Moran, K. M. | bioRxiv Science

bioRxiv2026

Perinatal Exposure to Organophosphate Flame Retardants Induces Sex- and Hormone-Dependent Alterations in Anxiety, Memory, Neurotransmitter Content, and Hippocampal Gene Expression

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. HighlightsO_LIAnxiety-like behavior in OPFR-treated females varied with ovarian hormone status C_LIO_LIHigh ovarian hormone OPFR females showed task-dependent changes in memory C_LIO_LIMales displayed impaired spatial memory following perinatal OPFR treatment C_LIO_LIPerinatal OPFR modifies hippocampal and prefrontal dopamine and norepinephrine C_LIO_LIOPFR treatment altered individual gene and functional gene module expression C_LI

pharmacology and toxicology↗

bioRxiv2025

Chronic social instability stress differentially affects the behavior and the transcriptome of the anterodorsal bed nucleus of the stria terminalis between male and female mice

Abstract Stress is comprised of systemic/physiological and processive/social factors, with social stressors requiring higher limbic processing. Sex is an important aspect of stress research as men and women show differing responses to stress and mood disorder development. We investigated how social stress affects the bed nucleus of the stria terminalis (BNST) and how sex may contribute. We used a chronic social instability stress (CSIS) paradigm to stress male and female mice for approximately 7 weeks. Afterwards, one cohort was used for avoidance behavior testing using the open field test, the elevated plus maze, the light/dark box emergence test, and the novelty suppressed feeding test. A second cohort was used for bulk RNA-sequencing of the anterodorsal (ad)BNST. A third cohort of CRH Cre+/Ai14 reporter mice were used for patch clamp electrophysiology in the adBNST. CSIS caused the females to be less avoidant, while the males became more avoidant. Low estrogen state in the females caused them to be less avoidant than in a high estrogen state. In the adBNST, we found major transcriptomic differences between the males and females. Males increased expression in more genes related to the RNA and protein processing whereas the females upregulated genes related to synaptic transmission. The transcriptome in the males is more sensitive to the stress than the females. Finally, CSIS caused adBNST CRH neurons to be hyperpolarized and have lower input resistance in males. In summary, social stress is differentially regulated between males and females, which may relate to the development of stress-related behavioral changes.

neuroscience↗