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Evidence that glyphosate inhibits the breakdown of Poison/"Vitamin A", both are connected to celiac disease

All of the hyperlinks in the quote below are live if you want to follow the references, a great paper by the trailblazer Dr. Stephanie Seneff:

Glyphosate, pathways to modern diseases II: Celiac sprue and gluten intolerance

4 Retinoic acid [Poison/"Vitamin A"], celiac disease and reproductive issues

In this section, we first establish that excess retinoic acid (RA) is a risk factor for celiac disease. We then show that excess RA leads to complications in pregnancy and teratogenic effects in offspring. Glyphosate has been shown to exhibit teratogenic effects in line with known consequences of excess RA exposure to the embryo, and we propose that the mechanism for this effect may be glyphosate's known disruption of CYP enzymes (Samsel & Seneff, 2013), which are involved in RA catabolism. This then links glyphosate to increased risk to celiac disease via its direct effects on RA. And it identifies a possibly important factor in the association of celiac disease with reproductive issues. We also discuss other adverse effects of excess retinoic acid and a possible relationship to impaired sulfate supply to the gut.

In celiac disease, T cells develop antibody responses against dietary gluten, a protein present in wheat (Jabri & Sollid, 2009). RA, a metabolite of vitamin A, has been shown to play a critical role in the induction of intestinal regulatory responses (Mora et al., 2008; Coombes et al., 2007; Mucida et al., 2007). The peptide in gluten, A-gliadin p31-43, induces interleukin 15 (IL-15), a key cytokine promoting T-cell activation (Hershko & Patz, 2008). RA synergizes with high levels of IL-15 to promote JNK phosphorylation (Nanda, 2011; DePaolo et al., 2011), which potentiates cellular apoptosis (Putcha et al., 2003). IL-15 is a causative factor driving the differentiation of precursor cells into anti-gluten CD4+ and CD8+ Th1 cells in the intestinal mucosa. Furthermore, in (DePaolo et al., 2011), it was discovered that RA exhibits an unanticipated co-adjuvant property to induce Th1 immunity to antigens during infection of the intestinal mucosa with pathogens. Retinoic acid has also been shown to directly suppress transglutaminase activity, another way in which it would negatively impact celiac disease (Thacher et al., 1985). Thus, it is becoming clear that excess exposure to RA would increase risk to celiac disease, and warnings have been issued regarding potential adverse effects of RA supplements on celiac disease.

It is well established that high RA levels leads to teratogenic effects both in human and experimental models. Brain abnormalities such as microcephaly, impairment of hindbrain development, mandibular and midfacial underdevelopment, and cleft palate are all implicated (Sulik et al., 1988; Clotman et al., 1998). Women with celiac disease are known to have higher rates of infertility, miscarriages, and birth defects in their offspring (Freeman, 2010; Martinelli et al., 2000; Dickey et al., 1996; Collin et al., 1996). Excess RA could be a significant factor in these complications.

A possible mechanism by which glyphosate might induce excess RA is via its interference with the CYP enzymes that metabolize RA. There are at least three known CYPs (CYP26A1, CYP26B1 and CYP26C1) that catabolize RA, and they are active in both the embryo and the adult (Taimi et al., 2004). A 1/5000 dilution of glyphosate was sufficient to induce reproducible malformations characteristic of RA exposure in frog embryos (Paganelli et al., 2010). Pathologies included shortening of the trunk, reduction in the size of the head, abnormally small eyes or the presence of only one eye (cyclopia), and other craniofacial malformations in the tadpole. Glyphosate's toxicity to tadpoles has been well demonstrated, as it killed nearly 100% of larval amphibians exposed in experimental outdoor pond mesocosms (Relyea, 2005).

According to official records, there has been a recent 4-fold increase in developmental malformations in the province of Chaco, Argentina, where glyphosate is used massively on GMO monocrops of soybeans (Carrasco, 2013). In Paraguay, 52 cases of malformations were reported in the offspring of women exposed during pregnancy to agrochemicals, including anencephaly, microcephaly, facial defects, cleft palate, ear malformations, polydactily, and syndactily (Benítez-Leite et al., 2009). In in vitro studies on human cell lines, DNA strand breaks, plasma membrane damage and apoptosis were observed following exposure to glyphosate-based herbicides (Gasnier et al., 2009). Another factor in teratogenetic effects of glyphosate may be the suppression of the activity of androgen-to-estrogen conversion by aromatase, a CYP enzyme (Gasnier et al., 2009).

Ingested vitamin A, a fat-soluble vitamin, is delivered to the blood via the lymph system in chylomicrons, and excess vitamin A is taken up by the liver as retinoic acid for catabolism by CYP enzymes (Russell, 2000). Any remaining retinoic acid that is not catabolized is exported inside LDL particles, and it lingers much longer as retinyl esters in the vasculature in this form (Krasinski et al., 1990). Excess retinoic acid is more readily stored in this way in LDL particles in the elderly. Vitamin A toxicity can lead to fatty liver and liver fibrosis (Russell, 2000) as well as hypertriglyceridemia (Ellis et al., 1986). Vitamin A has a negative effect on cholesterol sulfate synthesis (Jetten et al., 1989), which might negatively impact the liver's ability to maintain adequate supplies of cholesterol sulfate for the bile acids, and therefore also interfere with the supply of cholesterol sulfate to the gastrointestinal tract.

In summary, glyphosate's disruption of the CYP enzymes responsible for RA catabolism could lead to an excess bioavailability of RA that could contribute adversely to celiac disease, as well as damaging the liver and leading to teratogenic effects in offspring of exposed individuals.

In addition to higher risk to birth defects, individuals with celiac disease have increased risk to infertility (Meloni et al., 1999; Farthing et al., 1982). Increased incidence of hypogonadism, infertility and impotence was observed in a study of 28 males with celiac disease (Farthing et al., 1982). Marked abnormalities of sperm morphology and motility were noted, and endocrine dysfunction was suggested as a probable cause. In studies conducted on Sertoli cells in prepubertal rat testis, exposure to Roundup induced oxidative stress leading to cell death (de Liz Oliveira Cavalli et al., 2013). Roundup induced the opening of L-type voltage dependent calcium channels as well as ryanodine receptors, initiating ER stress and leading to calcium overload and subsequent necrosis. Glutathione was depleted due to upregulation of several glutathione-metabolizing enzymes. This suggests that Roundup would interfere with spermatogenesis, which would impair male fertility.

Regarding the last paragraph on sperm and fertility, I have many other posts on this blog-forum connecting Poison/"Vitamin A" and damage to the testicles (Sertoli cells and Leydig cells.  As always, there are no coincidences.

Dr. Garrett Smith, the "Nutrition Detective"
Licensed Naturopathic Physician (NMD) in Arizona
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