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Background <p>Controlled ovarian stimulation (COS) induces supraphysiologic levels of estrogen (E<sub>2</sub>), which have been associated with low birth weight and placental abnormalities in infants conceived through assisted reproductive technologies (ART). Uterine natural killer (uNK) cells play a crucial role in regulating placentation. Elevated E<sub>2</sub> has been shown to disrupt both the abundance and function of uNK cells. However, the molecular mechanisms underlying these effects remain incompletely understood.</p> Methods <p>We established mouse models for supraphysiological E<sub>2</sub> exposure and pyrrolidine dithiocarbamate (PDTC) treatment. Placental and fetal development were evaluated through histological observation and analysis. The abundance, subtype distribution and cytokine secretion profiles of uNK cells were assessed using flow cytometry and Luminex assays. In vitro co-culture systems were employed to investigate the regulatory effect of decidual stromal cells (DSCs) on uNK cells. Additionally, we examined the roles of decidualization, NF-κB signaling, BMP2, and CXCL8 through pharmacological interventions and targeted inhibition.</p> Results <p>COS-induced elevated E<sub>2</sub> significantly altered the abundance, subsets and cytokine secretion profiles of uNK cells, leading to reduced fetal weight and placental deficiencies in mice. Notably, supraphysiological E<sub>2</sub> did not directly affect uNK cells but rather influenced them via DSC-dependent paracrine signaling mechanisms. High levels of E<sub>2</sub> inhibited NF-κB pathway activity in DSCs, resulting in impaired decidualization as well as altered cytokine secretion profiles; among these alterations was a confirmed modulation by CXCL8 on the migration of uNK cells. Mechanistically, NF-κB P65 directly binds to the promoter region of BMP2 to regulate decidualization while also modulating CXCL8 secretion by binding to its promoter region.</p> Conclusion <p>Our findings indicate that the low birth weight associated with COS may be attributed to elevated estrogen levels, which can adversely affect the differentiation and function of uNK cells. This disruption may lead to abnormal placental morphology and functionality. These findings may contribute to the prevention and intervention of adverse pregnancy outcomes related to COS.</p>

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Inhibition of p65 nuclear translocation in decidual stromal cells underlies COS-induced supraphysiologic estrogen impairment of uNK cell function which drives placental abnormalities

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Haikun Yu,
  • Hui Mu,
  • Yujing Xiong,
  • Jiaqin Mao,
  • Hui Lei,
  • Xueyan Lu,
  • Jie Dong,
  • Ni Jin,
  • Jie Lu,
  • Shuqiang Chen,
  • Xiaohong Wang

摘要

Background

Controlled ovarian stimulation (COS) induces supraphysiologic levels of estrogen (E2), which have been associated with low birth weight and placental abnormalities in infants conceived through assisted reproductive technologies (ART). Uterine natural killer (uNK) cells play a crucial role in regulating placentation. Elevated E2 has been shown to disrupt both the abundance and function of uNK cells. However, the molecular mechanisms underlying these effects remain incompletely understood.

Methods

We established mouse models for supraphysiological E2 exposure and pyrrolidine dithiocarbamate (PDTC) treatment. Placental and fetal development were evaluated through histological observation and analysis. The abundance, subtype distribution and cytokine secretion profiles of uNK cells were assessed using flow cytometry and Luminex assays. In vitro co-culture systems were employed to investigate the regulatory effect of decidual stromal cells (DSCs) on uNK cells. Additionally, we examined the roles of decidualization, NF-κB signaling, BMP2, and CXCL8 through pharmacological interventions and targeted inhibition.

Results

COS-induced elevated E2 significantly altered the abundance, subsets and cytokine secretion profiles of uNK cells, leading to reduced fetal weight and placental deficiencies in mice. Notably, supraphysiological E2 did not directly affect uNK cells but rather influenced them via DSC-dependent paracrine signaling mechanisms. High levels of E2 inhibited NF-κB pathway activity in DSCs, resulting in impaired decidualization as well as altered cytokine secretion profiles; among these alterations was a confirmed modulation by CXCL8 on the migration of uNK cells. Mechanistically, NF-κB P65 directly binds to the promoter region of BMP2 to regulate decidualization while also modulating CXCL8 secretion by binding to its promoter region.

Conclusion

Our findings indicate that the low birth weight associated with COS may be attributed to elevated estrogen levels, which can adversely affect the differentiation and function of uNK cells. This disruption may lead to abnormal placental morphology and functionality. These findings may contribute to the prevention and intervention of adverse pregnancy outcomes related to COS.