Altered proteome, astrocyte activation and reduced structural plasticity and progesterone sensitivity in the ventromedial hypothalamus were associated with disrupted sexual behavior in adult female mice exposed to environmentally relevant doses of phthalates
Abstract
We have previously shown that chronic exposure of adult female mice to environmentally relevant doses of di(2-ethylhexyl) phthalate (DEHP) alone or in a phthalate mixture reduced sexual behavior. The present study was conducted to determine the associated molecular and cellular modifications occurring in the ventromedial hypothalamus (VMH), the brain area controlling this behavior. Adult C57BL/6J female mice were fed with chow diet containing the vehicle, DEHP alone at 5 (DEHP-5) or 50 µg/kg/d (DEHP-50), or DEHP-5 in a phthalate mixture. Proteomic analysis of the VMH identified 532 differentially expressed proteins between the vehicle and the two DEHP doses; differences were also seen between DEHP-5 and DEHP-50. Gene ontology enrichment analysis identified biological processes related to several cellular functions including metabolism, immune response, glutamatergic neurotransmission and gene transcription related to sex steroids. Immunohistochemical analyses indicated astrocyte activation along with elevated immunoreactivity of proinflammatory inducible nitric oxide synthase, and reduced laminin-immunoreactivity in the VMH of females exposed to DEHP alone or in a phthalate mixture. The number and phenotype of microglia were not affected. Additional analyses showed reduced dendritic spine density and expression levels of postsynaptic markers, as well as down-regulation of the progesterone receptor and up-regulation of aryl hydrocarbon receptor in the VMH. These data strongly suggest that exposure to environmentally relevant doses of DEHP alone or in a phthalate mixture impaired the proteome of the VMH, leading to cellular alterations including reduced sensitivity to progesterone, diminished structural neuroplasticity and increased neuroinflammation, all possibly underlying impaired behavioral processing in female mice.
Related
- Activation of the endocytosis pathway stratifies subtypes and therapeutic sensitivity in colorectal cancer
- Emotion knowledge is structured in a grid-like coordinate system in the human ventromedial prefrontal cortex
- Mu-opioid receptor-positive neurons in rostral ventromedial medulla drive pain sensitization after traumatic brain injury in both male and female mice
- Progesterone receptor modulators for endometriosis
- Screening strategy versus drug efficacy: Revisiting the evidence for vaginal progesterone in short cervix
BibTeX
@article{adam2026altered,
title = {{Altered proteome, astrocyte activation and reduced structural plasticity and progesterone sensitivity in the ventromedial hypothalamus were associated with disrupted sexual behavior in adult female mice exposed to environmentally relevant doses of phthalates}},
author = {Nolwenn Adam and Manon Letard and Valérie Grange-Messent and Elodie Desroziers and Sakina Mhaouty-Kodja},
journal = {Journal of Hazardous Materials},
year = {2026},
month = oct,
doi = {10.1016/j.jhazmat.2026.142582},
url = {https://hal.science/hal-05784410v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Altered proteome, astrocyte activation and reduced structural plasticity and progesterone sensitivity in the ventromedial hypothalamus were associated with disrupted sexual behavior in adult female mice exposed to environmentally relevant doses of phthalates
AU - Nolwenn Adam
AU - Manon Letard
AU - Valérie Grange-Messent
AU - Elodie Desroziers
AU - Sakina Mhaouty-Kodja
PY - 2026
DA - 2026/10/07
JO - Journal of Hazardous Materials
DO - 10.1016/j.jhazmat.2026.142582
UR - https://hal.science/hal-05784410v1
AB - We have previously shown that chronic exposure of adult female mice to environmentally relevant doses of di(2-ethylhexyl) phthalate (DEHP) alone or in a phthalate mixture reduced sexual behavior. The present study was conducted to determine the associated molecular and cellular modifications occurring in the ventromedial hypothalamus (VMH), the brain area controlling this behavior. Adult C57BL/6J female mice were fed with chow diet containing the vehicle, DEHP alone at 5 (DEHP-5) or 50 µg/kg/d (DEHP-50), or DEHP-5 in a phthalate mixture. Proteomic analysis of the VMH identified 532 differentially expressed proteins between the vehicle and the two DEHP doses; differences were also seen between DEHP-5 and DEHP-50. Gene ontology enrichment analysis identified biological processes related to several cellular functions including metabolism, immune response, glutamatergic neurotransmission and gene transcription related to sex steroids. Immunohistochemical analyses indicated astrocyte activation along with elevated immunoreactivity of proinflammatory inducible nitric oxide synthase, and reduced laminin-immunoreactivity in the VMH of females exposed to DEHP alone or in a phthalate mixture. The number and phenotype of microglia were not affected. Additional analyses showed reduced dendritic spine density and expression levels of postsynaptic markers, as well as down-regulation of the progesterone receptor and up-regulation of aryl hydrocarbon receptor in the VMH. These data strongly suggest that exposure to environmentally relevant doses of DEHP alone or in a phthalate mixture impaired the proteome of the VMH, leading to cellular alterations including reduced sensitivity to progesterone, diminished structural neuroplasticity and increased neuroinflammation, all possibly underlying impaired behavioral processing in female mice.
SN - 0304-3894
SN - 1873-3336
ER -