Bisphenol A (BPA) is a chemical compound commonly used in the production of plastics for daily lives and industry. As BPA is well known for its adverse health effects, several alternative materials have been developed. This study comprehensively analyzed the toxicity of BPA and its three substitutes including bisphenol S (BPS), bisphenol F (BPF), and tetramethyl bisphenol F (TMBPF) on aging, healthspan, and mitochondria using an in vivo Caenorhabditis elegans (C. elegans) model animal and cultured mammalian fibroblast cells. C. elegans treated with 1 mM BPA exhibited abnormalities in the four tested parameters related to development and growth, including delayed development, decreased body growth, reduced reproduction, and abnormal tissue morphology. Exposure to the same concentration of each alternative including TMBPF, which has been proposed as a relatively safe BPA alternative, detrimentally affected at least three of these events. Moreover, all bisphenols (except BPS) remarkably shortened the organismal lifespan and increased age-related changes in neurons. Exposure to BPA and BPF resulted in mitochondrial abnormalities, such as reduced oxygen consumption and mitochondrial membrane potential. In contrast, the ATP levels were noticeably higher after treatment with all bisphenols. In mammalian fibroblast cells, exposure to increasing concentrations of all bisphenols (ranging from 50 μM to 500 μM) caused a severe decrease in cell viability in a dose-dependent manner. BPA increased ATP levels and decreased ROS but did not affect mitochondrial permeability transition pores (mPTP). Notably, TMBPF was the only bisphenol that caused a significant increase in mitochondrial ROS and mPTP opening. These results suggest that the potentially harmful physiological effects of BPA alternatives should be considered.

Doxorubicin is a highly effective chemotherapeutic agent widely used to treat a variety of cancers. However, the clinical application of doxorubicin is limited due to its adverse effects on several tissues. One of the most serious side effects of doxorubicin is cardiotoxicity, which results in life-threatening heart damage, leading to reduced cancer treatment success and survival rate. Doxorubicin-induced cardiotoxicity results from cellular toxicity, including increased oxidative stress, apoptosis, and activated proteolytic systems. Exercise training has emerged as a non-pharmacological intervention to prevent cardiotoxicity during and after chemotherapy. Exercise training stimulates numerous physiological adaptations in the heart that promote cardioprotective effects against doxorubicin-induced cardiotoxicity. Understanding the mechanisms responsible for exercise-induced cardioprotection is important to develop therapeutic approaches for cancer patients and survivors. In this report, we review the cardiotoxic effects of doxorubicin and discuss the current understanding of exercise-induced cardioprotection in hearts from doxorubicin-treated animals.

Melatonin protects against Cadmium (Cd)-induced toxicity, a ubiquitous environmental toxicant that causes adverse health effects by increasing reactive oxygen species (ROS) production and mitochondrial dysfunction. However, the underlying mechanism remains unclear. Here, we demonstrate that Cd exposure reduces the levels of mitochondrially-localized signal transducer and activator of transcription 3 (mitoSTAT3) using human prostate stromal cells and mouse embryonic fibroblasts. Melatonin enhances mitoSTAT3 abundance following Cd exposure, which is required to attenuate ROS damage, mitochondrial dysfunction, and cell death caused by Cd exposure. Moreover, melatonin increases mitochondrial levels of GRIM-19, an electron transport chain component that mediates STAT3 import into mitochondria, which are downregulated by Cd. In vivo, melatonin reverses the reduced size of mouse prostate tissue and levels of mitoSTAT3 and GRIM-19 induced by Cd exposure. Together, these data suggest that melatonin regulates mitoSTAT3 function to prevent Cd-induced cytotoxicity and could preserve mitochondrial function during Cd-induced stress.

The synthetic antioxidant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6-PPD) is widely used in rubber products, but its toxicity in non-aquatic animals remains poorly understood. We investigated 6-PPD toxicity in mouse embryonic fibroblasts (MEFs) and Caenorhabditis elegans (C. elegans). In MEFs, 6-PPD caused dose-dependent increases in cell death, apoptosis, and mitochondrial dysfunction, along with elevated reactive oxygen species (ROS). In C. elegans, 6-PPD exposure led to higher mortality, delayed development, reduced reproduction, and shortened lifespan. Mitochondrial impairment, increased ROS, decreased mobility, and weakened stress tolerance were also observed. High-performance liquid chromatography (HPLC) analysis detected trace amounts of 6-PPD in C. elegans, whereas 6-PPD Quinone (6-PPDQ) was not detected within the analytical range. Furthermore, we found that 6-PPD upregulated the conserved transcription factor skinhead-1 (SKN-1/Nrf2) transcription factor. While SKN-1 was necessary for the reduced lifespan and early mortality caused by 6-PPD exposure, its loss failed to prevent the mitochondrial defects induced by 6-PPD exposure. Notably, SKN-1 gain-of-function mutations under basal conditions impaired mitochondrial function, and 6-PPD exposure further exacerbated these defects. These findings indicate that 6-PPD disrupts mitochondria through both SKN-1-dependent and SKN-1-independent mechanisms. Overall, our study demonstrates that 6-PPD impairs development, reproduction, healthspan, and lifespan through the SKN-1/Nrf2 pathway, with mitochondrial dysfunction mediated by both SKN-1/Nrf2-dependent and independent mechanisms.