Immune cell type and DNA methylation vary with reproductive status in women: possible pathways for costs of reproduction

Calen P Ryan; Meaghan J Jones; Rachel D Edgar; Nanette R Lee; Michael S Kobor; Thomas W McDade; Christopher W Kuzawa

doi:10.1093/emph/eoac003

Immune cell type and DNA methylation vary with reproductive status in women: possible pathways for costs of reproduction

Evol Med Public Health. 2022 Feb 2;10(1):47-58. doi: 10.1093/emph/eoac003. eCollection 2022.

Authors

Calen P Ryan¹, Meaghan J Jones^{2

3}, Rachel D Edgar⁴, Nanette R Lee⁵, Michael S Kobor^{6

7}, Thomas W McDade^{1

7

8}, Christopher W Kuzawa^{1

8}

Affiliations

¹ Department of Anthropology, Northwestern University, Evanston, IL 60208, USA.
² Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
³ Children's Hospital Research Institute, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
⁴ EMBL-EBI, Wellcome Genome Campus, Hinxton CB10 1SD, UK.
⁵ University of San Carlos Office of Population Studies Foundation Inc., Cebu City 6000, Philippines.
⁶ BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
⁷ Child and Brain Development Program, Canadian Institute for Advanced Research, Toronto, ON M5G 1Z8, Canada.
⁸ Institute for Policy Research, Northwestern University, Evanston, IL 60208, USA.

Abstract

Background: Consistent with evolutionarily theorized costs of reproduction (CoR), reproductive history in women is associated with life expectancy and susceptibility to certain cancers, autoimmune disorders and metabolic disease. Immunological changes originating during reproduction may help explain some of these relationships.

Methodology: To explore the potential role of the immune system in female CoR, we characterized leukocyte composition and regulatory processes using DNA methylation (DNAm) in a cross-sectional cohort of young (20-22 years old) women differing in reproductive status.

Results: Compared to nulliparity, pregnancy was characterized by differential methylation at 828 sites, 96% of which were hypomethylated and enriched for genes associated with T-cell activation, innate immunity, pre-eclampsia and neoplasia. Breastfeeding was associated with differential methylation at 1107 sites (71% hypermethylated), enriched for genes involved in metabolism, immune self-recognition and neurogenesis. There were no significant differences in DNAm between nulliparous and parous women. However, compared to nullipara, pregnant women had lower proportions of B, CD4T, CD8T and natural killer (NK) cells, and higher proportions of granulocytes and monocytes. Monocyte counts were lower and NK counts higher among breastfeeding women, and remained so among parous women.

Implications: Our findings point to widespread differences in DNAm during pregnancy and lactation. These effects appear largely transient, but may accumulate with gravidity become detectable as women age. Nulliparous and parous women differed in leukocyte composition, consistent with more persistent effects of reproduction on cell type. These findings support transient (leukocyte DNAm) and persistent (cell composition) changes associated with reproduction in women, illuminating potential pathways contributing to CoR. Lay Summary: Evolutionary theory and epidemiology support costs of reproduction (CoR) to women's health that may involve changes in immune function. We report differences in immune cell composition and gene regulation during pregnancy and breastfeeding. While many of these differences appear transient, immune cell composition may remain, suggesting mechanisms for female CoR.

Keywords: breastfeeding; epigenome; evolution; immunomethylomics; pregnancy.

Grants and funding

R01 HL085144/HL/NHLBI NIH HHS/United States