Majid Tarar Jasim, Majid Motovali-Bashi
This study integrated genetic susceptibility (Brca1) with environmental metal co-exposure to explain infertility through oxidative and apoptotic mechanisms. The findings showed that trace elements differentially affected reproductive outcomes in Brca1-compromised females, highlighting the reproductive risks posed by Cd and Co and the more nuanced role of zinc. By demonstrating the combined toxicogenetic interaction between DMBA and metal exposure, this work outlined a mechanistic model linking oxidative damage in the mammary gland to declining fertility.
OBJECTIVE: Infertility remains a multifactorial disorder influenced by both genetic and environmental factors, yet the molecular interplay between these two dimensions is poorly understood. The Brca1 gene, classically known for its tumor-suppressive role in mammary tissue, also plays a crucial role in maintaining oocyte quality and ovarian reserve. Mutations or dysregulation of Brca1 may therefore link mammary toxicity to reproductive failure. This study investigated the impact of environmental exposure to the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), in conjunction with selected trace elements [cadmium (Cd), cobalt (Co), and zinc (Zn)], on fertility, oxidative balance, and Brca1 expression in female rats.
MATERIALS AND METHODS: In this experimental study, female Wistar rats were treated with DMBA alone or combined with Cd, Co, or Zn for 20 weeks. Serum oxidative stress biomarkers [malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT)] and mammary gland immunohistochemistry for Brca1, apoptosis, and necrosis were evaluated. Fertility outcomes and cell viability [evaluated using the (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) (MTT) assay] were examined to correlate systemic redox imbalance with reproductive performance.
RESULTS: Co- or Cd-combined exposure to DMBA markedly increased oxidative stress and mammary apoptosis, resulting in the lowest fertility rates. In contrast, Zn-co-treatment partially restored antioxidant capacity and reduced cell death, suggesting a modulatory rather than strictly protective role. Dysregulated Brca1 expression across all treatment groups supports a mechanistic link between mammary genotoxicity and impaired fertility.
CONCLUSION: This study integrated genetic susceptibility (Brca1) with environmental metal co-exposure to explain infertility through oxidative and apoptotic mechanisms. The findings showed that trace elements differentially affected reproductive outcomes in Brca1-compromised females, highlighting the reproductive risks posed by Cd and Co and the more nuanced role of zinc. By demonstrating the combined toxicogenetic interaction between DMBA and metal exposure, this work outlined a mechanistic model linking oxidative damage in the mammary gland to declining fertility.