What does this research mean for the field?

Excessive folic acid exposure disrupts placental endocrine function and increases the secretion of placental growth hormone (GH2), providing a plausible mechanistic link to the increased risk of gestational diabetes mellitus. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To investigate how increased folic acid exposure affects trophoblast function and hormone secretion, potentially linking excess folic acid to gestational diabetes.

June 1, 2026Frontiers in Nutrition0 citationsOpen Access

Excess folic acid disrupts placental endocrine function in vitro: a potential mechanism linking elevated folic acid exposure with gestational diabetes mellitus

JWJessica Williamson AAAnya L. Arthurs MSMelanie D. Smith

Key Points

To investigate how increased folic acid exposure affects trophoblast function and hormone secretion, potentially linking excess folic acid to gestational diabetes.
Cultured trophoblast cells and human placental explants across varying folic acid dosages (0 nM to 2000 nM).
Assessed trophoblast proliferation, migration, and invasion in real-time; measured hormone secretion via ELISA; and analyzed folate receptor expression by immunoblotting.
Statistical analyses were conducted with 40 nM FA as the reference for comparison.
Folic acid exposure caused a U-shaped response in trophoblast proliferation, migration, and hormone secretion compared to physiological norm.
Excess folic acid significantly increased placental growth hormone secretion by 26% (p = 0.03), linked to maternal insulin resistance.
Both deficiency and excess led to similar changes in placental function, indicating sensitivity to folic acid levels.

Abstract

Background High folic acid (FA; synthetic folate) intake is associated with increased risk of gestational diabetes mellitus (GDM), but the underlying mechanisms remain unknown. As the placenta is a key regulator of maternal glucose homeostasis, it represents a plausible target for FA-mediated effects. Objective To determine how increased FA exposure modulates trophoblast function, placental folate receptor/transporter expression, and secretion of hormones that maintain maternal euglycaemia, providing a potential mechanism linking excess FA to GDM. Methods Trophoblast cells (HTR-8/SVneo, JEG-3 and BeWo) and early- to mid-gestation human placental explants ( n = 66) were cultured across a FA dose range representing acute physiological deficiency to excess (0 nM, 10 nM, 40 nM; 200 nM; 2000 nM). Trophoblast proliferation, migration and invasion were assessed in real time; placental explant proliferation and apoptosis by immunohistochemistry; folate receptor/transporter abundance by immunoblotting; and hormone secretions by enzyme-linked immunosorbent assays (ELISA). Statistical analyses were performed relative to 40 nM FA (physiological norm). Results FA exposure produced a U-shaped response in trophoblast proliferation, migration, invasion, placental folate receptor (FOLR1) expression and human placental lactogen (hPL) secretion, where both acute deficiency and excess induced similar results relative to physiological norm. Notably, only excess FA significantly increased placental growth hormone (GH2) secretion (↑26%, p = 0.03), a hormone that promotes maternal insulin resistance. Conclusion Human placental function and folate transport pathways are sensitive to FA exposure under conditions of deficiency and excess. Because folate deficiency is known to compromise pregnancy health, these findings suggest that excessive FA exposure may also disrupt placental function and perturb maternal and infant outcomes. The selective increase in GH2 under FA excess offers a plausible mechanism linking high FA exposure to increased GDM risk. Given widespread FA food fortification and increased use of high-dose prenatal supplements, the potential impact of FA excess on overall pregnancy metabolic health warrants urgent consideration.

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