the electron transport chain.

  12. Short-term ZEN exposure in mice caused intestinal flora imbalance and altered intestinal mucosal immune function, inducing a severe mucosal inflammatory response.

  13. Zen has been shown to increase oxidative stress and reduce the activity of important anti oxidant enzymes such as GPX (1-8) and SOD (1-3).


Organ Damage Due To Zen

Zearalenone studies have shown damage to reproductive organs, the intestines, the immune system, liver, kidney and spleen. In animals it can induce an enlarged uterus, ovarian atrophy, endometrial changes, vaginal prolapse, swelling of the vulva and vagina , enlarged breast glands, anestrus , decreased fertility, increased embryonic and fetal death, and abortion.


Zen can activate the pregnane X receptor and thereby increase the transcription of many genes, including Cytochrome P 450 enzymes. Zearalenone has been found to affect hundreds of genes with a mix up-regulated and down-regulated related to cellular signaling pathways , cytokine networks and the inflammation response.


Food and cooking considerations for Zen :

Zen can grow Fusarium in Soy, which has its own estrogenic qualities. A double whammy. Corn, soy, and wheat are often contaminated with Zen. High relative humidity during storage favors production of ZEN.


Zen is relatively resistant to degradation unfortunately. Zen is known for being fairly stable under normal cooking temperatures except under alkaline conditions, or during heating under a high degree of pressure. High temperatures, milling, dehulling, fermentation, and UV light all help lower the Zen load.


Binders for Zearalanone


Cholestyramine / Chitosan / Welchol - Yes


Saccharomyces cerevisiae - Yes!

Saccharomyces cerevisiae cell walls are used to bind aflatoxins, ochratoxin, and zearalenone in animals foods. Also acts as a competitor for C-Diff and Candida! The alpha mannan oligosaccharides and Beta-D-glucan in the cell wall help bind Zen. More acidic conditions favor mycotoxin adsorption on yeast cell walls in simulated gastrointestinal environments. Sacch B also can help biotransform zearalanone and improve clearance this way. The strains (S. cerevisiae CS, LL74 and LL83) were found to most effective for this.


Gluconamannan - somewhat helpful - Given the effect on Beta-D-Glucans


Peach Stone [12] - Yes

The pit of a peach has a composition of biological polymers like cellulose, lignin, and hemicellulose. These compounds increase the intensity of the hydroxyl and phenol groups which give it the adsorbing quality. Has a large surface area for binding sites - modified unmodified peach stone best for Zen.


Charcoal / Clays - yes - but data is in vitro

"This study was conducted to evaluate the ability (adsorptive power) of five adsorbents--activated carbon, bentonite, talc, sandstone, and calcium sulfate--to trap ZEA in vitro. Activated carbon was the best adsorbent, binding 100% ZEA (pH 3 and 7.3) at 0.1, 0.25, 0.5, and 1% dose levels. Bentonite, talc,and calcium sulfate were less efficient than activated carbon but still could bind ZEA to some extent."[7]


The Use Of Gut Flora (L. Plantarum, Bacillus) [10,11,14,16,17,18]

B. lincheniformis, B. megaterium, B. cereus - BC7, B. Subtillus, and B. thuringiensis) efficacious in binding Zen with the addition of manganese.


Lactic acid bacteria with high esterase activity such as Lactobacillus plantarum, and specifically Lactobacillus plantarum BCC 47723 A may be helpful.


Zen uses primarily the Glucuronidation, Sulfation, and Methylation Phase 2 Detox Pathways

Understanding your genetic status for key genes in these pathways will be helpful. Avoiding foods and compounds that inhibit these pathways will be helpful as well as your nutritional status for the key cofactors in these pathways. Lastly, designing a diet and supplement regimen to help activate these pathways (upregulate) will be helpful.


Oxidative Stress in Zen Toxicity

"Our results demonstrated that ZEN inhibits cell proliferation which was accompanied by an increase in the generation of free radicals as measured by fluorescent 2,7-dichlorofluorescein (DCF) and Malondialdehyde (MDA). As an adaptive response to this redox status, we showed an induction of heat shock protein expression (Hsp 70) and an activation of antioxidant enzymes; catalase and Superoxide Dismutase (SOD). Moreover, a loss of mitochondrial membrane potential (Δѱm) was observed."[1]


Estrogen Related Imbalances That May Lead Reproductive System Diseases

"One of these mycotoxins is zearalenone, which is classified as a xenoestrogen, an exogenous compound which resembles the structure of naturally occurring estrogens with its chemical structure. This property of zearalenone determines its ability to bind to estrogen receptors of cell and its bioaccumulation. This leads to disorders of the hormonal balance of the body, which in consequence may lead to numerous diseases of reproductive system such as prostate, ovarian, cervical or breast cancers. High risk posed by long-term exposure to contaminated food forces the modern science to develop and implement effective methods of zearalenone neutralisation."[13]


