Lead (Pb), a heavy metal environmental pollutant, poses a threat to the health of humans and birds. Inflammation is one of the most common pathological phenomena in the case of illness and poisoning. However, the underlying mechanisms of inflammation remain unclear. The cerebellum and the thalamus are important parts of the nervous system. To date, there have been no reports of Pb inducing inflammation in animal cerebellums or thalami. Selenium (Se) can relieve Pb poisoning. Therefore, we aimed to explore the mechanism by which Se alleviates Pb toxicity to the cerebellums and thalami of chickens by establishing a chicken Pb or/and Se treatment model. Our results demonstrated that exposure to Pb caused inflammatory damage in cerebellums and thalami, evidenced by the characteristics of inflammation, the decrease in anti-inflammatory factors (interleukin (IL)-2 and interferon-γ (INF-γ)), and the increase in pro-inflammatory factors (IL-4, IL-6, IL-12β, IL-17, and nitric oxide (NO)). Moreover, we found that the IL-2/IL-17–NO pathway took part in Pb-caused inflammatory injury. The above findings were reversed by the supplementation of dietary Se, meaning that Se relieved inflammatory damage caused by Pb via the IL-2/IL-17–NO pathway. In addition, an up-regulated oxidative index malondialdehyde (MDA) and two down-regulated antioxidant indices (glutathione (GSH) and total antioxidant capacity (TAC)) were recorded after the chickens received Pb stimulation, indicating that excess Pb caused an oxidant/antioxidant imbalance and oxidative stress, and the oxidative stress mediated inflammatory damage via the GSH–IL-2 axis. Interestingly, exposure to Pb inhibited four glutathione peroxidase (GPx) family members (GPx1, GPx2, GPx3, and GPx4), three deiodinase (Dio) family members (Dio1, Dio2, and Dio3), and fifteen other selenoproteins (selenophosphate synthetase 2 (SPS2), selenoprotein (Sel)H, SelI, SelK, SelM, SelO, SelP1, SelPb, SelS, SelT, SelU, and selenoprotein (Sep)n1, Sepw1, Sepx1, and Sep15), suggesting that Pb reduced antioxidant capacity and resulted in oxidative stress involving the SPS2–GPx1–GSH pathway. Se supplementation, as expected, reversed the changes mentioned above, indicating that Se supplementation improved antioxidant capacity and mitigated oxidative stress in chickens. For the first time, we discovered that the SPS2–GPx1–GSH–IL-2/IL-17–NO pathway is involved in the complex inflammatory damage mechanism caused by Pb in chickens. In conclusion, this study demonstrated that Se relieved Pb-induced oxidative stress and inflammatory damage via the SPS2–GPx1–GSH–IL-2/IL-17–NO pathway in the chicken nervous system. This study offers novel insights into environmental pollutant-caused animal poisoning and provides a novel theoretical basis for the detoxification effect of Se against oxidative stress and inflammation caused by toxic pollutants.

Lead (Pb), a hazardous heavy metal, can damage the health of organisms. However, it is not clear whether Pb can damage chicken cerebellums and thalami. Selenium (Se), an essential nutrient for organisms, has a palliative effect on Pb poisoning in chickens. In our experiment, a model of chickens treated with Pb and Se alone and in combination was established to investigate the molecular mechanism of Se alleviating Pb-caused damage in both chicken cerebellums and thalami. Our morphological results indicated that Pb caused apoptotic lesions, such as mitochondrial and nuclear damage. Further, the anti-apoptotic gene Bcl-2 decreased; on the contrary, four pro-apoptotic genes (p53, Bax, Cyt c, and Caspase-3) increased under Pb treatment, meaning that Pb caused apoptosis via the p53-Cyt c-Caspase-3 pathway. Furthermore, we further demonstrated that Pb elevated four HSPs (HSP27, HSP40, HSP70, and HSP90), as well as HSP70 took part in the molecular mechanism of Pb-caused apoptosis. In addition, we found that Pb exposure led to oxidative stress via up-regulating the oxidant H₂O₂ and down-regulating four antioxidants (CAT, SOD, GST, and GPx). Moreover, Pb decreased three Se-containing factors (Txnrd1, Txnrd2, and Txnrd3), further confirming that Pb caused oxidative stress. Interestingly, Se supplementation reversed the above changes caused by Pb and alleviated Pb-induced oxidative stress and apoptosis. A time dependency was demonstrated for Bcl-2, Bax, and Cyt c in the cerebellums, as well as CAT, GPx, and p53 in the thalami of Pb-exposed chickens. HSP70 in cerebellums and HSP27 in thalami were more sensitive than those in thalami and cerebellums, respectively, under Pb exposure. Pb-induced apoptosis of thalami was more severe than cerebellums. In conclusion, after Pb treatment, Txnrds mediated oxidative stress, oxidative stress up-regulated HSPs, and finally, HSP70 triggered apoptosis. Se supplementation antagonized Pb-induced oxidative stress and apoptosis via the mitochondrial pathway and selenoproteins in chicken cerebellums and thalami. This study provides new information for the mechanism of environmental pollutant poisoning and the detoxification of Se on abiotic stress.

