Transient developmental exposure to low doses of bisphenol F negatively affects neurogliogenesis and olfactory behaviour in adult mice

Abstract

Neural stem cells in the murine subventricular zone (SVZ) reactivate during postnatal development to generate neurons and glia throughout adulthood. We previously demonstrated that a postnatal thyroid hormone (TH) peak orchestrates this remodelling, rendering this process vulnerable to endocrine disruption. We exposed mice to 2 or 200 µg/kg bw/day of the bisphenol A-replacement and suspected TH-disruptor bisphenol F (BPF) in the drinking water, from embryonic day 15 to postnatal day 21 (P21). In parallel, one group was exposed to the TH-synthesis blocker propylthiouracil (0.15 % PTU). In contrast to PTU, BPF exposure did not affect serum TH levels at P15, P21 or P60. RNA-seq on dissected SVZs at P15 revealed dysregulated neurodevelopmental genes in all treatments, although few overlapped amongst the conditions. We then investigated the phenotype at P60 to analyse long-term consequences of transient developmental exposure. As opposed to hypothyroid conditions, and despite dysregulated oligodendrogenesis-promoting genes in the P15 SVZ exposed to the highest dose of BPF, immunostainings for myelin and OLIG2/CC1 showed no impact on global myelin content nor oligodendrocyte maturation in the P60 corpus callosum, apart from a reduced thickness. The highest dose did reduce numbers of newly generated SVZ-neuroblasts with 22 %. Related to this were behavioural alterations. P60 mice previously exposed to the highest BPF dose memorized an odour less well than control animals did, although they performed better than PTU-exposed animals. All mice could discriminate new odours, but all exposed groups showed less interest in social odours. Our data indicate that perinatal exposure to low doses of BPF disrupts postnatal murine SVZ remodelling, and lowers the adult neuron/oligodendroglia output, even after exposure had been absent for 40 days. These anomalies warrant further investigation on the potential harm of alternative bisphenol compounds for human foetal brain development.