Lactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice Article Swipe
André Alberto Weber
,
Xiaojing Yang
,
Elvira Mennillo
,
Jeffrey Ding
,
Jeramie D. Watrous
,
Mohit Jain
,
Shujuan Chen
,
Michael Karin
,
Robert H. Tukey
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1101/2022.05.20.492880
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1101/2022.05.20.492880
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.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2022.05.20.492880
- https://www.biorxiv.org/content/biorxiv/early/2022/05/21/2022.05.20.492880.full.pdf
- OA Status
- green
- Cited By
- 1
- References
- 59
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4281298657
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4281298657Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1101/2022.05.20.492880Digital Object Identifier
- Title
-
Lactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn miceWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2022Year of publication
- Publication date
-
2022-05-21Full publication date if available
- Authors
-
André Alberto Weber, Xiaojing Yang, Elvira Mennillo, Jeffrey Ding, Jeramie D. Watrous, Mohit Jain, Shujuan Chen, Michael Karin, Robert H. TukeyList of authors in order
- Landing page
-
https://doi.org/10.1101/2022.05.20.492880Publisher landing page
- PDF URL
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https://www.biorxiv.org/content/biorxiv/early/2022/05/21/2022.05.20.492880.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://www.biorxiv.org/content/biorxiv/early/2022/05/21/2022.05.20.492880.full.pdfDirect OA link when available
- Concepts
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Endocrinology, Internal medicine, Fatty liver, Nonalcoholic fatty liver disease, Unfolded protein response, Lactation, Lipogenesis, Medicine, AMPK, Steatosis, Triglyceride, Biology, Endoplasmic reticulum, Lipid metabolism, Kinase, Disease, Cell biology, Cholesterol, Protein kinase A, Pregnancy, GeneticsTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
1Total citation count in OpenAlex
- Citations by year (recent)
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2023: 1Per-year citation counts (last 5 years)
- References (count)
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59Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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