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Endocrinology2026; 167(9); bqag083; doi: 10.1210/endocr/bqag083

Compartmentalization of DHCR7 links 7-DHC metabolism to B-ring unsaturated steroid synthesis in the equine fetal gonad.

Abstract: The endocrinology of equine pregnancy is unique, but many of its unusual phenomena closely resemble pregnancy in women. Placental estrone synthesis uses fetal adrenal androgen precursors in women, but from the fetal gonads in mares, peaking midway through the 11-month gestation. Unique to equine pregnancies, other estrogens like equilin, typified by an unsaturated B-ring sterol structure, are synthesized from 7-dehydrocholesterol (7-DHC), the immediate precursor to cholesterol, without cholesterol formation, peaking later in gestation. Currently, the spatial and temporal regulation underlying the redirection of 7-DHC from cholesterol to B-ring unsaturated steroid synthesis in equine fetal gonads remains unknown. Here, we investigate the developmental dynamics of the equine fetal gonads from the fourth to eleventh gestational month using RNA sequencing, immunofluorescence imaging, RNAScope, and gas chromatography-mass spectrometry. Our results suggest that placental estrone synthesis correlates with the expression of the last enzyme in the cholesterol synthesis pathway, 7-dehydrocholesterol reductase (DHCR7) in the fetal gonad, and its downregulation may drive the accumulation of 7-DHC and the synthesis of B-ring unsaturated steroids. B-ring unsaturated steroid secretion is the hallmark of Smith-Lemli-Opitz Syndrome in humans, resulting from mutations in the gene encoding DHCR7 in affected patients. This naturally occurring phenomenon in equine pregnancies may offer a unique comparative model for understanding the metabolic consequences of 7-DHC accumulation in these patients and a platform for drug development.
© The Author(s) 2026. Published by Oxford University Press on behalf of the Endocrine Society.
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Publication Date: 2026-07-25 PubMed ID: 42500910PubMed Central: PMC13429798DOI: 10.1210/endocr/bqag083Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This study investigates how the enzyme DHCR7 in equine fetal gonads regulates the metabolism of 7-dehydrocholesterol (7-DHC) and links it to the production of unique B-ring unsaturated steroids during horse pregnancy.
  • The findings provide insights into the distinct steroid synthesis pathways in horses and offer a potential animal model for understanding related human disorders caused by DHCR7 mutations.

Background and Significance

  • Unique Equine Pregnancy Endocrinology: Horse pregnancy features distinctive hormonal regulation that resembles aspects of human pregnancy but with unique differences.
  • Steroid Production Differences: In human pregnancy, placental estrone is synthesized using androgen precursors from the fetal adrenal glands, but in horses, these precursors come from the fetal gonads.
  • B-ring Unsaturated Steroids: Horses produce special estrogens such as equilin, characterized by an unsaturated B-ring in their steroid structure, derived from 7-DHC rather than cholesterol, which peaks later in gestation.
  • Clinical Relevance: In humans, mutations in the DHCR7 gene lead to Smith-Lemli-Opitz Syndrome (SLOS), characterized by abnormal B-ring unsaturated steroid secretion due to accumulation of 7-DHC.

Research Focus

  • The study aims to understand how 7-DHC is redirected from cholesterol synthesis to B-ring unsaturated steroid synthesis specifically in equine fetal gonads during gestation.
  • It explores the spatial (where in the gonad) and temporal (when during gestation) regulation of the enzyme DHCR7, which converts 7-DHC to cholesterol.
  • This helps explain how horses naturally produce B-ring unsaturated steroids, differing from standard cholesterol metabolism.

Methodologies

  • Sample Period: Analysis was conducted on equine fetal gonads from the fourth to the eleventh month of gestation to track developmental changes.
  • Techniques Used:
    • RNA sequencing to measure gene expression changes throughout development.
    • Immunofluorescence imaging and RNAScope to localize and quantify DHCR7 enzyme presence and mRNA expression in the fetal gonad tissues.
    • Gas chromatography-mass spectrometry (GC-MS) to measure steroid profiles, including levels of 7-DHC and derived B-ring unsaturated steroids.

