Sexual dimorphism in adult zebrafish marrows regulates blood cell composition and immune response

Hematopoiesis sustains lifelong blood production and immunity and is strongly influenced by biological sex. Males and females differ in their hematopoietic composition and susceptibility to infection and hematologic disease. Because current models cannot readily disentangle the independent contributions of sex chromosomes versus hormones, the mechanisms underlying sexual dimorphism remain poorly understood. Zebrafish have proven to be a powerful, translatable system for studying hematopoiesis, and offer a unique opportunity to isolate hormonal contributions due to their absence of sex chromosomes. However, whether sex is regulated in the zebrafish hematopoietic system remained unknown. Here, we discovered pronounced sexual dimorphism in the adult zebrafish marrow, with compositional differences peaking at reproductive age. Transcriptome analysis of marrows revealed conservation of sex-specific programs between zebrafish and human datasets. Upon immune challenge with lipopolysaccharide, all major blood lineages exhibited sex-biased changes in their composition and transcriptomes with the largest responses in erythroid and myeloid cell types. Among these sex differences was an unexpected immunoregulation of the erythroid lineage across maturation states. These findings establish biological sex as a major regulator of zebrafish hematopoiesis and immunity, paralleling humans, and lay the groundwork necessary for future mechanistic studies on sexual dimorphism in hematologic health and disease.