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Updated: Jul 10, 2025
Long-term Behavioral and Reproductive Consequences of Embryonic Exposure to Low-dose Toxicants
Published on: March 6, 2018
A "toxic window" study on the hippocampal development of mice offspring exposed to azithromycin at different doses,
Liyi Wei1, Tingting Wang1, Mingcui Luo1
1Department of Obstetric, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
Background:
Azithromycin, one of the new-generation macrolides, is an effective medicine for the treatment of mycoplasma infection during pregnancy. Epidemiological studies have reported adverse pregnancy outcomes with prenatal azithromycin exposure (PAzE). However, the effect of PAzE on fetal hippocampal development is unclear. This study aimed to explore the effects and potential mechanism of PAzE-induced fetal hippocampal development at different doses, courses, and time.
Method:
Pregnant mice were administered azithromycin by gavage at different doses (50, 100 or 200 mg/kg.d), different courses (gestational day (GD)15-17 for three consecutive days, or GD17 once a day) and different time (GD10-12, GD15-17).
Results:
Compared with the control group, morphological development damage of the fetal hippocampus was observed in the PAzE group, with a dysbalance in neuronal proliferation and apoptosis, decreased expression of the neuronal-specific marker Snap25, NeuN, PSD95 and Map2, increased expression of the glial-specific marker Iba1, GFAP, and S-100β, and decreased expression of P2ry12. The PAzE-induced hippocampal developmental deficiency varied based on different doses, courses, and time, and the developmental toxicity was most significant in the late pregnancy, high dose, multi-course group (AZHT). The significant reduction of SOX2 and Wnt, which were related to regulation of neural progenitor cells (NPCs) proliferation in PAzE fetus compared with the control group indicated that the SOX2/Wnt signaling may be involved in PAzE-induced hippocampal developmental toxicity.
Conclusion:
In this study, PAzE was associated with hippocampal developmental toxicity in a variety of nerve cells. Hippocampal developmental toxicity due to azithromycin was most significant in the late pregnancy, high-dose (equivalent to maximum clinical dose) and multi-course group (AZHT). The findings provide an experimental and theoretical foundation for guiding the sensible use of medications during pregnancy and effectively assessing the risk of fetal hippocampal developmental toxicity.
Insights
Prenatal azithromycin exposure (PAzE) can harm fetal hippocampal development, particularly at high doses late in pregnancy. This study reveals PAzE-induced toxicity in nerve cells, highlighting risks associated with maternal medication use.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Azithromycin is a macrolide antibiotic used for mycoplasma infections during pregnancy.
- Epidemiological studies suggest adverse pregnancy outcomes linked to prenatal azithromycin exposure (PAzE).
- The specific impact of PAzE on fetal hippocampal development remains unclear.
Purpose of the Study:
- To investigate the effects of PAzE on fetal hippocampal development.
- To explore the underlying mechanisms of PAzE-induced toxicity.
- To assess dose, course, and timing-dependent effects of PAzE.
Main Methods:
- Pregnant mice were administered azithromycin via gavage at varying doses (50-200 mg/kg/day).
- Exposure varied in duration (3 consecutive days or single dose) and timing during gestation (GD10-12, GD15-17).
- Fetal hippocampus development, neuronal markers, glial markers, and signaling pathways were analyzed.
Main Results:
- PAzE caused morphological damage and dysregulated neuronal proliferation/apoptosis in the fetal hippocampus.
- Decreased expression of neuronal markers (Snap25, NeuN, PSD95, Map2) and increased glial markers (Iba1, GFAP, S-100β) were observed.
- Toxicity was most pronounced with high doses, late pregnancy, and multi-course exposure (AZHT), linked to SOX2/Wnt signaling pathway disruption.
Conclusions:
- PAzE is associated with hippocampal developmental toxicity affecting various nerve cells.
- The most significant toxicity occurred in the late pregnancy, high-dose, multi-course group (AZHT).
- Findings support cautious azithromycin use during pregnancy and risk assessment for fetal neurodevelopmental toxicity.
