Perinatal Exposure to Organophosphate Flame Retardants Induces Sex- and Hormone-Dependent Alterations in Anxiety,...

Developmental exposure to organophosphate flame retardants (OPFRs) is a public health concern due to their endocrine-disrupting potential. We examined perinatal exposure to tris(1,3-dichloro-2-propyl) phosphate, triphenyl phosphate, and tricresyl phosphate in mice. Adult male and female offspring were assessed for memory and anxiety-like behavior. Dopamine and norepinephrine were quantified in the hippocampus and prefrontal cortex (PFC), and bulk RNA sequencing was conducted for the hippocampus. OPFR-treated females in high ovarian hormone states spent less time in the open field test (OFT) center, the Y-maze unknown arm, and with the displaced object in spatial object recognition (SOR) indicating increased anxiety-like behavior and impaired spatial memory. These females also illustrated improved memory on the short-term Barnes maze, and a trending improvement in the novel object recognition test. Females in low ovarian hormone states, demonstrated a trend in center OFT exploration. OPFR-treated males displayed disruption in memory in the SOR and the short- and long-term Barnes maze. Perinatal OPFR reduced hippocampal dopamine in males and altered prefrontal dopamine in females in a hormone-dependent manner. OPFR-treated females in high ovarian hormones states demonstrated a trending decrease in PFC norepinephrine. Perinatal OPFR treatment caused differential gene expression in 121 individual genes and alteration to functional modules related to RNA processing, cellular metabolism, and extracellular organization. Hormone status also affected gene OPFR-induced altered expression, with similarity between males and high ovarian hormone state females. Our findings suggest that perinatal OPFR exposure causes widespread, sex specific, and hormone dependent disruptions in behavior, neurochemistry, and gene expression in adulthood.

Anxiety-like behavior in OPFR-treated females varied with ovarian hormone statusHigh ovarian hormone OPFR females showed task-dependent changes in memoryMales displayed impaired spatial memory following perinatal OPFR treatmentPerinatal OPFR modifies hippocampal and prefrontal dopamine and norepinephrineOPFR treatment altered individual gene and functional gene module expression.