Dietary aflatoxin-induced stunting in a novel rat model: evidence for toxin-induced liver injury and hepatic growth hormone resistance.
BACKGROUND
Despite a strong statistical correlation between dietary aflatoxin B1 (AFB1)-exposure and childhood stunting, the causal mechanism remains speculative. This issue is important because of emerging interest in reduction of human aflatoxin exposure to diminish the prevalence and complications of stunting. Pediatric liver diseases cause growth impairment, and AFB1 is hepatotoxic. Thus, liver injury might mediate AFB1-associated growth impairment. We have developed a rat model of dietary AFB1-induced stunting to investigate these questions.


METHODS
Newly-weaned rats were given AFB1-supplemented- or control-diets from age 3-9 wk, and then euthanized for serum- and tissue-collection. Food intake and weight were serially assessed, with tibial-length determined at the experimental endpoint. Serum AFB1-adducts, hepatic gene and protein expression, and liver injury markers were quantified using established methodologies.


RESULTS
AFB1-albumin adducts correlated with dietary toxin contamination, but such contamination did not affect food consumption. AFB1-exposed animals exhibited dose-dependent wasting and stunting, liver pathology, and suppression of hepatic targets of growth hormone (GH) signaling, but did not display increased mortality.


CONCLUSIONS
These data establish toxin-dependent liver injury and hepatic GH-resistance as candidate mechanisms by which AFB1-exposure causes growth impairment in this mammalian model. Interrogation of modifiers of stunting using this model could guide interventions in at-risk and affected children.
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
Brittany
B
Knipstein
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
Jiansheng
J
Huang
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
Emily
E
Barr
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
Philip
P
Sossenheimer
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
Dennis
D
Dietzen
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Patricia A
PA
Egner
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
John D
JD
Groopman
1] Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri [2] Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri.
David A
0000000240564084
DA
Rudnick
D016604:Aflatoxin B1 / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D004032:Diet; D005506:Food Contamination; D013006:Growth Hormone / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D023421:Models, Animal; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
D013006:Growth Hormone; D016604:Aflatoxin B1