Abstract Detail

Secondary Metabolites

Pestka, James [1].

Trichothecenes produced by Fusarium species.

Consumption of toxic chemicals by animals and humans often elicits two major pathophysiologic effects, anorexia and emesis. A potential underlying mechanism for these responses is the aberrant activation of enteroendocrine cells (EECs) resulting in secretion of peptide and amine hormones that can activate the nucleus tractus solitarius (NTS) in the brain.  Although EECs comprise only about 1% of intestinal epithelial cells, in total they represent one of the largest endocrine organs in the body. The downstream processes for these gut-brain pathways are well-understood, particularly with regard to canonical involvement of serotonin (5-HT) and enterochromaffin cells (EC, an EEC subset). However, surprisingly little is known about the early upstream events that initiate anorexia and emesis with regard to 1) identities of specific toxin chemoreceptors, 2) intracellular signaling mechanisms, 3) specific contributions of different (>15) EEC lineages, and 4) the role of the diverse hormones secreted by those lineages. Deoxynivalenol (DON), colloquially known as “vomitoxin”, is a prototypical enteroendocrine disruptor that has global public health significance. Produced by the fungal plant pathogen Fusarium graminearum in cereal crops, DON and other trichothecene mycotoxins are potent ribotoxic stressors and translational inhibitors that are of immense public health significance. Regulatory tolerances have been established for DON because of its potential to impair growth as well as its etiological association with human gastroenteritis outbreaks.  The latter are characterized by rapid onset of appetite loss, nausea, diarrhea, cramping and vomiting.  Notably, DON has been linked to food poisoning outbreaks affecting 1900 school children in 7 U.S. states and 130,000 people in Anhui province in China.  We have discovered that DON induces in vitro and in vivo the release of several gut hormones that: 1) elicit potent anorectic and emetic effects and 2) involve activation of at least three EEC lineages: I-cells, L-cells and EC-cells. We have further found that G-protein coupled calcium-sensitive receptor (CaSR) and transient receptor potential A1 channel (TRPA1) cooperate to mediate DON-induced increase in intracellular calcium concentration and hormone release in EECs. The expected outcome of this work will be to demonstrate the involvement of several novel receptors, EEC lineages and hormones in mycotoxin-induced anorexia and emesis.  This contribution is significant because it opens the door for innovative research on the mechanisms and classification of putative enteroendocrine disrupting natural metabolites or anthropogenic contaminants, an entirely new investigative area in the endocrine disruption field.

1 - Michigan State University, Food Science and Human Nutrition, East Lansing, MI, 48824, USA

Keywords:
trichothecenes
fusarium
mycotoxins.

Presentation Type: Symposium or Colloquium Presentation
Session: SY3
Location: Room 104 AB/Kellogg Hotel and Conference Center
Date: Monday, June 9th, 2014
Time: 4:30 PM
Number: SY3004
Abstract ID:102
Candidate for Awards:None