Zen Induced Toxicity, Oxidative Stress, and Apoptosis In Human Embryonic Stem Cells

"Moreover, differentiation of human embryonic stem cell (hESC) was initiated by embryoid bodies (EBs) formation; EBs were exposed to different concentrations of ZEN for 24 h to detect cellular reactive oxygen species (ROS) generation, the mitochondrial transmembrane potential (MMP), apoptosis, cell cycle, and the related protein expression. Based on the results of the three endpoints and functions of ZEN in mEST and hEST, ZEN was evaluated to have strong embryonic toxicity both by two models. The increases in cellular ROS and loss of MMP were observed at 2 and 4 μg/ml concentrations. Flow cytometry showed that ZEN induced cell cycle arrest and apoptosis. The upregulation of p53, caspase-9, caspase-3, and the ratio of Bax/Bcl-2 were observed at 2 and 4 μg/ml concentrations. Collectively these results demonstrate that ZEN has strong embryonic toxicity and induces oxidative stress and apoptosis in differentiated human ESCs." [20]


Oxidative Stress and Ferroptosis

Recently, it has been reported that mycotoxins such as deoxynivalenol and zearalenone can induce ferroptosis in the reproductive organ by reducing antioxidant capacity, downregulating the expression levels of glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1), disrupting iron homeostasis and accumulating lipid peroxidation, ultimately resulting in spermatogenesis damage. [15]


Zen disrupts Copper Transporters ATP7A, ATP7B

"The expression levels of ATPase copper transporting alpha (ATP7A) and ATPase copper transporting beta (ATP7B) were significantly downregulated (p < 0.01), while the expression of solute carrier family 31 member 1 (SLC31A1) was not modified in the ZEA group compared with the NC group." [8]


Potential Strategies Of Antioxidants :

NAC

NAC for most people is the limiting compound for the creation of glutathione.


"Porcine small intestinal epithelial (SIEC02) cells were selected to assess the effect of ZEN exposure on the intestine. Cells were exposed to ZEN (20 µg/mL) or pretreated with (81, 162, and 324 µg/mL) N-acetylcysteine (NAC) prior to ZEN treatment. Results indicated that the activities of glutathione peroxidase (Gpx) and glutathione reductase (GR) were reduced by ZEN, which induced reactive oxygen species (ROS) and malondialdehyde (MDA) production. Moreover, these activities increased apoptosis and mitochondrial membrane potential (ΔΨm), and regulated the messenger RNA (mRNA) expression of Bax, Bcl-2, caspase-3, caspase-9, and cytochrome c (cyto c). Additionally, NAC pretreatment reduced the oxidative damage and inhibited the apoptosis induced by ZEN. It can be concluded that ZEN-induced oxidative stress and damage may further induce mitochondrial apoptosis, and pretreatment of NAC can degrade this damage to some extent."[5]


Selenium

Selenium has been shown to prevent ZEN damage to chicken spleen lymphocytes. Treatment with selenium blocked ROS generation, improved anti oxidative capacity, and reversed apoptosis and estrogen receptor stress-related genes and protein expression. Most glutathione enzymes use selenium as their cofactor.


"The results show that ZEN induced an increase in ROS generation and lipid peroxidation, and a decrease in levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione (GSH). The results of apoptosis morphologically from acridine orange/ethidium bromide (AO/EB) fluorescent staining and flow cytometry analysis show apparent apoptosis in the ZEN-treated group, and was confirmed by the upregulation of caspase-3, -12 and downregulation of Bcl-2. Meanwhile, ZEN activated the endoplasmic reticulum (ER) stress by upregulating ER stress-related molecular sensors (GRP78, ATF6, ATF4, IRE). However, co-treatment with Se effectively blocked ROS generation, improved anti oxidative capacity, and reversed apoptosis and ER stress-related genes and protein expression. Taken together, these data suggest that oxidative stress and ER stress play a vital role in ZEN-induced apoptosis, and Se had a significant preventive effect on ZEN-induced apoptosis in chicken spleen lymphocyte via ameliorating the ER stress signaling pathway."[4]


Silymarin / Milk Thistle

Silymarin, a group of constituents from the herb Milk thisle - Silybum marinanum has been shown

to be protective in the face of ZEN-induced liver toxicity and reproductive toxicity in a rat study. It was thought it might be due to the herbs improvement in the antioxidant capacity and regulation in the genes related to protein synthesis, ZEN metabolism, hormone synthesis, and ABC transporters in the tissues. Helps keep the BSEP open to avoid 'herx' reactions from high estrogen or overloaded MRP2 proteins that escort toxins into the bile.


