Induction of apoptosis in the gonads of Mytilus edulis by metformin and increased temperature, via regulation of CASP8, HSP70, BCL2 and FAS

Pharmaceutically Active Compounds (PhACs) and Endocrine Disrupting Compounds (EDCs) have been considered as Contaminants of Emerging Concern (CECs), in response to evidence that these substances may adversely affect aquatic organisms. Here we expose mussels for 7 days to metformin, the most commonly prescribed anti-diabetes treatment, at a concentration of 40 μg/L and a high temperature of 20°C. Histopathology of gonad tissue showed apoptosis-related alterations, including follicle degeneration and atresia. The variation in expression of apoptosis-related genes in mussel gonads: CASP8, HSP70, BCL2 and FAS was also investigated. The results suggest that apoptotic changes such as atresia and follicle degeneration are likely regulated by many different interactions between these regulatory genes. This apoptotic condition, when caused by temperature, may be induced by CASP-8 acting as an initiator. Conversely, metformin may cause this condition by suppressing the anti-apoptotic gene BCL2, thus promoting the apoptotic process. Interestingly, apoptosis and follicle degeneration are more likely to be FAS-mediated, following the synergistic effect of metformin and temperature. The potential of metformin to act as a non-traditional EDC, due to its impact on the reproductive system in mussels is discussed.