Early maternal separation accelerates the progression of endometriosis in adult mice

Qiqi Long, Xishi Liu, Sun‐Wei Guo
Reproductive biology and endocrinology : RB&E · 2020 · vol. 18(1) , pp. 63 · doi:10.1186/s12958-020-00600-4 · PMID:32532293 · PMC7291455 · W3034784148
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

Early maternal separation in mice accelerated endometriosis progression by decreasing dopamine receptor D2 expression and activating adrenergic receptor β2 signaling, leading to increased angiogenesis.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

This study tested whether early-life adversity modeled as neonatal maternal separation in female Balb/C mice accelerates endometriosis progression in adulthood, using groups separated from dams for 3 h/day (PND 1–21) versus non-separated controls and assessing anxiety/depression-like behaviors and pain-related behavior before and after induction of endometriosis by intraperitoneal injection of uterine fragments. In adulthood, maternal separation increased anxiety/depression-like behaviors and produced a more severe endometriosis phenotype, with lesion weight more than doubling and generalized hyperalgesia increasing relative to controls. Mechanistically, immunohistochemistry indicated reduced dopamine receptor D2 (DRD2) expression and activation of ADRB2/cAMP-response element binding protein (CREB) signaling, with increased angiogenesis and lesion progression. A key limitation is the small number of animals per behavioral and endometriosis groups (3 per behavioral subgroup and 8 per endometriosis subgroup), which may constrain robustness of behavioral and mechanistic conclusions. This paper is centrally about endometriosis — it directly shows neonatal maternal separation accelerates endometriosis progression in adult mice via ADRB2/CREB-associated angiogenesis.

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Abstract

BACKGROUND: A large body of research highlights the importance of early-life environmental impact on the health outcome in adulthood. However, whether early-life adversity (ELA) has any impact on the development of endometriosis is completely unclear. In this study, we tested the hypothesis that ELA, as manifested by neonatal separation, can accelerate the progression of endometriosis in mouse through activation of the adrenergic receptor β2 (ADRB2) signaling pathway, leading to increased angiogenesis and progression of endometriotic lesions. METHODS: Eight female Balb/C mice, in late pregnancy, were used used for this study, which later gave birth to 22 female newborn pubs. Eleven additional female Balb/C mice were also used as donors of uterine tissues. The 22 newborn pubs were randomly divided into 2 equal-sized groups, maternal separation (MS) and no separation (NS). Pubs in the MS group were separated from their dams for 3 h/day from postnatal day (PND) 1 to 21, while those in the NS control remained in the home cage with their dams. In adulthood (8-week old), 3 mice in each group were randomly selected to undergo a battery of behavior tests. The remaining 8 mice in each group were induced with endometriosis by intraperitoneal injection of uterine fragments from donor mice. Four weeks after the induction, all mice were sacrificed and their endometriotic lesions were excised for quantification and then prepared for immunohistochemistry analysis. RESULTS: We confirmed that MS during infancy resulted in anxiety and depression-like behaviors as previously reported. We also found that in MS mice the lesion weight was increased by over 2 folds and generalized hyperalgesia was also significantly increased as compared with NS mice. Immunostaining analysis demonstrated that MS accelerated the development of endometriosis likely through decreased dopamine receptor D2 (DRD2) expression and activation of the ADRB2/cAMP-response element binding protein (CREB) signaling pathway, leading to increased angiogenesis and progression of endometriotic lesions. CONCLUSIONS: Exposure of female mouse pups to ELA such as MS during their infancy period accelerates the progression of endometriosis, possibly through altered neuronal wiring and hyperactivity of the hypothalamic-pituitary-adrenal axis.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Hyperalgesia Hyperalgesia Hyperalgesia Hyperalgesia Maternal Deprivation Peritoneal Diseases Peritoneal Diseases Peritoneal Diseases Peritoneal Diseases Peritoneal Diseases Receptors, Adrenergic, beta-2 Receptors, Adrenergic, beta-2 Animals Animals, Newborn Anxiety

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