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Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation.

ABSTRACT: Sex disparities in cardiac homeostasis and heart disease are well documented, with differences attributed to actions of sex hormones. However, studies have indicated sex chromosomes act outside of the gonads to function without mediation by gonadal hormones. Here, we performed transcriptional and proteomics profiling to define differences between male and female mouse hearts. We demonstrate, contrary to current dogma, cardiac sex disparities are controlled not only by sex hormones but also through a sex-chromosome mechanism. Using Turner syndrome (XO) and Klinefelter (XXY) models, we find the sex-chromosome pathway is established by X-linked gene dosage. We demonstrate cardiac sex disparities occur at the earliest stages of heart formation, a period before gonad formation. Using these datasets, we identify and define a role for alpha-1B-glycoprotein (A1BG), showing loss of A1BG leads to cardiac defects in females, but not males. These studies provide resources for studying sex-biased cardiac disease states.

SUBMITTER: Shi W

PROVIDER: S-EPMC9290207 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation.

Shi Wei W Shi Wei W Sheng Xinlei X Dorr Kerry M KM Hutton Josiah E JE Emerson James I JI Davies Haley A HA Andrade Tia D TD Wasson Lauren K LK Greco Todd M TM Hashimoto Yutaka Y Federspiel Joel D JD Robbe Zachary L ZL Chen Xuqi X Arnold Arthur P AP Cristea Ileana M IM Conlon Frank L FL

Developmental cell 20211015 21

Sex disparities in cardiac homeostasis and heart disease are well documented, with differences attributed to actions of sex hormones. However, studies have indicated sex chromosomes act outside of the gonads to function without mediation by gonadal hormones. Here, we performed transcriptional and proteomics profiling to define differences between male and female mouse hearts. We demonstrate, contrary to current dogma, cardiac sex disparities are controlled not only by sex hormones but also throu ...[more]

PMID: 34655525

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Project description:BackgroundFor more than 150 years, research studies have documented greater variability across males than across females ("greater male variability"-GMV) over a broad range of behavioral and morphological measures. In placental mammals, an ancient difference between males and females that may make an important contribution to GMV is the different pattern of activation of X chromosomes across cells in females (mosaic inactivation of one the two X chromosomes across cells) vs males (consistent activation of a single X chromosome in all cells). In the current study, variability in hearing thresholds was examined for human listeners with thresholds within the normal range. Initial analyses compared variability in thresholds across males vs. across females. If greater across-male than across-female variability was present, and if these differences in variability related to the different patterns X-chromosome activation in males vs. females, it was expected that correlations between related measures within a given subject (e.g., hearing thresholds at given frequency in the two ears) would be greater in males than females.MethodsHearing thresholds at audiometric test frequencies (500-6000 or 500-8000 Hz) were extracted from two datasets representing more than 8500 listeners with normal hearing (4590 males, 4376 females). Separate data analyses were carried out on each dataset to compare: (1) relative variability in hearing thresholds across males vs. across females at each test frequency; (2) correlations between both across-ear and within-ear hearing thresholds within males vs. within females, and (3) mean thresholds for females vs. males at each frequency.ResultsA consistent pattern of GMV in hearing thresholds was seen across frequencies in both datasets. In addition, both across-ear and within-ear correlations between thresholds were consistently greater in males than females. Previous studies have frequently reported lower mean thresholds for females than males for listeners with normal hearing. One of the datasets replicated this result, showing a clear and consistent pattern of lower mean thresholds for females. The second data set did not show clear evidence of this female advantage.ConclusionsHearing thresholds showed clear evidence of greater variability across males than across females and higher correlations across related threshold measures within males than within females. The results support a link between the observed GMV and the mosaic pattern of X-activation for females that is not present in males.

Project description:Background and objectiveThe role of biological sex is seldom considered in characterizing lung cancer, the deadliest cancer in both the United States and the world. Lung cancer has traditionally been regarded as a male disease; as such, research in female-specific phenomena is frequently conflicting or absent. Currently, disparities in lung cancer incidence are primarily driven by females, especially non-smokers and those of younger age. This narrative review provides insight into sex-specific characteristics of lung cancer, highlighting risk factors, diagnosis patterns, carcinogenesis, and treatment outcomes in females.MethodsThe PubMed database was searched on July 26, 2023 to identify research published between 2013 and 2023 in English. Sixty-three articles were considered relevant, and their full texts and citations were studied to compile information for this narrative review.Key content and findingsExposure-related risk factors, including personal tobacco use, are thought to impact female lung cancer risk more profoundly. However, studies on occupational exposures are underpowered to conclude risk in females. Data characterizing the effect of endogenous and exogenous hormonal exposures on female lung cancer risk remain two-sided. Screening guidelines are tailored to white males, exacerbating sex and race disparities. The effect of biological sex on carcinogenesis and the immune system response to cancer is not fully understood, though the female immune system clearly reacts more aggressively to lung cancer. In early-stage disease, females have greater survival in the perioperative setting and during follow-up of several years, attributed to favorable histopathology and healthier baseline status. Sex-specific response to systemic treatment continues to be optimized as lack of standardization in randomized trials makes interpreting results difficult when aggregated.ConclusionsBiological sex plays a critical role in non-small cell lung cancer (NSCLC), though further study is needed to depict the complex web of factors that affect lung cancer risk, development, and outcomes. Female underrepresentation in studies has contributed to this lack of understanding. As these disparities are eliminated, we can move towards more effective treatment for both sexes in this pervasive yet deadly disease.

Dataset Information

Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation.

Publications

Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation.

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