Detection of the dietary xenoglycan N-glycolylneuraminic acid (Neu5Gc) and anti-Neu5Gc antibodies within reproductive tracts of male and female infertility subjects

Sroga, Julie M.; Wu, Diana; Ma, Fang; Tecle, Eillen; Ressler, I.B.; Maxwell, Rose; Ferrari, Rachael; Whigham, Leah D.; Gagneux, Pascal; Lindheim, Steven R.

doi:10.15761/cogrm.1000120

Cited by 7 publications

(10 citation statements)

References 23 publications

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“…In humans, ␣-Neu5Gc antibodies appear after weaning, possibly promoted by the combination of dietary Neu5Gc and its presentation on antigens of NTHi (35). Together with the finding of reduced clinical pregnancy rates in the presence of Neu5Gc antigen and directed antibodies in human fertility patients (14), our results suggest that the uterine mucosal immune system can produce ␣-Neu5Gc antibodies independently in Cmah Ϫ/Ϫ mouse model immunized by NTHi (intraperitoneal injection). We detected dietary Neu5Gc on epididymal sperm from Cmah Ϫ/Ϫ mice fed with PSM without blood-testis barrier damage, suggesting that there might be another underlying mechanism for Neu5Gc accumulation on human sperm where the majority of men do not show incorporated Neu5Gc despite life-long red meat diets.…”

Section: Discussionsupporting

confidence: 56%

“…This phenomenon shares mechanisms with ASA, a well accepted cause for human infertility as an immunologic factor targeting certain substances on sperm that have been known to be antigenic for more than a century (51), but also includes autoimmunity in the female. Evidence from our findings in a humanized mouse model together with our published clinical findings (14) provide justification to study xenosialitis as a factor underlying human infertility by means of large-scale, comprehensive, and multicenter research. In light of the many profound differences between human and mouse reproductive biology, ranging from sperm count and mating behavior to female reproductive tract anatomy, diet, and immunology, our findings can only hint at potential mechanisms in humans.…”

Section: Discussionsupporting

confidence: 55%

“…Effects of ␣-Neu55Gc Antibodies on Receptivity and Decidualization of Endometrium-Results from our clinical study with in vitro fertilization patients pointed to failure of implantation as the main reason for low clinical pregnancy rates in women with xenoglycan and ␣-Neu5Gc antibodies in their uterus (14). No Neu5Gc was found in Cmah Ϫ/Ϫ mouse endometrium even after long time feeding with PSM in our present study, and the failure of this model might be due to differences in mouse and human endometrial metabolism and regeneration.…”

Section: Resultsmentioning

confidence: 86%

“…It has been proposed that circulating anti-sialic acid antibodies target incorporated non-human sialic acid and contribute to chronic inflammation in various tissues (10 -12). Our objective is to determine whether xenoglycan-antibody interactions also affect human infertility (13) given tentative evidence from a clinical study (14). Sialic acids (Sias) are nine-carbon backbone, acidic, amino sugars that decorate the surfaces of all vertebrate cells in high abundance (tens to hundreds of millions of molecules per cell).…”

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confidence: 99%

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A Mouse Model for Dietary Xenosialitis

Deng²,

Secrest³

et al. 2016

Journal of Biological Chemistry

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Humans can incorporate the xenoglycan N-glycolylneuraminic acid (Neu5Gc) from the diet into reproductive tissues and secretions. Most humans also have circulating antibodies specific for this dietary xenoglycan. The potential for inflammation induced by incorporated Neu5Gc and circulating anti-Neu5Gc antibodies, termed xenosialitis, has been discussed as a factor influencing several human diseases. Potential effects of xenosialitis on human fertility remain unknown. Here, we investigate possible adverse effects of the presence of Neu5Gc on sperm or endometrium combined with anti-Neu5Gc antibodies in semen or uterine secretions in a mouse model. We use Cmah ؊/؊ mice, humanized for Neu5Gc deficiency. We find that the viability, migration, and capacitation of sperm with incorporated Neu5Gc are negatively affected when these are exposed to anti-Neu5Gc antibodies. In addition, we find that after copulation, activated uterine neutrophils and macrophages show increased phagocytosis of sperm in the presence of anti-Neu5Gc antibodies via the complement receptor 3 (C3R) and Fc␥ I/II/III (Fc receptor). Furthermore, Neu5Gc in endometrial cells combined with the presence of anti-Neu5Gc antibodies alters the receptivity and decidualization of endometrial explants. These studies provide mechanistic insights on how Neu5Gc on sperm and/or endometrium combined with antiNeu5Gc antibodies in semen and uterine fluid might contribute to unexplained human infertility.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 86%

mentioning

confidence: 99%

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A Mouse Model for Dietary Xenosialitis

Deng²,

Secrest³

et al. 2016

Journal of Biological Chemistry

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“…Although not yet studied, it is also possible that meat processing improves the digestibility, absorption, and metabolic incorporation of Neu5Gc. Similarly, although not yet studied, we believe that xenosialitis may represent the missing link that connects red meat consumption to other inflammatory diseases such as atherosclerosis (Pham et al, 2009), type 2 diabetes (Pan et al, 2011), rheumatoid arthritis (Pan et al, 2011), macular degeneration (Ersoy et al, 2014; Chong et al, 2009) and possibly certain forms of infertility (Sroga et al, 2015). Interventional studies using animal models could be used to address these hypotheses further, eventually leading to potential solutions to this problem.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 95%

Human risk of diseases associated with red meat intake: Analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid

Alisson-Silva

Kawanishi

Varki

2016

Molecular Aspects of Medicine

130

103

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One of the most consistent epidemiological associations between diet and human disease risk is the impact of red meat consumption (beef, pork, and lamb, particularly in processed forms). While risk estimates vary, associations are reported with all-cause mortality, colorectal and other carcinomas, atherosclerotic cardiovascular disease, type II diabetes, and possibly other inflammatory processes. There are many proposed explanations for these associations, some long discussed in the literature. Attempts to explain the effects of red meat consumption have invoked various red meat-associated agents, including saturated fat, high salt intake, Trimethylamine–N-oxide (TMAO) generation by microbiota, and environmental pollutants contaminating red meat, none of which are specific for red meat. Even the frequently mentioned polycyclic aromatic carcinogens arising from high temperature cooking methods are not red meat specific, as these are also generated by grilling poultry or fish, as well as by other forms of cooking. The traditional explanations that appear to be more red meat specific invoke the impact of N-nitroso compounds, heme iron, and the potential of heme to catalyze endogenous nitrosation. However, heme can be denatured by cooking, high levels of plasma hemopexin will block its tissue delivery, and much higher amounts of heme likely originate from red blood cell breakdown in vivo. Therefore, red meat-derived heme could only contribute to colorectal carcinoma risk, via direct local effects. Also, none of these mechanisms explain the apparent human propensity i.e., other carnivores have not been reported at high risk for all these diseases. A more recently proposed hypothesis involves infectious agents in beef from specific dairy cattle as agents of colorectal cancer. We have also described another mechanistic explanation for the human propensity for risk of red-meat associated diseases that is consistent with most observations: metabolic incorporation of a non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) into the tissues of red meat consumers and the subsequent interaction with inflammation-provoking antibodies against this “xenoautoantigen”. Overall, we conclude that while multiple mechanisms are likely operative, many proposed theories to date are not specific for red meat, and that the viral and xenoautoantigen theories deserve further consideration. Importantly, there are potential non-toxic dietary antidotes, if the xenoautoantigen is indeed correct.

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