Abstract
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 Fcγ 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 anti-Neu5Gc antibodies in semen and uterine fluid might contribute to unexplained human infertility.
Highlights
Humans can incorporate the xenoglycan N-glycolylneuraminic acid (Neu5Gc) from the diet into reproductive tissues and secretions
Human ␣-Neu5Gc antibodies appear during late infancy, correlating with weaning, exposure to dietary Neu5Gc, and exposure to common bacteria, such as non-typeable Haemophilus influenzae (NTHi), which incorporate Neu5Gc into their cell surface lipooligosaccharides [35]
The immune serum strongly reduced the staining for CD52, indicating that the Neu5Gc on CD52 targeted by the mouse ␣-Neu5Gc antibodies partially blocked CD52 staining (Fig. 1D)
Summary
Humans can incorporate the xenoglycan N-glycolylneuraminic acid (Neu5Gc) from the diet into reproductive tissues and secretions. 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. The CmahϪ/Ϫ mouse (human-like model) has been used in dietary studies to prove that Neu5Gc can be metabolically incorporated following ingestion of Neu5Gc-rich glycoprotein [31]. These experiments have shown that Neu5Gc is incorporated into the small intestine and subsequently appears in circulation at a steady-state level for several hours, followed by metabolic incorporation into multiple peripheral tissues [31]. A recent study demonstrated that Neu5Gc from diet increased the incidence of cancer in a mouse model [12]
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