Sex-specific neurotoxicity and transgenerational effects of an emerging pollutant, tris(1,3-dichloro-2-propyl)phosphate (TDCIPP)

The growing production and usage of flame retardants (FRs) results in their extensive environmental distribution, potentially posing a threat on both ecological and human health. Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP), a commonly used FR, is commonly found in aquatic ecosystems, and aquatic organisms, including fish, may be exposed to TDCIPP during specific stages of their life cycles, or across generations. Here, we aim to identify and compare the neurotoxic effects of TDCIPP on the brains of female and male adult marine medaka (Oryzias melastigma) across three generations (F0 to F3). Sex-specific effects of TDCIPP related to synaptic transmission signaling pathways and regulation of neuronal synaptic plasticity underlying 1917 differentially expressed genes (DEGs) were evident in the brain transcriptomes of F0 females, while only five DEGs were found in F0 males. However, chronic exposure over three generations (F0 to F3) revealed neurotoxic effects of TDCIPP on both sexes with males altering their innate immune response and visual perception upon prolonged exposure. Lastly, female medaka exhibited signals of transgenerational effects at the F3, as shown by increased transcriptional adjustments of 2347 DEGs including epigenetic regulatory genes. This outcome resulted from the ancestral exposure to TDCIPP only in F0, without any direct TDCIPP exposure in F1 and F2. Our findings show that even brief exposure to TDCIPP result in long-lasting effects, posing a significant risk to marine organisms and potentially other vertebrates.