Dietary Exposure to the Endocrine Disruptor Tolylfluanid Promotes Global Metabolic Dysfunction in Male Mice

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.

Metabolism disrupting chemicals and metabolic disorders

“…For example, in vivo exposure to DEHP down-regulates expression of adipocyte insulin signaling intermediates [515], while rats exposed to BPA demonstrated a reduction of insulin signaling intermediates in both muscle [516] and liver [517]. Cadmium exposure has been shown to promote glucose intolerance with a specific reduction in adipose expression of Glut4 [518] and TCDD has been shown to also reduce glucose uptake in adipose and brain [519, 520]. In addition, the fungicide tolylfluanid promotes glucose intolerance with concomitant global and adipose-specific insulin resistance, with the latter resulting from a specific down-regulation of insulin receptor substrate-1 (IRS-1) [521].…”

Transgenerational effects of obesogens

“…Several other chemicals have been identified as obesogens, in vivo. These include the fungicides triflumizole, tolylfluanid and the plasticizer diethylhexyl phthalate . Tolylfluanid was shown to act via the glucocorticoid receptor whereas triflumizole acts through PPARγ .…”

Obesogens: an emerging threat to public health

“…One way to minimize EDC exposure is to consume organic fruits, vegetables and grain products insofar as possible. An increasing number of fungicides routinely applied to fruits and vegetables are being identified as obesogens and metabolic disruptors 73, 102 and the levels of agrochemical residues such as glyphosate on corn, wheat and rice continues to rise 103 . It may also be reasonable to recommend that women minimize the use of cosmetics and personal care products containing EDCs (such as parabens and phthalates).…”