Reproductive and transgenerational toxicity of bisphenol S exposure in pregnant rats: Insights into hormonal imbalance and steroid biosynthesis pathway disruption.

Bisphenol S (BPS) is an alternative chemical to bisphenol A commonly used in food packaging materials. It raises concerns due to potential adverse effects on human health. However, limited evidence exists regarding reproductive toxicity from BPS exposure, and the mechanism of associated transgenerational toxicity remains unclear. In this study, pregnant SD rats were exposed to two different doses of BPS (0.05 or 20 mg/kg) from GD6 to PND21. The objective was to investigate reproductive and transmissible toxicity induced by BPS, explore endocrine effects, and uncover potential underlying mechanisms in rats. Perinatal exposure to BPS in the F0 generation significantly decreased the rate of body weight, ovarian organ coefficient, and growth and development of the F1 generation. Notably, these changes included abnormal increases in body weight and length, estrous cycle disruption, and embryonic dysplasia in F1. 4D-DIA proteomic and PRM analyses revealed that exposure to 20 mg/kg group significantly altered the expression of proteins, such as Lhcgr and Akr1c3, within the steroid biosynthetic pathway. This led to elevated levels of FSH and LH in the blood. The hypothalamic-pituitary-ovarian (HPO) axis, responsible for promoting fertility through the cyclic secretion of gonadotropins and steroid hormones, was affected. RT-qPCR and Western blot results demonstrated that the expression of GnRH in the hypothalamus was decreased, the GnRHR in the pituitary gland was decreased, and the expression of FSHß and LHß in the pituitary gland was increased. Overall, BPS exposure disrupts the HPO axis, hormone levels, and steroid biosynthesis in the ovaries, affecting offspring development and fertility. This study provides new insights into the potential effects of BPS exposure on the reproductive function of the body and its relevant mechanisms of action.

Resveratrol induces apoptosis in SGC-7901 gastric cancer cells.

The aim of the present study was to investigate the effect of resveratrol on apoptosis in SGC-7901 gastric cancer cells and its molecular mechanisms of action. Following resveratrol treatment, the inhibition rate of SGC-7901 cells was determined using an MTT assay. The morphological changes in apoptosis were observed by fluorescence microscopy based on acridine orange/ethidium bromide double staining. Furthermore, cell cycle and apoptosis were detected using flow cytometry, and the expression levels of nuclear factor κB (NF-κB) as well as apoptosis-associated proteins [B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), cleaved caspase-3 and cleaved caspase-8] were analyzed by western blotting. The results of the present study indicated that resveratrol was able to significantly inhibit the viability of SGC-7901 cells in a dose- and time-dependent manner. When treated with 200 µM resveratrol, the inhibition rate of SGC-7901 cells reached ~50%. In the presence of resveratrol, the proportion of apoptotic cells was also increased in a dose-dependent manner. Flow cytometry revealed that resveratrol induced S-phase arrest of SGC-7901 cells. When treated with 50, 200 and 400 µM resveratrol, the proportions of SGC-7901 cells in the S-phase were respectively increased to 33.8±2.42, 60.01±2.43 and 56.05±2.67%, compared with 25.62±3.29% for the control group cells in S-phase. Additionally, the levels of the pro-apoptotic proteins Bax, cleaved caspase-3 and cleaved caspase-8 were upregulated in a dose-dependent manner, whereas the level of the anti-apoptotic protein Bcl-2 was downregulated dose-dependently. Importantly, the activation of NF-κB (p65) was evidently decreased following treatment with resveratrol compared with in the control group. In conclusion, the results of the present study revealed that resveratrol was able to inhibit viability and induce apoptosis in SGC-7901 cells by suppressing NF-κB activation. Therefore, resveratrol may be considered as a potential drug candidate for the treatment of gastric cancer.

High-throughput transcriptome sequencing reveals the combined effects of key e-waste contaminants, decabromodiphenyl ether (BDE-209) and lead, in zebrafish larvae.

