RT Journal Article
SR Electronic
T1 Lactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.20.492880
DO 10.1101/2022.05.20.492880
A1 André A. Weber
A1 Xiaojing Yang
A1 Elvira Mennillo
A1 Jeffrey Ding
A1 Jeramie D. Watrous
A1 Mohit Jain
A1 Shujuan Chen
A1 Michael Karin
A1 Robert H. Tukey
YR 2022
UL http://biorxiv.org/content/early/2022/05/21/2022.05.20.492880.abstract
AB Pediatric non-alcoholic fatty liver disease (NAFLD) is escalating in the United States, with a limited mechanistic understanding. Triclosan (TCS) is a high-volume antimicrobial additive that has been detected in human breastmilk and shown in adult mice to cause hepatosteatosis. To examine the effect of TCS presented to neonatal mice through lactation, we exposed pregnant females to TCS in their diet and evaluated its impact on nursing neonates. TCS is efficiently transferred by lactation to newborn mice, causing significant fatty liver (FL) during the suckling period. Lactational delivery stimulated hepatosteatosis, triglyceride accumulation, endoplasmic reticulum (ER) stress, inflammation, and liver fibrosis. These events were mirrored by inhibition of key metabolic regulators, FGF21 and AMPK. De novo lipogenesis (DNL) induced by lactational TCS exposure was blocked in mice deficient in hepatic ATF4 . In primary hepatocytes, siRNA specific inhibition of PERK, an ATF4 upstream activator and initiator of ER stress, blocked TCS induced DNL. Also, in the absence of PPARα, which targets regulation of ATF4, TCS induced triglyceride accumulation and the induction of DNL was blocked. The administration of obeticholic acid (OCA), a potent FXR agonist, as well as activation of intestinal mucosal-regenerative gp130 signaling, led to reduced liver ATF4 expression, PPARα signaling, and DNL when neonates were exposed to TCS. In summary, TCS exposure via lactation leads to early indicators of NAFLD development accompanied by hepatosteatosis that were mediated in a PERK-eIF2α-ATF4-PPARα cascade. These studies indicate that mother to child transmission of environmental toxicants such as TCS may underlie the recent increases in pediatric NAFLD.Competing Interest StatementThe authors have declared no competing interest.