Antibodies to folate receptors impair embryogenesis and fetal development in the rat.

Abstract

Folic acid (FA) supplementation reduces neural tube defects (NTDs) by 70%. However, the cause of most NTDs cannot be attributed to folate deficiency, to mutations of genes that encode folate pathway enzymes, and folate receptors (FRs) that mediate cellular folate uptake. Mouse embryos nullizygous for the ortholog of the FRalpha gene have lethal congenital abnormalities that are preventable by administration of folinic acid to the dams. To determine whether antibodies to FRs are similarly teratogenic, we studied a rat model. Immunohistochemistry with an antiserum to rat FRs was used to identify the receptors on reproductive tissues and embryos. Gestation day (GD) 8 rats received intraperitoneal injections of antiserum to the FRs, and their embryos were examined 2-9 days later. Some rats received pharmacologic doses of folinic acid or dexamethasone before the antiserum was administered. The FRs are present on oocytes, the oviduct, and uterine epithelial cells, and in the embryo at all stages examined between GD4 and GD15. The antiserum has a dose-related effect on embryo viability and organogenesis. Folinic acid prevented teratogenicity resulting from smaller doses of antiserum, but not that caused by larger doses. Resorption of embryos with the larger doses of the antiserum was prevented by dexamethasone. FRs are expressed on oocytes, epithelial cells of reproductive organs, and embryonic and extraembryonic tissues. Antiserum to FRs administered to pregnant rats causes embryonic damage. Embryo lethality with smaller doses of antiserum is preventable by administration of folinic acid, while larger doses cause embryo damage by immune-mediated cell lysis, which can be prevented by dexamethasone.