ATF3 as a response factor to regulate Cd-induced reproductive damage by activating the NRF2/HO-1 ferroptosis pathway

Area of Science:

• Reproductive Toxicology
• Cellular Mechanisms
• Environmental Health

Background:

• Cadmium (Cd) is a reproductive toxicant known to induce ferroptosis.
• The precise molecular pathways of Cd-induced germ cell ferroptosis are not fully elucidated.
• Understanding these mechanisms is crucial for addressing male reproductive health issues.

Purpose of the Study:

• To systematically investigate the molecular mechanisms of Cd-induced germ cell ferroptosis.
• To identify key transcription factors and proteins involved in the process.
• To explore potential therapeutic interventions.

Main Methods:

• Oral administration of Cadmium Chloride (CdCl2) to male mice and treatment of TM3 and TM4 cell lines.
• Assessment of iron overload, oxidative stress, and mitochondrial morphology.
• RNA sequencing to identify differential gene expression.
• Intervention studies targeting ferroptosis and HO-1 activity.
• Analysis of ATF3 and NRF2 pathway activation.

Main Results:

• Cd exposure caused iron overload, oxidative stress, and mitochondrial damage indicative of ferroptosis in testes.
• Significant upregulation of Atf3 and Hmox1 (HO-1) was observed in Cd-exposed germ cells.
• Intervention against ferroptosis or HO-1 mitigated Cd-induced cell death.
• ATF3 overexpression activated the Keap1-Nrf2 pathway, increasing NRF2 and HO-1 expression and promoting ferroptosis.
• ATF3 silencing reversed NRF2 and HO-1 expression levels.

Conclusions:

• Cadmium induces germ cell ferroptosis through an ATF3-mediated activation of the NRF2/HO-1 signaling pathway.
• This pathway contributes to testicular injury and reproductive toxicity.
• Targeting the ATF3-NRF2/HO-1 axis presents a potential strategy for treating Cd-induced testicular damage.