Epidemiological evidence links tri-n-butyl phosphate (TNBP) exposure to gestational diabetes mellitus (GDM), but mechanistic insights remain unclear. This study demonstrated that gestational TNBP exposure induced a GDM-like phenotype in pregnant mice, characterized by glucose intolerance, but not in nonpregnant female mice. This pregnancy-specific susceptibility might be attributed to significantly higher internal levels of TNBP and its metabolites dibutyl phosphate (DNBP) and dibutyl-3-hydroxybutyl phosphate (3-OH-TNBP) than the nonpregnant mice, subsequently exacerbating insulin resistance in the pregnant mice. The hyperglycemia in pregnant mice was closely associated with the reduced expression of estrogen receptors (p In vitro validation using pregnancy hormone-primed HepG2 cells confirmed that TNBP and its metabolites induced ERα-mediated glucose dysregulation, with a potency order of 3-OH-TNBP > DNBP > TNBP. These findings establish a novel mechanism by which gestational TNBP exposure disrupts maternal glucose homeostasis via ERα signaling suppression.
Deng et al. (Wed,) studied this question.