Cell line-specific modulation of inflammation by oestradiol in an in vitro model of antenatal depression

Antenatal depression is linked to adverse neurodevelopmental outcomes in offspring, likely mediated by a multitude of biological mechanisms, including elevated maternal cytokines. However, factors modulating fetal vulnerability or resilience to inflammatory exposure remain unclear. This study examines whether the steroid hormone, oestradiol, can modulate inflammatory responses in an in vitro model of hippocampal neurogenesis, using two fetal hippocampal progenitor cell lines: female-derived HPC0A07/03C and male-derived HIP-009. Cells were pre-treated with oestradiol for 24- and 48-hours during proliferation, followed by interleukin-1beta (IL-1β) exposure prior to the initiation of differentiation. Markers of proliferation and neurogenesis, as well as inflammatory cytokines and kynurenine pathway metabolites, were assessed. In female HPC0A07/03C cells, oestradiol pre-treatment prevented IL-1β-induced proliferation and apoptosis, and reduced cytokine production. Conversely, in male HIP-009 cells, oestradiol pre-treatment did not prevent IL-1β-induced reduction of proliferation and apoptosis and indeed enhanced inflammatory responses after 48 h. In terms of differentiation, IL-1β produced opposite effects on neurogenesis across cell lines, increasing neuronal maturation in female HPC0A07/03C cells, but decreasing neurite complexity in male HIP-009 cells. Notably, oestradiol pre-treatment in both lines reduced neuronal differentiation and increased kynurenine levels, suggesting potentially detrimental long-term effects. These results highlight complex, potentially cell-line-dependent, sex-specific hormone-immune interactions shaping fetal neurodevelopment and underscore the need to investigate these interactions when assessing risks and developing therapeutic interventions for inflammation-related neurodevelopmental disorders.