Premium
Triclosan (TCS) Exposure in Neonatal Mice Leads to ER Stress, Inflammation and Lipid Accumulation in Liver
Author(s) -
Weber Andre Alberto,
Mennillo Elvira,
Ding Jeffrey,
Jain Mohit,
Chen Shujuan,
Tukey Robert
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06619
Subject(s) - endocrinology , medicine , unfolded protein response , endoplasmic reticulum , oxidative stress , inflammation , lactation , triglyceride , nuclear receptor , chemistry , fatty liver , receptor , biology , biochemistry , cholesterol , gene , pregnancy , genetics , disease , transcription factor
Triclosan (TCS) is an antimicrobial agent used in multiple personal care products and is represented as an emerging environmental contaminant worldwide. Recent findings have demonstrated that TCS can accumulate in human breast milk. Neonatal humanized UGT1 ( hUGT1 ) mice, which exhibit severe levels of total serum bilirubin (TSB), were breastfed from females fed with a diet containing 120 ppm TCS. Newborn mice exhibited levels of TCS in their serum that were comparable to those quantitated in human blood samples. After 14 days, TSB levels decreased dramatically in TCS exposed neonates and UGT1A1 was significantly induced (13‐fold) in liver. The nuclear receptors, CAR, PXR and PPARα, when activated can induce UGT1A1 expression, were upregulated in TCS breastfed mice. The environmental sensor NRF2 is also increased in TCS breastfed mice along with target genes, Ho‐1 and Nqo‐1 . At day 21, TCS neonates showed an increase in endoplasmic reticulum (ER) stress markers such as p‐eIF2α and ATF4 when compared to control mice. Caspase‐1 and p20 are also increased, together with a host of cytokines indicating pyroptosis in liver. TCS neonates at 21 days also present a reduction in fatty acid oxidation genes ( Pparα , Cyp4a10 , Cyp4a14 , Cpt1a ) and an increase in fatty acid synthase genes ( Fasn and Srebp1‐c ). At this age TCS mice presented accumulation of lipids in liver with an increase in triglyceride contents. These results suggest that activation of nuclear receptors induce hepatic UGT1A1 following TCS exposure by lactation while eliciting early signs of oxidative stress that leads to ER stress and inflammation that may be linked to fatty liver. Support or Funding Information Supported by National Institute of Health Grants (ES010337 and GM126074) and seed grant from the UCSD BreastMilk MoMI CORE.