Maternal Anti-Mullerian Hormone Excess and Its Effects on Offspring Brain Development in the Preeclamptic-Like BPH/5 Mouse

Preeclampsia, a hypertensive disorder of pregnancy, is a leading cause of maternal and fetal morbidity and mortality worldwide. Beyond the peripartum, preeclampsia is associated with lifelong adverse offspring outcomes, including neurodevelopmental, metabolic, and reproductive disorders. However, the underlying mechanisms remain poorly understood. Abnormal pubertal development in children born from preeclamptic mothers may arise from prenatal exposure to a dysregulated maternal endocrine milieu. Elevated serum levels of anti-mullerian hormone (AMH) have been reported in preeclamptic women and may disrupt offspring hypothalamic development and reproductive outcomes. Downstream to AMH, dysregulated SMAD signaling in the brain is also associated with abnormal offspring pubertal onset and reproductive disorders. We have previously described abnormal pubertal development and irregular estrous cyclicity in offspring from the Blood Pressure High Subline 5 (BPH/5) mouse, a spontaneous model of superimposed preeclampsia. Herein, our primary objective is to investigate circulating AMH concentration in the preeclamptic-like BPH/5 dams during late gestation and the potential influence on BPH/5 fetal brain AMH/SMAD signaling. We hypothesized that serum AMH levels would be greater in BPH/5 dams at embryonic day (e)18.5 than the Blood Pressure Normal Subline 3 (BPN/3) dams. Additionally, we hypothesized that expression of the AMH receptor ( Amhr2 ) and downstream SMAD signaling proteins ( Smad1, Smad3, and Smad8 ) would be dysregulated in BPH/5 e18.5 fetal brain. To test these hypotheses, BPH/5 and BPN/3 mice were intra-strain time mated. Serum samples (n=4-6/group) were collected at e18.5 and AMH ELISA was performed at University of Virginia Ligand Core (AL-113; ANSH Labs). BPH/5 and BPN/3 offspring brains (n=12-26/group) were harvested at e18.5 for qRT-PCR analysis. To further characterize BPH/5 peripubertal phenotype, body weights and anogenital distances were assessed in a second cohort of BPH/5 and BPN/3 males and females at postnatal day (PD) 21. Inter-strain comparisons were conducted using Student’s t-tests (GraphPad Prism 10.3.1). Serum AMH concentration was 3-fold higher in BPH/5 dams at e18.5 compared to BPN/3 dams (P < 0.0001 ). Interestingly, Amhr2 was lower (P < 0.01) in BPH/5 vs. BPN/3 e18.5 fetal brains. Downstream, Smad3 was also downregulated in BPH/5 e18.5 fetal brains (P < 0.05), while Smad1 and Smad8 did not differ between strains (P > 0.05). At PD21, BPH/5 male and female offspring had lower body weight than sex-matched BPN/3 controls (P < 0.05). While female AGD was similar between strains, it was longer in BPH/5 males compared to BPN/3 (P < 0.05). In conclusion, BPH/5 dams recapitulate high circulating AMH levels reported in a subset of preeclamptic women during late gestation. Notably, this was associated with fetal brain Amhr2 and Smad3 downregulation. It remains to be further explored whether altered AMH/SMAD3 signaling in offspring from preeclamptic pregnancies is associated with the BPH/5 peripubertal phenotype. This study provides novel insights into the molecular mechanisms that may lead to abnormal reproductive development in children born after preeclampsia. Michigan State University Discretionary Funding Initiative This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.