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Updated: Aug 29, 2026
Modifying Levels of Maternal Dietary Folic Acid or Choline to Study the Impact of Deficiencies on Offspring Health Outcomes
Published on: June 28, 2024
Antibodies to folate receptors impair embryogenesis and fetal development in the rat
Maria da Costa1, Jeffrey M Sequeira, Sheldon P Rothenberg
1SUNY-Downstate Medical Center, Department of Medicine, Brooklyn, New York 11203, USA. maria.dacosta@downstate.edu
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Antibodies targeting folate receptors (FRs) can cause embryonic damage in rats. While folinic acid can prevent some damage, dexamethasone is effective against immune-mediated cell lysis, highlighting FRs
Area of Science:
- Reproductive biology and developmental toxicology.
Background:
- Folic acid (FA) supplementation significantly reduces neural tube defects (NTDs).
- However, the etiology of most NTDs is not linked to folate deficiency or genetic mutations in folate pathways.
- Folate receptors (FRs) mediate cellular folate uptake, and their role in embryonic development is critical.
Purpose of the Study:
- To investigate whether antibodies against folate receptors (FRs) can induce teratogenic effects in a rat model.
- To determine the protective effects of folinic acid and dexamethasone against FR antibody-induced embryonic damage.
Main Methods:
- Immunohistochemistry was used to detect FRs in reproductive tissues and embryos.
- Pregnant rats received intraperitoneal injections of antiserum to FRs on gestation day 8.
- Embryos were examined for viability and organogenesis; some dams received folinic acid or dexamethasone prior to antiserum administration.
Main Results:
- FRs were identified in oocytes, oviduct, uterine epithelial cells, and throughout embryonic development (GD4-GD15).
- Antiserum to FRs demonstrated a dose-dependent effect on embryo viability and organogenesis.
- Folinic acid mitigated teratogenicity from lower antiserum doses, while dexamethasone prevented embryo resorption caused by higher doses.
Conclusions:
- Folate receptors are expressed in key reproductive and embryonic tissues.
- Antibodies targeting FRs can induce significant embryonic damage in a dose-dependent manner.
- Folinic acid and dexamethasone offer partial and complete protection, respectively, against FR antibody-induced teratogenicity, suggesting immune-mediated mechanisms.
