Mobilization of the Environmental Toxicant Chlorpyrifos during Weight Loss and Its Impact on Liver and Adipose Tissue Metabolism in Mice

BACKGROUND: Fat-soluble toxicants, such
as chlorpyrifos
(CPF) can accumulate in adipose tissue and the liver. During weight
loss, these compounds may be released into the circulation, but the
metabolic consequences of this mobilization remain poorly understood. OBJECTIVES: This study aimed to investigate the mobilization
of CPF during weight loss and its effects on liver health and adipose
tissue metabolism in mice. METHODS: C57BL/6J mice were
fed a high-fat diet (HFD) or a low-fat diet (LFD) and exposed to 2
mg/kg BW/day CPF by oral gavage. Weight loss was induced by β3-adrenergic
stimulation (CL316243) or treadmill exercise for 4 or 10 weeks. CPF
was quantified in serum and tissues using HPLC. Tissue histology,
expression of genes related to CPF metabolism, liver injury markers,
and metabolic protein levels were assessed. RESULTS:
CPF-exposed LFD mice showed more severe liver fibrosis and adipose
inflammation than did their HFD counterparts. While obese mice had
lower adipose CPF concentrations, they showed higher hepatic accumulation.
CPF-exposed weight loss mice had higher levels of CPF in adipose tissue,
liver, and brain and higher expression of CPF metabolism-related genes,
including Paraoxinase-1 and cytochrome P450 genes, and greater glucose
intolerance compared to their counterparts without CPF administration.
Molecular analyses revealed suppressed AMPK signaling and P62 accumulation,
indicating mitophagy disruption in CPF-exposed mice after weight loss.
These effects occurred even at human-relevant low doses (0.45 mg/kg
of BW/day) and persisted across sexes. DISCUSSION: Weight
loss mobilizes CPF and its metabolites from fat stores, leading to
tissue accumulation and damage. Even low-dose exposure contributes
to hepatic and metabolic disruption in mice, highlighting the potential
risk of toxicant mobilization during fat reduction.