Ancestral Tributyltin Exposure Produces Male-Specific Brown Adipose Thermogenic Dysregulation
- 1Department of Developmental and Cell Biology, University of California, Irvine, CA, USA, 92697-2300
- 2Krantz Family Center for Cancer Research, Massachusetts General Hospital, Bldg 149, 13th Street, Charlestown, MA, 02129, USA
- 3Department of Biomedical Engineering, University of California, Irvine, CA, USA, 92697-2300
Abstract
Obesity is a global health challenge increasingly linked to environmental obesogens. Tributyltin (TBT), a model obesogen that activates PPARγ and RXR, promotes transgenerational obesity in mice, but whether developmental and ancestral exposure impairs energy balance remains unclear. Brown adipose tissue (BAT) contributes to energy expenditure and thermoregulation through UCP1-dependent and -independent pathways. We tested whether TBT exposure disrupts BAT function in F1 and F3 descendants of exposed F0 dams.
We measured body composition before and after high-fat diet (HFD) challenge and assessed resting core body temperature, BAT gene expression, mitochondrial DNA (mtDNA) content, and mitochondrial electron transport chain (ETC) capacity. TBT-line males accumulated more fat after HFD without changes in lean mass despite similar mass-scaled food intake. Before HFD, core body temperature was lower in F1 and F3 TBT-line males, indicating impaired thermal homeostasis before increased adiposity. Candidate-gene qPCR did not show uniform suppression of thermogenic genes; instead, Ucp1 mRNA increased while Ucp2 mRNA decreased in F1 males, indicating dysregulation. Transcriptomal profiling revealed altered thermogenic signaling and consistent downregulation of mitochondrial electron transport chain genes across F1 and F3 males. Relative mtDNA content was unchanged, whereas complex-specific respirometry revealed reduced complex I- and II-associated respiratory capacity, providing evidence of impaired electron transport. No consistent effects occurred in females.
These findings identified an early, male-associated BAT phenotype characterized by thermogenic dysregulation, reduced mitochondrial ETC capacity, and impaired thermal homeostasis. They support a model in which impaired BAT mitochondrial function contributes to later susceptibility to diet-induced adiposity.
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BibTeX
@misc{huang2026ancestral,
title = {{Ancestral Tributyltin Exposure Produces Male-Specific Brown Adipose Thermogenic Dysregulation}},
author = {Yikai Huang and Richard C. Chang and Katelyn Uyen Nguyen and Kaitlin To and Myah Gibbs and Harunori Honjoh and Toshi Shioda and Bruce Blumberg},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.1101/2025.11.04.686561},
url = {https://doi.org/10.1101/2025.11.04.686561},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - Ancestral Tributyltin Exposure Produces Male-Specific Brown Adipose Thermogenic Dysregulation
AU - Yikai Huang
AU - Richard C. Chang
AU - Katelyn Uyen Nguyen
AU - Kaitlin To
AU - Myah Gibbs
AU - Harunori Honjoh
AU - Toshi Shioda
AU - Bruce Blumberg
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.1101/2025.11.04.686561
UR - https://doi.org/10.1101/2025.11.04.686561
AB - Obesity is a global health challenge increasingly linked to environmental obesogens. Tributyltin (TBT), a model obesogen that activates PPARγ and RXR, promotes transgenerational obesity in mice, but whether developmental and ancestral exposure impairs energy balance remains unclear. Brown adipose tissue (BAT) contributes to energy expenditure and thermoregulation through UCP1-dependent and -independent pathways. We tested whether TBT exposure disrupts BAT function in F1 and F3 descendants of exposed F0 dams. We measured body composition before and after high-fat diet (HFD) challenge and assessed resting core body temperature, BAT gene expression, mitochondrial DNA (mtDNA) content, and mitochondrial electron transport chain (ETC) capacity. TBT-line males accumulated more fat after HFD without changes in lean mass despite similar mass-scaled food intake. Before HFD, core body temperature was lower in F1 and F3 TBT-line males, indicating impaired thermal homeostasis before increased adiposity. Candidate-gene qPCR did not show uniform suppression of thermogenic genes; instead, Ucp1 mRNA increased while Ucp2 mRNA decreased in F1 males, indicating dysregulation. Transcriptomal profiling revealed altered thermogenic signaling and consistent downregulation of mitochondrial electron transport chain genes across F1 and F3 males. Relative mtDNA content was unchanged, whereas complex-specific respirometry revealed reduced complex I- and II-associated respiratory capacity, providing evidence of impaired electron transport. No consistent effects occurred in females. These findings identified an early, male-associated BAT phenotype characterized by thermogenic dysregulation, reduced mitochondrial ETC capacity, and impaired thermal homeostasis. They support a model in which impaired BAT mitochondrial function contributes to later susceptibility to diet-induced adiposity.
SN - 2692-8205
ER -