Placental iron transport under maternal stress: a missing link in foetal programming and mental health.

Background Environmental stress and iron deficiency are increasingly recognised as prevalent challenges during pregnancy, with significant implications for both maternal and foetal health. Environmental stressors such as chronic maternal anxiety can elevate cortisol levels and trigger inflammatory responses which might subsequently disrupt foetal brain development. Concurrently, iron deficiency during critical windows of gestation can hinder the formation of brain structures and neurotransmitter systems vital for emotional regulation and cognitive function after birth. Iron deficiency and exposure to stress are among the most prevalent nutritional and environmental challenges during pregnancy, and their combined influence may substantially increase the risk of neuropsychiatric disorders in the offspring. Although the individual effects of each factor are relatively well understood, their interaction during gestation remains unexplored. Methods In the present study, we employed human placental samples from mildly stressed and non-stressed mothers, a chronic environmental stress mouse model, and advanced in vitro techniques to examine whether gestational environmental stress alters placental iron transport. Findings Our findings indicate that stress enhanced placental iron uptake and accumulation, but paradoxically reduced iron transfer to the foetus-an effect observed exclusively in females and reproducible in vitro following both stress exposure and dexamethasone treatment. Interpretation These results provide insights into the sex-specific impact of environmental stress on placental and foetal iron availability and highlight a previously unrecognised pathway through which prenatal stress could influence long-term health trajectories in the offspring. Funding This study was supported by the Swiss National Science Foundation (SNF grant no. 310030₁97408), the Swiss National Science Foundation via the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland (grant no. 51NF40₁85544) and the Swiss 3R Competence Centre (3RCC; grant no OC-2019-019). TF was supported by the Hans Sigrist Foundation, Switzerland.