Saroj Kumar Das

Bisphenol S (BPS), a widely used substitute for bisphenol A (BPA), is increasingly detected in consumer products and aquatic environments, yet its neurotoxic potential remains insufficiently understood. Building on our previous findings that BPS induces anxiety-like behaviour and oxidative damage in zebrafish, the present study investigates the mechanistic basis of BPS-mediated neurotoxicity with a focus on stress-activated kinase signalling, antioxidant defences, and neurotrophic regulation. Adult zebrafish were exposed to a sub-lethal concentration of BPS (63.93 µM) for 7, 14, and 21 days, followed by neurobehavioral, biochemical, molecular, and histological analyses. Chronic BPS exposure resulted in pronounced anxiety-like behaviour and deficits in recognition memory, as evidenced by performance impairments in the novel tank diving test and novel object recognition test. These behavioural alterations coincided with elevated oxidative stress, including increased lipid peroxidation and protein carbonylation, alongside a progressive decline in superoxide dismutase activity. BPS also caused a significant, time-dependent rise in intracellular calcium levels, suggesting disrupted cellular homeostasis. Neuromorphological assessment revealed marked neuronal loss and pyknosis in the periventricular grey zone of the optic tectum, consistent with oxidative and excitotoxic damage. At the molecular level, western blot analysis showed robust activation of the c-Jun N-terminal kinase (JNK) pathway, evidenced by elevated phosphorylated c-Jun, accompanied by a substantial reduction in Nrf2 expression, indicating suppressed antioxidant defence capacity. In parallel, expression of brain-derived neurotrophic factor (BDNF) was significantly decreased following prolonged exposure, pointing to impaired neurotrophic support and synaptic plasticity. Together, these findings demonstrate that BPS induces neurobehavioral disturbances through a multifaceted mechanism involving oxidative stress, calcium dysregulation, activation of pro-apoptotic JNK signalling, suppression of Nrf2-mediated antioxidant activity, and inhibition of BDNF expression.

The contamination of life-sustaining environments with synthetic pollutants such as plastic-derived compounds has increased at an alarming rate in recent decades. Among such contaminants, di-2-ethylhexyl phthalate (DEHP) is an extensively used compound in plastics and plastic products to make them flexible. DEHP causes several adverse effects such as reproductive toxicity leading to infertility, miscarriage and litter size reduction, disruption of the thyroid endocrine system, oxidative stress, neurodevelopmental defect and cognitive impairment. An aquatic environment is a fragile site, where the accumulation of DEHP poses a significant threat to living organisms. In this context, the present study focused on whether the neurobehavioural transformation following exposure to DEHP is an outcome of augmented oxidative stress and neuromorphological alteration in the zebrafish brain. Our preliminary findings advocate that DEHP acts as a typical neurotoxicant in inducing neurobehavioural transformation in zebrafish. Furthermore, our study also supports the idea that DEHP itself acts as a potent neurotoxicant by altering the glutathione biosynthetic pathway through the induction of oxidative stress in the zebrafish brain. Similarly, our findings also link the abovementioned neurobehavioural transformation and oxidative stress with augmented neuronal pyknosis and chromatin condensation in the periventricular grey zone of the zebrafish brain following chronic exposure to DEHP. Therefore, the overall conclusion of the present study advocates the potential role of DEHP in inducing neuropathological manifestation in the zebrafish brain. Future research directed towards elucidating the neuroprotective efficacy of natural compounds against DEHP-induced neurotoxicity may provide a new line of intervention.

DZIP3/hRUL138 is a poorly characterized RNA-binding RING E3-ubiquitin ligase with functions in embryonic development. Here we demonstrate that DZIP3 is a crucial driver of cancer cell growth, migration, and invasion. In mice and zebrafish cancer models, DZIP3 promoted tumor growth and metastasis. In line with these results, DZIP3 was frequently overexpressed in several cancer types. Depletion of DZIP3 from cells resulted in reduced expression of Cyclin D1 and a subsequent G1 arrest and defect in cell growth. Mechanistically, DZIP3 utilized its two different domains to interact and stabilize Cyclin D1 both at mRNA and protein levels. Using an RNA-binding lysine-rich region, DZIP3 interacted with the AU-rich region in 3′ untranslated region of Cyclin D1 mRNA and stabilized it. Using a RING E3-ligase domain, DZIP3 interacted and increased K63-linked ubiquitination of Cyclin D1 protein to stabilize it. Remarkably, DZIP3 interacted with, ubiquitinated, and stabilized Cyclin D1 predominantly in the G1 phase of the cell cycle, where it is needed for cell-cycle progression. In agreement with this, a strong positive correlation of mRNA expression between DZIP3 and Cyclin D1 in different cancer types was observed. Additionally, DZIP3 regulated several cell cycle proteins by modulating the Cyclin D1–E2F axes. Taken together, this study demonstrates for the first time that DZIP3 uses a unique two-pronged mechanism in its stabilization of Cyclin D1 to drive cell-cycle and cancer progression.Significance:These findings show that DZIP3 is a novel driver of cell-cycle and cancer progression via its control of Cyclin D1 mRNA and protein stability in a cell-cycle phase-dependent manner.