Dietary exposure to the endocrine disruptor tolylfluanid promotes global metabolic dysfunction in male mice

Shane M. Regnier, Andrew G. Kirkley, Honggang Ye, Essam El-Hashani, Xiaojie Zhang, Brian A. Neel, Wakanene Kamau, Celeste C. Thomas, Ayanna K. Williams, Emily T. Hayes, Nicole L. Massad, Daniel N. Johnson, Lei Huang, Chunling Zhang, Robert M. Sargis*

*Corresponding author for this work

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Environmental endocrine disruptors are implicated as putative contributors to the burgeoning metabolic disease epidemic. Tolylfluanid (TF) is a commonly detected fungicide in Europe, and previous in vitro and ex vivo work has identified it as a potent endocrine disruptor with the capacity to promote adipocyte differentiation and induce adipocytic insulin resistance, effects likely resulting from activation of glucocorticoid receptor signaling. The present study extends these findings to an in vivo mouse model of dietary TF exposure. After 12 weeks of consumption of a normal chow diet supplemented with 100 parts per million TF, mice exhibited increased body weight gain and an increase in total fat mass, with a specific augmentation in visceral adipose depots. This increased adipose accumulation is proposed to occur through a reduction in lipolytic and fatty acid oxidation gene expression. Dietary TF exposure induced glucose intolerance, insulin resistance,and metabolic inflexibility, while also disrupting diurnal rhythms of energy expenditure and food consumption. Adipose tissue endocrine function was also impaired with a reduction in serum adiponectin levels. Moreover, adipocytes from TF-exposed mice exhibited reduced insulin sensitivity, an effect likely mediated through a specific down-regulation of insulin receptor substrate-1 expression, mirroring effects of ex vivo TF exposure. Finally, gene set enrichment analysis revealed an increase in adipose glucocorticoid receptor signaling with TF treatment. Taken together, these findings identify TF as a novel in vivo endocrine disruptor and obesogen in mice, with dietary exposure leading to alterations in energy homeostasis that recapitulate many features of the metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)896-910
Number of pages15
JournalEndocrinology
Volume156
Issue number3
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology

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    Regnier, S. M., Kirkley, A. G., Ye, H., El-Hashani, E., Zhang, X., Neel, B. A., Kamau, W., Thomas, C. C., Williams, A. K., Hayes, E. T., Massad, N. L., Johnson, D. N., Huang, L., Zhang, C., & Sargis, R. M. (2015). Dietary exposure to the endocrine disruptor tolylfluanid promotes global metabolic dysfunction in male mice. Endocrinology, 156(3), 896-910. https://doi.org/10.1210/en.2014-1668