"Dietary silymarin supplementation at 100, 200, and 500 mg/kg protected rats from ZEN-induced hepatotoxicity and reproductive toxicity, potentially through improvement in the antioxidant capacity and regulation in the genes related to protein synthesis, ZEN metabolism, hormone synthesis, and ABC transporters in the tissues" [3]


Melatonin Reduces Oxidative Stress In Bovine ovarian Granulosa Cells

"This study investigated the effects of β-zol and HT-2 on bovine ovarian granulosa cells (BGCs), and how melatonin may counteract these effects. β-zol and HT-2 inhibited cell proliferation in a dose-dependent manner, and induced apoptosis of BGCs. They also yielded upregulation of the apoptosis-related genes Bax/Bcl-2 and Caspase3 and phosphorylation of p38MAPK. Increases in intracellular ROS were observed along with higher levels of mRNA anti-oxidation markers SOD1, SOD2, and CAT. SOD1, SOD2, malonaldehyde (MDA), and glutathione peroxidase (GSH-px) activities increased, as did the levels of SOD1 and SOD2 proteins. All of these effects were reduced or entirely attenuated in BGCs pre-treated with melatonin. Our results demonstrate that melatonin has protective effects against mycotoxin-induced apoptosis and oxidative stress in BGCs"[2]


Natural Antioxidants A, C, E, Circumin, Lycopene [6]

Some of these tested that have shown some benefit with ZEN are vitamin A, E, C as well as curcumin and lycopene have been shown to modulate oxidative stress.


Chrysin [6]

Chrysin is a flavonoid found in many plants. It was given to mice at the same time they were given ZEN Chrysin attenuated the toxic effects caused by ZEN in blood and testes of mice. Chrysintreatment increased the number and motility of sperm, testosterone levels, restored antioxidant defenses and reduced the inflammation and apoptosis process.

Chrysin is in honey, propolis and the herb Passion flower.


Kefir

"The co-treatment as well as the pre-treatment by kefir showed a reduction of ZEN induced damages for all tested markers. However, the pre-treatment seems to be the most efficient, it prevented almost all ZEN hazards. Consequently, oxidative damage appears to be a key determinant of ZEN induced toxicity in cultured HCT-116 cells. In conclusion, we showed that kefir may better exert its virtue on preventive mode rather than on curative one." [1]


Kefir will usually add to histamine issues if they are present; proceed with caution.


DIM

DIM, can effectively lower high estrogen, of which high estrogen is implicated in closing the Bile Salt Export Pump BSEP - (ABCB11), which is controlled by the FXR Receptor (NR1H4), resulting in 'herx' reactions.


If you would like to review your genetics, look at testing options, or discuss strategies to expedite the clearance of Zen, please contact me to set up an appointment. I encourage you to look into the references cited below should you feel called to explore this topic in more detail.

  

 References

  1. Protective effects of kefir against zearalenone toxicity mediated by oxidative stress in cultured HCT-116 cells. Emna El Golli-Bennour, Rim Timoumi, et. al.  Toxicon. 2019 Jan:157:25-34.

  2. Melatonin alleviates β-zearalenol and HT-2 toxin-induced apoptosis and oxidative stress in bovine ovarian granulosa cells. Fangxiao Yang 1Lian Li, et. al. Environ Toxicol Pharmacol. . 2019 May:68:52-60. doi: 10.1016/j.etap.2019.03.005. Epub 2019 Mar 7.

  3. The Journal of Nutrition Biochemical, Molecular, and Genetic Mechanisms Dietary Silymarin Supplementation Alleviates Zearalenone-Induced Hepatotoxicity and Reproductive Toxicity in Rats Xin Gao, Zhuo-Hui Xiao. 2018 American Society for Nutrition. 1209 First published online August 3, 2018; doi: https://doi.org/10.1093/jn/nxy114

  4. Protective effects of selenium against zearalenone-induced apoptosis in chicken spleen lymphocyte via an endoplasmic reticulum stress signaling pathway. Xiau, Xu, et al. Published: 29 October 2018. Cell and Stress Chaperones. Pages 77–89, Articles/PMC6215273/.

  5. Protective Effect of N-Acetylcysteine against Oxidative Stress Induced by Zearalenone via Mitochondrial Apoptosis Pathway in SIEC02 Cells. . Wang, Li, et. al. Toxins (Basel). 2018 Oct; 10(10): 407. Published online 2018 Oct 9. doi: 10.3390/toxins10100407

  6. Mycotoxins and oxidative stress: where are we? E.O. da Silva1, A.P.F.L. Bracarense1* and I.P. Oswald. World Mycotoxin Journal, 2018; 11 (1): 113-133 Wageningen Academic Publishers SPECIAL ISSUE: 10 years World Mycotoxin Journal ISSN 1875-0710 print, ISSN 1875-0796 online, DOI 10.3920/WMJ2017.2267 113 1.

