Developmental low-dose bisphenol A exposure leads to extensive transcriptome female masculinization and male feminization later in life

Thomas Lind; Linda Dunder; Margareta H Lejonklou; P Monica Lind; Håkan Melhus; Lars Lind

doi:10.1038/s43856-025-01119-8

Developmental low-dose bisphenol A exposure leads to extensive transcriptome female masculinization and male feminization later in life

Commun Med (Lond). 2025 Oct 1;5(1):410. doi: 10.1038/s43856-025-01119-8.

Authors

Thomas Lind¹, Linda Dunder², Margareta H Lejonklou², P Monica Lind², Håkan Melhus³, Lars Lind⁴

Affiliations

¹ Department of Medical Sciences, Section of Clinical Pharmacogenomics and Osteoporosis, Uppsala University, Uppsala, Sweden. thomas.lind@medsci.uu.se.
² Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Uppsala, Sweden.
³ Department of Medical Sciences, Section of Clinical Pharmacogenomics and Osteoporosis, Uppsala University, Uppsala, Sweden.
⁴ Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.

Abstract

Background: Bisphenol A (BPA) is an endocrine disruptor, and exposure to low doses in utero has been associated with the development of metabolic diseases. Previous studies have suggested that bone marrow (BM) may be particularly susceptible to BPA exposure.

Methods: Here, we investigate how developmental exposure to low levels of BPA affects the BM transcriptome and the blood metabolic profile in Fischer 344 rats later in life. We compare these effects to those observed in human metabolic syndrome (MetS) using a population-based cohort.

Results: The results show an unexpectedly extensive sex-biased effect on the BM transcriptome from a BPA dose approximately eight times lower than the recent temporary European Food Safety Authority (EFSA) human tolerable daily intake (TDI) and a higher dose considered safe in 2015. BPA exposure induces sex-specific changes in gene expression, progressing toward a hypometabolic cancer-like state in females and a hypermetabolic autoimmunity-like state in males, with a blood metabolic profile that significantly overlaps with human MetS in a cross-sectional study.

Conclusions: We conclude that developmental low-dose BPA exposure might induce metabolic syndrome specifically in males, possibly by affecting T cell activity in a sex-specific manner. Our study provides biologically plausible and convincing evidence for significant effects from low-dose BPA exposure, supporting the substantial lowering of the human BPA TDI by EFSA based on its critical effects on T cells.

Plain language summary

Bisphenol A (BPA) is a chemical used to produce plastics, often used for storing food and beverages. Many studies have demonstrated a connection between BPA exposure and adverse health effects. Animal research indicates that low doses of BPA may have stronger impacts than higher doses. We gave pregnant rats drinking water with BPA levels similar to those considered safe for humans in 2015. We observed lasting effects in their offspring exposed to low-dose BPA. BPA caused notable female masculinization and male feminization. These sex-specific effects resembled those seen in people with metabolic syndrome, a set of health problems that raise the risk of diabetes and heart disease. Our results imply that reducing BPA use in food and beverage containers could help prevent these outcomes.

Grants and funding

216-2012-475/Svenska Forskningsrådet Formas (Swedish Research Council Formas)