Background/Objectives: In 4-octylphenol (4-OP), a toxic environmental pollutant with endocrine disruptive effect, the use of 4-OP causes pollution in the freshwater environment and poses risks to aquatic organisms. Common carps (Cyprinus carpio L.) live in freshwater and are experimental animals for studying the toxic effects of environmental pollutants on fish. Its heart is susceptible to toxicants. However, whether 4-OP has a toxic effect on common carp heart remains unknown. Methods: Here, we conducted a common carp 4-OP exposure experiment (carp treated with 17 μg/L 4-OP for 45 days), aiming to investigate whether 4-OP has a toxic effect on common carp hearts. We observed the microstructure and ultrastructure of carp heart and detected autophagy genes, mitochondrial fission genes, mitochondrial fusion genes, glycolytic enzymes, AMPK, ATPase, and oxidative stress factors, to investigate the molecular mechanism of 4-OP induced damage in common carp hearts. Results: Our results showed that 4-OP exposure caused mitochondrial damage, autophagy, and damage in common carp hearts. 4-OP exposure increased the levels of miR-144, and eight autophagy factors (Beclin1, RB1CC1, ULK1, LC3-I, LC3-II, ATG5, ATG12, and ATG13), and decreased the levels of four autophagy factors (PI3K, AKT, mTOR, and SQSTM1). Furthermore, 4-OP exposure induced the imbalance between mitochondrial fission and fusion and mitochondrial dynamics imbalance, as demonstrated by the increase in three mitochondrial fission factors (Mff, Drp1, and Fis1) and the decrease in three mitochondrial fusion factors (Mfn1, Mfn2, and Opa1). Moreover, excess 4-OP treatment caused energy metabolism disorder, as demonstrated by the reduction in four ATPase (Na⁺K⁺-ATPase, Ca²⁺Mg²⁺-ATPase, Ca²⁺-ATPase, and Mg²⁺-ATPase), elevation in four glycolysis genes (HK1, HK2, LDHA, and PGK1), reduction in glycolysis gen (PGAM2), and the elevation in energy-sensing AMPK. Finally, 4-OP treatment induced the imbalance between antioxidant and oxidant and oxidative stress, as demonstrated by the increase in oxidant H₂O₂, and the decreases in five antioxidant factors (CAT, SOD, T-AOC, Nrf2, and HO-1). Conclusions: miR-144 mediated autophagy by targeting PI3K, mTOR, and SQSTM1, and the miR-144/PI3K-AKT-mTOR/ULK1 pathway was involved in 4-OP-induced autophagy. Mff-Drp1 axis took part in 4-OP-caused mitochondrial dynamics imbalance, and mitochondrial dynamics imbalance mediated autophagy via Mfn2-SQSTM1, Mfn2/Beclin1, and Mff-LC3-II axes. Energy metabolism disorder mediated mitochondrial dynamics imbalance through the AMPK-Mff-Drp1 pathway. Oxidative stress mediated energy metabolism disorder via the H₂O₂-AMPK axis. Taken together, oxidative stress triggered energy metabolism disorder, induced mitochondrial dynamics imbalance, and caused autophagy via the H₂O₂-AMPK-Mff-LC3-II pathway. Our study provided references for the toxic effects of endocrine disruptor on common carp hearts, and provided a basis for assessing environmental pollutant-induced damage in common carp heart. We only studied the toxic effects of 4-OP on common carp, and the toxic effects of 4-OP on other fish species need to be further studied.