Key Findings

  • DHCR7 Expression Correlates with Estrone Synthesis: Expression of DHCR7, the enzyme that converts 7-DHC to cholesterol, was found to be high when placental estrone synthesis peaked.
  • Downregulation of DHCR7 Leads to 7-DHC Accumulation: Later in gestation, DHCR7 expression decreases in the fetal gonads, resulting in accumulation of 7-DHC.
  • Redirection to B-ring Unsaturated Steroid Synthesis: The buildup of 7-DHC enables the fetal gonads to synthesize equilin and other B-ring unsaturated steroids without going through cholesterol formation.
  • Compartmentalization within the Gonad: The data suggest that localization of DHCR7 activity within specific gonadal regions is important for directing metabolic pathways either toward cholesterol or B-ring unsaturated steroid production.

Implications and Future Directions

  • Comparative Model for Human Disease: This natural horse model mimics some biochemical features of Smith-Lemli-Opitz Syndrome (SLOS), offering insights into the metabolic consequences of 7-DHC accumulation seen in human patients with DHCR7 mutations.
  • Drug Development Platform: Since horses naturally produce these B-ring unsaturated steroids, they could serve as a useful model for testing therapies aimed at modulating steroidogenesis or managing SLOS.
  • Broader Endocrinology Insights: Understanding this unique steroidogenic pathway expands our knowledge of species differences in reproductive endocrinology and cholesterol precursor metabolism.

Cite This Article

APA
Malin K, Conley AJ, Verstraete M, Norris J, Hsu YC, Holl W, van Heule M, Vieira F, Scoggin KE, Ball B, Takahashi K, de la Fuente A, Newman JW, Carossino M, Dini P. (2026). Compartmentalization of DHCR7 links 7-DHC metabolism to B-ring unsaturated steroid synthesis in the equine fetal gonad. Endocrinology, 167(9), bqag083. https://doi.org/10.1210/endocr/bqag083

Publication

Endocrinology
ISSN: 1945-7170
NlmUniqueID: 0375040
Country: United States
Language: English
Volume: 167
Issue: 9
PII: bqag083

Researcher Affiliations

Malin, Katarzyna
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Conley, Alan J
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Verstraete, Margo
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
  • Department of Morphology, Imaging, Orthopedics, Rehabilitation and Nutrition, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
Norris, Jamie
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Hsu, Ya-Chen
  • West Coast Metabolomics Center, Genome Center, University of California, Davis, CA 95616, USA.
Holl, William
  • Department of Pathobiological Sciences and Louisiana Animal Disease Diagnostic Laboratory, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
van Heule, Machteld
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
  • Department of Morphology, Imaging, Orthopedics, Rehabilitation and Nutrition, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
Vieira, Flávia
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Scoggin, Kirsten E
  • Department of Veterinary Science, Gluck Equine Research Center, University of Kentucky, Lexington, KY 40546, USA.
Ball, Barry
  • Department of Veterinary Science, Gluck Equine Research Center, University of Kentucky, Lexington, KY 40546, USA.
Takahashi, Kazuki
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
de la Fuente, Alejandro
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Newman, John W
  • West Coast Metabolomics Center, Genome Center, University of California, Davis, CA 95616, USA.
  • Department of Nutrition, University of California Davis, Davis, CA 95616, USA.
  • Obesity and Metabolism Research Unit, USDA Western Human Research Center, Davis, CA 95616, USA.
Carossino, Mariano
  • Department of Pathobiological Sciences and Louisiana Animal Disease Diagnostic Laboratory, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
Dini, Pouya
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.

MeSH Terms

  • Animals
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • Oxidoreductases Acting on CH-CH Group Donors / genetics
  • Dehydrocholesterols / metabolism
  • Female
  • Horses
  • Pregnancy
  • Placenta / metabolism
  • Male
  • Gonads / metabolism
  • Gonads / embryology
  • Cholesterol / metabolism
  • Fetus / metabolism
  • Steroids / biosynthesis

Grant Funding

  • T32OD011147 / National Institute of Health
  • T32 OD011147 / NIH HHS
  • John P. Hughes Endowment at the University of California, Davis
  • 2032-10700-003-000-D / Kenneth Burns Endowed Chair in Veterinary Medicine at the Louisiana State University School of Veterinary Medicine
  • State of California

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