GR-C/EBPα-IGF1 axis mediated azithromycin-induced liver developmental toxicity in fetal mice
Kexin Liu1, Guihua Wang1, Li Li1
1Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
Abstract:
Azithromycin is considered an effective drug to treat the perinatal mycoplasma infection. However, there is a lack of studies on developmental toxicity of azithromycin. In this study, we observed the developmental toxicity of fetal liver induced by prenatal azithromycin exposure (PAE) in mice and explored the potential mechanism. Pregnant Kunming mice were intraperitoneally injected with azithromycin (37.5 and 150 mg/kg·d) from gestational day (GD) 9 to 18. After PAE, the bodyweight gain rates of pregnant mice and the birthweights of the offspring were decreased, and the liver morphology, development indexes and metabolic function were all altered in different degree in the PAE fetuses. Meanwhile, PAE decreased the fetal serum insulin-like growth factor 1 (IGF1) levels and liver IGF1 signal pathway expression, accompanied by glucocorticoid receptor-CCAAT enhancer-binding protein α (GR-C/EBPα) signal enhancement. Furthermore, azithromycin disturbed hepatocyte differentiation, maturation and metabolic function via upregulating GR-C/EBPα signal and reducing the expression and secretion levels of IGF1 in HepG2 cells. These changes could be reversed by GR siRNA or exogenous IGF1. These results indicated that PAE could cause fetal liver developmental toxicity in mice, and one of the main mechanisms was that azithromycin activated the GR-C/EBPα signal, inhibited the IGF1 signal pathway, and then disturbed the hepatic proliferation, apoptosis, differentiation, and glycose and lipid metabolism.
Insights
Prenatal azithromycin exposure (PAE) in mice caused fetal liver developmental toxicity. Azithromycin disrupted liver development and metabolism by altering insulin-like growth factor 1 (IGF1) and glucocorticoid receptor-CCAAT enhancer-binding protein α (GR-C/EBPα) signaling.
Area of Science:
- Toxicology
- Developmental Biology
- Pharmacology
Background:
- Azithromycin is effective for perinatal infections but its developmental toxicity is understudied.
- Prenatal exposure to medications can impact fetal development and organ function.
Purpose of the Study:
- To investigate the developmental toxicity of azithromycin on fetal liver in mice.
- To explore the underlying molecular mechanisms of azithromycin-induced developmental toxicity.
Main Methods:
- Pregnant mice received azithromycin injections during critical developmental periods.
- Fetal liver development, morphology, metabolic function, and key signaling pathways (IGF1, GR-C/EBPα) were assessed.
- In vitro studies using HepG2 cells were conducted to confirm mechanisms.
Main Results:
- Prenatal azithromycin exposure reduced maternal weight gain and offspring birthweight.
- Fetal liver morphology, development, and metabolic functions were significantly altered.
- Azithromycin exposure decreased IGF1 signaling while enhancing GR-C/EBPα signaling, impacting hepatocyte function.
Conclusions:
- Prenatal azithromycin exposure induces fetal liver developmental toxicity in mice.
- The mechanism involves the activation of GR-C/EBPα and inhibition of IGF1 signaling, disrupting hepatic development and metabolism.
- These effects on liver development and metabolism could be reversed by targeting GR or supplementing IGF1.