PBDEs and heavy metals are two major contaminants at e-waste disposal sites, but their combined effects remain largely unexplored. In the present study, the transcriptomic profiles of zebrafish larvae were examined after acute exposure of embryos to 200 µg/L BDE-209, 20 µg/L lead (Pb) or their mixture (Mix). Stimulation of steroidogenic pathway and vitellogenesis in the BDE-209 and Mix treatments indicated the estrogenic activities of BDE-209, while Pb antagonized those estrogenic effects in the Mix treatment. Increased heart rates were observed in zebrafish exposed to the Pb and Mix treatments. The cardiac dysfunction probably resulted from the promotion of angiogenesis, increased adrenergic drive and induction of the formation of blood clot. Furthermore, the Pb and Mix treatments activated neuroendocrine regulation of the pituitary in a positive feedback loop, via the thyrotropin-releasing hormone receptor, thus increasing thyroid hormone production self-adaptively. Overall, the interaction between BDE-209 and Pb led to synergistic and antagonistic effects on gene transcriptions, with concerted contribution from their individual toxicological properties.

Effect of combined exposure to lead and decabromodiphenyl ether on neurodevelopment of zebrafish larvae.

The effect of combined exposure to decabromodiphenyl ether (BDE-209) and lead (Pb) on neurodevelopment of zebrafish (Danio rerio) larvae was investigated. Zebrafish embryos were exposed to Pb (0, 5, 10, 20 µg/L) and BDE-209 (0, 50, 100, 200 µg/L), either alone or in combination (Mix1: 5 + 50 µg/L, Mix2: 10 + 100 µg/L, Mix3: 20 + 200 µg/L) for up to 144 h post-fertilization. Growth of secondary motoneuron axons and expression of genes related to central nervous system development was significantly inhibited in Mix3 co-exposure group. A significant increase in reactive oxygen species (ROS), lipid peroxidation, DNA damage, and perturbation of the antioxidant system was detected in the Mix3 group compared to single-toxicant treatments or control. Depressed locomotor activity was recorded in the Mix2 and Mix3 groups. Addition of N-acetyl cysteine to Mix3 eliminated excessive ROS, and protected against lipid peroxidation, DNA damage, and locomotor dysfunction. Pb uptake was increased in the presence of BDE-209, but BDE-209 bioconcentration and the ability to metabolize BDE-209 were decreased in the presence of Pb. These results suggest that BDE-209 and Pb have a synergistic disruptive effect on neurodevelopment in zebrafish larvae by enhanced generation of ROS, which is a major factor that contributes to developmental neurotoxicity.

Impact of co-exposure with lead and decabromodiphenyl ether (BDE-209) on thyroid function in zebrafish larvae.

Polybrominated diphenyl ethers (PBDEs) and metals are the main contaminants at waste electrical and electronic equipment ("e-waste") recycling sites. However, the potential environmental health effects of mixtures of PBDEs and metals are not known. We investigated co-exposure of lead (Pb) with decabromodiphenyl ether (BDE-209) on thyroid function in zebrafish larvae. Seven groups of embryos/larvae of zebrafish were treated with Pb (0, 2, 5, 10, 15, 20, and 30 µg/L), six groups were exposed to BDE-209 (0, 50, 100, 200, 400, and 800 µg/L), and nine groups of zebrafish larvae were treated with Pb and BDE-209 (5, 10, and 20 µg/L Pb; 50, 100, and 200 µg/L BDE-209). Embryos/larvae were exposed from 2h post-fertilization (hpf) until 144 hpf, and thyroid hormone (TH) content measured. Pb exposure significantly decreased whole-body TH contents (triiodothyroxine (T3) and thyroxine (T4)) but BDE-209 exposure significantly increased T3 and T4 levels. Pb or BDE-209 treatment alone caused a predicted downregulation of TH transport (i.e., expression of the mRNA or proteins of transthyretin). Chemical analyses showed Pb uptake to be increased by BDE-209, but BDE-209 bioconcentration was decreased and the ability to metabolize BDE-209 was reduced in the presence of Pb. We also found that a mixture of the two chemicals had a synergistic effect on TH levels in zebrafish.