  7. In vitro binding of zearalenone to different adsorbents. Dante J Bueno 1Liliana Di Marco. J Food Prot. . 2005 Mar;68(3):613-5. doi: 10.4315/0362-028x-68.3.613. PMID: 15771192. DOI: 10.4315/0362-028x-68.3.613

  8. Effects of Zearalenone on Apoptosis and Copper Accumulation of Goat Granulosa Cells In Vitro. Lie, Ma, et. al. Biology (Basel). 2023 Jan; 12(1): 100. Published online 2023 Jan 9. doi: 10.3390/biology12010100. PMCID: PMC9856194. PMID: 36671791

  9. Zearalenone, an estrogenic mycotoxin, is an immunotoxic compound

  10. Isolation and characterization of the Bacillus cereus BC7 strain, which is capable of zearalenone removal and intestinal flora modulation in mice. Yue Wang , Jian Zhang, et al.. Toxicon. . 2018 Dec 1:155:9-20. doi: 10.1016/j.toxicon.2018.09.005. Epub 2018 Sep 26.

  11. Characterization of a cold-active esterase from Lactobacillus plantarum suitable for food fermentations. María Esteban-Torres 1José Miguel Mancheño, et. al. J Agric Food Chem.

  12. IN VITRO EVALUATION OF THE EFFICACY OF PEACH STONES AS MYCOTOXIN BINDERS. Z o r i c a R. L o p i č i ć 1 , A l e k s a n d r a S. B o č a r o v – S t a n č i ć 2 , M i r j a n a D. S t o j a n o v i ć, et. al. Jour. Nat. Sci, Matica Srpska Novi S № 124, 287—296, 2013. UDC 634.25:544.725 DOI: 10.2298/ZMSPN1324287L.

  13. Zearalenone and its metabolites: Effect on human health, metabolism and neutralisation methods. A Rogowska 1P Pomastowski. Toxicon . 2019 Apr 15:162:46-56. doi: 10.1016/j.toxicon.2019.03.004. Epub 2019 Mar 6. PMID: 30851274. DOI: 10.1016/j.toxicon.2019.03.004

  14. Qin, X., Su, X., Tu, T., Zhang, J., Wang, X., Wang, Y., Wang, Y., Bai, Y., Yao, B., Luo, H., & Huang, H. (2021). Enzymatic degradation of multiple major mycotoxins by dye-decolorizing peroxidase from bacillus subtilis. Toxins, 13(6), 429. https://doi.org/10.3390/toxins13060429  

  15. Effect of Zearalenone-Induced Ferroptosis on Mice Spermatogenesis. Li, Zhu, et al. Animals (Basel) . 2022 Nov 3;12(21):3026. PMID: 36359150. PMCID: PMC9657494. DOI: 10.3390/ani12213026.

  16. Detoxification Strategies for Zearalenone Using Microorganisms: A Review. Wang, Wu, et. al. Microorganisms. 2019 Jul; 7(7): 208. Published online 2019 Jul 21. doi: 10.3390/microorganisms7070208. PMCID: PMC6680894. PMID: 31330922

  17. Huang,W.; Chang, J.;Wang, P.; Liu, C.; Yin, Q.; Zhu, Q.; Lu, F.; Gao, T. Effect of the combined compound probiotics with mycotoxin-degradation enzyme on detoxifying aflatoxin B1 and zearalenone. J. Toxicol. Sci. 2018, 43, 377–385. Microorganisms 2019, 7, 208 14 of 14

  18. Huang, W.; Chang, J.; Wang, P.; Liu, C.; Yin, Q.; Song, A.; Gao, T.; Dang, X.; Lu, F. Effect of compound probiotics and mycotoxin degradation enzymes on alleviating cytotoxicity of swine jejunal epithelial cells induced by aflatoxin B1 and zearalenone. Toxins (Basel) 2019, 11, 12.

  19. Zearalenone induces NLRP3-dependent pyroptosis viaactivation of NF-κB modulated by autophagy in INS-1 cells. Xue Wang, Liping Jiang ,Toxicology. Volume 428. 1 December 2019 , 152304. Science Direct. https://doi.org/10.1016/j.tox.2019.152304

  20. Zearalenone causes embryotoxicity and induces oxidative stress and apoptosis in differentiated human embryonic stem cells. Hanwen Cao , Yuan Zhi, et. al. Toxicology in Vitro. Volume 54, February 2019, Pages 243-250. https://doi.org/10.1016/j.tiv.2018.09.020

  21. Effects and Underlying Mechanisms of Zearalenone Mycotoxin at Concentrations Close to the EC Recommendation on the Colon of Piglets after Weaning, by Valeria Cristina Bulgaru

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