Lactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice

Abstract

Here we show that Triclosan (TCS), a high-volume antimicrobial additive that has been detected in human breastmilk, can be efficiently transferred by lactation to newborn mice, causing significant fatty liver (FL) during the suckling period. These findings are relevant since pediatric non-alcoholic fatty liver disease (NAFLD) is escalating in the United States, with a limited mechanistic understanding. Lactational delivery stimulated hepatosteatosis, triglyceride accumulation, endoplasmic reticulum (ER) stress, signs of inflammation, and liver fibrosis. De novo lipogenesis (DNL) induced by lactational TCS exposure is shown to be mediated in a PERK-eIF2α-ATF4-PPARα cascade. 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. It is yet to be investigated but mother to child transmission of TCS or similar toxicants may underlie the recent increases in pediatric NAFLD.

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“…TCS could interfere with reproductive health through oxidative stress [58], hormonal dysregulation [59], germ cell autophagy and apoptosis, steroidogenesis suppression [60], and mitochondrial dysfunction [61]. Long-term exposure to TCS might have unfavorable health effects on the liver, and it could perturb liver metabolic function, aggravate liver fibrosis, accelerate hepatocellular carcinoma development through lipid metabolism disorder [62], induce oxidative stress, facilitate mitochondrial dysfunction [63], and modulate hepatocyte apoptosis [64].…”

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“…Univariate analysis identified a total of 44 proteins that were changed with unadjusted P <0.05 (Figure 3B and Supplementary Table 7). Notably, the protein with the largest fold decrease in the eIF2B HOM CSF was MUP17 (log 2 fold change (FC): -1.3, adjusted P <0.05), a major urinary protein (MUP) and a member of the broader lipocalin protein family, which has been shown to be decreased by ER stress (Weber, Yang et al 2022). Several proteins associated with microglial activation (PLA2G7, CSF1R, LYSZ, and SIRPA) and intracellular organelle associated proteins (CPE, CTSB, CLSTN1, CTSD, HEXA, GM2A, and ALDH2) were also higher in homozygous mice relative to wild-type controls (Figure 3B and Supplementary Table 7).…”

Triclosan administration to humanized UDP-glucuronosyltransferase 1 neonatal mice induces UGT1A1 through a dependence on PPARα and ATF4

“…Epidemiological studies have detected TCS in human tissue samples, including breastmilk ( 4 , 5 , 6 ). Chronic TCS exposure to adult mice has been associated with the development of hepatocellular carcinoma (HCC) ( 7 ), nonalcoholic fatty liver disease (NAFLD) ( 8 , 9 ), and ulcerative colitis ( 5 ). However, the impact of TCS exposure on the pathophysiology of cellular function is just starting to be understood.…”

“…Previous studies have shown that TCS administration activates the integrated stress response (ISR) in the liver ( 8 , 9 ). The ISR is a signaling network that helps the cell adapt to a host of variable environments which are focused on maintaining cell homeostasis ( 25 , 26 ).…”

“…The delivery of TCS to newborns through lactation can profoundly disrupt neonatal liver homeostasis, especially altering lipid metabolism ( 9 ). In the present study, we will show that lactational and oral TCS exposure to neonates dramatically affects the expression and activation of NRs and stress sensors in the liver.…”