Lead (Pb) pollution is a global public health issue, yet the mechanisms underlying Pb-induced kidney aging remain poorly understood. Selenium (Se), an essential trace element critical for kidney health, primarily exerts its physiological roles via selenoproteins; among them, membrane-bound selenoproteins strategically localized at the endoplasmic reticulum and plasma membrane, have emerged as potential molecular links in Se-mediated protection. In this study, Hyline chicken models (treated with 350.00 mg/L Pb or/and 1.00 mg/kg Se) and HK-2 cell models (treated with 200 μM Pb or/and 2.5 μM Se) were established to investigate the protective mechanism of Se to Pb poisoning in kidneys, with emphasis on membrane-bound selenoproteins and kidney aging. Results showed that Pb significantly decreased (p < 0.05) membrane-bound selenoproteins and induced kidney aging. Inflammation and autophagy were involved, as Pb significantly increased (p < 0.05) pro-inflammatory cytokines interleukin-4 (IL-4) and interleukin-12β (IL-12β), and autophagy-related genes autophagy related 5 (ATG5), BCL2 interacting coiled coil protein 1 (Beclin 1), and microtubule-associated protein 1A/1B-light chain 3 (LC3-II) while significantly suppressing (p < 0.05) interleukin-2 (IL-2) and mammalian target of rapamycin (mTOR). Se had a relieving effect on it, as evidenced by significantly reversing (p < 0.05) the changes in the above indicators. Interestingly, Selenoprotein T (SELENOT), as a hub membrane-bound selenoprotein, is sensitive to Pb poisoning (Pb exposure decreased SELENOT mRNA expression to 56%, 34%, and 19% of the control levels at 30, 60, and 90 days, respectively). Knockdown of SELENOT aggravated Pb-induced inflammation, autophagy, and cellular senescence, meaning that SELENOT protected against kidney aging via suppressing inflammation and autophagy under Pb stress. These findings establish membrane-bound selenoproteins as essential molecular hubs that orchestrate inflammation resolution and autophagy in Se’s antagonism against Pb-induced kidney aging, highlighting promising therapeutic targets for nephropathy.

Manganese (Mn) pollution in aquatic environments poses threats to fish health, yet the molecular mechanisms of Mn-induced cardiac injury remain poorly understood. Epigallocatechin-3-gallate (EGCG), the major bioactive catechin in green tea, exhibits potent antioxidant and anti-inflammatory properties. Bioinformatics revealed overlap between Mn toxicity targets and EGCG-modulated genes, enriched in oxidative stress, ER stress and inflammation-related mechanisms. Therefore, this study aimed to investigate the molecular mechanisms by which Mn exposure induces cardiotoxicity in common carp and to evaluate whether dietary EGCG supplementation confers protection against cardiac injury, with particular focus on the roles of integrated stress response (ISR) and inflammation. Carp were exposed to Mn²⁺ with or without dietary EGCG. We found that Mn exposure resulted in myocardial histological structural damage, elevated serum cardiac injury markers, and reduced myocardial ATPase activities, indicating cardiac injury at the structural and biochemical levels. Mechanistically, Mn-induced oxidative stress (decreased SOD1, CAT, NRF2; increased MDA) was associated with ER stress and ISR-related transcript changes (upregulated HSPA5, DDIT3, eiF2AK4, atf4b) and triggered inflammatory responses (increased IL-1β, IL-6, IFN-γ, iNOS/NO), alongside upregulated inflammatory signaling nodes (NF-κB, STAT3, JUN, MAPK1, MAPK14b). EGCG supplementation significantly reversed these pathological changes. Importantly, ISRIB treatment in EPC epithelial cells and H9c2 rat cardiac-derived myoblasts attenuated Mn-induced inflammatory gene expression, providing supporting mechanistic evidence that ISR-associated signaling may contribute to inflammation, although these in vitro findings do not directly confirm the proposed mechanism in carp cardiomyocytes. Taken together, these findings support a proposed mechanistic framework in which waterborne Mn exposure is associated with oxidative stress, ER stress, and ISR-related signaling, together with inflammatory responses and cardiac injury in common carp, rather than a conclusively demonstrated causal pathway. Dietary EGCG supplementation attenuated these Mn-associated responses and was associated with reduced cardiac injury. Our work provide a new mechanistic way of thinking for understanding heavy metal-caused cardiac injury in fish and improving the current application potential of EGCG as an experimental dietary intervention for aquatic pollution stress management.