# The impact of sex and gender on disease progression, from developmental origins

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2021 · $570,717

## Abstract

Abstract
The maternal fetal interface is hormonal and immunologically rich environment that is important for normal
placentation during the first trimester of pregnancy. This is also where adult diseases have developmental
origins. Both the hormonal and immunologic milieus at this stage of gestation are already sexually dimorphic.
We identified sexually dimorphic gene expression globally and among individual cell types of the first trimester
placenta impacted by signaling at the maternal fetal interface, which includes members of the TGF-β superfamily,
specifically TGFβ-1 and BMPs in males. Among individual cell types, ligands from the CCL family were most
highly representative in females whereas IL1RN and MMP9 were highly expressed in males, with their
corresponding receptors present on the maternal surface. Dihydrotestosterone, which is only produced by the
male fetus, in addition to TGFβ1 and estradiol were identified as significant upstream regulators in individual cell
types of the first trimester placenta. However, the hormonal environment may not be the only biologically sex
different factor influencing the immune system, as we have also identified key transcription regulators in early
gestation that may account for developmental origins of immune disease.
Throughout the lifespan, hormones have been implicated to play a significant role in immune dysfunction and
development of disease, as overall there is a higher prevalence of autoimmune diseases in females, such as
systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. Yet men are more likely to develop
ankylosing spondylitis. Furthermore, males have increased prevalence of asthma compared to females in
childhood, but the sexually dimorphic prevalence changes post-puberty, suggesting testosterone may be
protective. There are also potential gender differences that influence the immune system. However, post
puberty, hormonal regulation becomes sexually dimorphic again and it becomes difficult to separate the
influence of hormones which is a function of biologic sex on the immune system from the influence of gender
which is due to external influences.
Therefore, in order to better understand the influence of biological sex during developmental origins of
immune function, including the effect of the hormonal milieu, we intend to identify sex specific transcriptional
regulatory signatures in the first trimester placenta. Furthermore, since sex hormones ar e not dimorphic in
early childhood, prior to puberty, we intend to better understand the influence of gender on developmental
differences of the immune system, prior to hormonal influences, to identify the critical drivers of sexual
dimorphism in immune function. Our goal is to identify sex unique regulators of immune dysfunction that can
ultimately be used as a more personalized approach to treating immunologic diseases.

## Key facts

- **NIH application ID:** 10260551
- **Project number:** 5R01AI154535-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Margareta Pisarska
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $570,717
- **Award type:** 5
- **Project period:** 2020-09-10 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260551

## Citation

> US National Institutes of Health, RePORTER application 10260551, The impact of sex and gender on disease progression, from developmental origins (5R01AI154535-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10260551. Licensed CC0.

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