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Exposure to low-dose cadmium induces testicular ferroptosis
Lijuan Xiong1, Bin Zhou2, Jamie L Young3
1Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Emergency, The Affiliated Children's Hospital of Nanchang University, Nanchang, Jiangxi, China.
Abstract:
As an environmental pollutant, cadmium (Cd) has been widely reported to induce male infertility due to its gonadotoxicity. However, the specific mechanism of Cd-induced testicular damage remains unclear. We investigated whether Cd causes testicular injury through ferroptosis. Male C57BL/6 J mice were exposed to 0, 0.5, or 5 ppm Cd via drinking water, starting in utero, and continuing through 24 weeks post-weaning. The results showed that Cd accumulated in the testes in a dose-dependent manner. Cd exposure at a concentration of 5 ppm, but not 0.5 ppm, caused a mass loss and detachment of germ cells, as well as a decreased meiotic index and testis weight. Exposure to 5 ppm Cd caused iron accumulation, increased levels of malondialdehyde (MDA) and nitro tyrosine (3-NT), and decreased expression of Nrf2, HO-1 and SOD2. We also found that exposure to 5 ppm Cd significantly decreased the expression of SLC7A11, a marker of ferroptosis in mice, along with the expression of SLC40A1 mRNA and ferritin heavy chain (FTH) protein, whereas there was no obvious change in the mRNA expression of Tfrc, ZIP8, ZIP14, and NCOA4. These findings indicate that 5 ppm Cd exposure increased testicular ferroptosis, which may be attributed to the reduction of stored iron export.
Insights
Cadmium (Cd) exposure causes male infertility by inducing testicular damage through ferroptosis. This occurs due to increased iron accumulation and reduced iron export, impacting male reproductive health.
Area of Science:
- Environmental Toxicology
- Reproductive Biology
- Cellular Pathology
Background:
- Cadmium (Cd) is an environmental pollutant known to cause male infertility.
- The precise mechanisms underlying cadmium-induced testicular damage are not fully understood.
Purpose of the Study:
- To investigate if cadmium exposure induces testicular injury via ferroptosis.
- To elucidate the specific molecular pathways involved in cadmium's effects on testicular tissue.
Main Methods:
- Male C57BL/6J mice were exposed to varying concentrations of cadmium (0, 0.5, or 5 ppm) from in utero through 24 weeks post-weaning.
- Evaluated cadmium accumulation, testicular histopathology, germ cell integrity, meiotic index, and testis weight.
- Assessed markers of oxidative stress (malondialdehyde, nitro tyrosine) and ferroptosis (SLC7A11, SLC40A1, FTH, Nrf2, HO-1, SOD2).
Main Results:
- Cadmium accumulated in testes in a dose-dependent manner.
- 5 ppm cadmium exposure led to testicular mass loss, germ cell detachment, decreased meiotic index, and reduced testis weight.
- Cadmium exposure increased iron accumulation, oxidative stress markers (MDA, 3-NT), and ferroptosis markers (decreased SLC7A11, SLC40A1, FTH, Nrf2, HO-1, SOD2).
Conclusions:
- Cadmium exposure at 5 ppm induces testicular damage and male infertility through ferroptosis.
- This ferroptosis is linked to increased iron accumulation and impaired iron export mechanisms in the testes.
