Bin Wan

The present study aimed to establish a physiologically based toxicokinetic (PBTK) model to investigate the absorption, retention, and transport of inhaled nano-sized titanium dioxide (TiO₂-NPs) particles in rats, thereby providing a basis for understanding the absorption, distribution, and elimination mechanisms of TiO₂-NPs in various organs. A detailed respiratory module and the Hill coefficient equation were adopted in the PBTK model. Calibration and validation of the model were conducted using the only two available inhalation biodistribution datasets for TiO₂-NPs found in the literature, encompassing different doses and exposure conditions. The overall fit with both datasets was acceptable with R² value of 0.95 in respiratory system and 0.88 in the secondary organs. The sensitivity analysis indicated that the alveolar–interstitial transfer rate (K_{alv_inter}) and tissue–blood distribution coefficients (P_lu, P_li, P_ki) significantly influenced the retention of TiO₂-NPs in pulmonary regions and distribution to secondary organs, with these parameters exhibiting time-dependent behavior. The PBTK model demonstrates a good predictive performance for TiO₂-NPs content in all rat organs, with simulated values consistently ranging within 0.5- to 2-fold of the measured data. In last, we developed a PBTK model that can well predict the in vivo distribution of inhaled TiO₂-NPs and provided a novel computational tool for cross-species extrapolation of human inhalation exposure and subsequent biodistribution.

N-(1,3-Dimethylbutyl)-N'-phenyl-1,4-phenylenediamine (6PPD) and its oxidation product 6PPD-quinone (6PPDQ) showed different acute toxicities and bioaccumulation potencies in fish. In this study, we compared the thyroid disrupting effects of 6PPD and 6PPDQ through in vitro, in silico, and in vivo assays. Interestingly, although 6PPD and 6PPDQ showed similar docking affinities with thyroid hormone receptor (TR) isoforms and GH3 cell inhibition effects, the thyroid signaling pathway, eye development, phototactic behaviors, and cell density in the retinal layer in the larval zebrafish were significantly affected only following 6PPD exposure. Further investigation demonstrates that 6PPD can act as a TR antagonist to reduce the opsin protein abundance and inhibit the cone photoreceptor cell proliferation, which finally alters the retinal layer structure and causes microphthalmus in zebrafish. Especially, under environmental relevant concentration exposure, 6PPD induced alterations of trβ, opn1lw1, opn1mw1, rpe65a, nr2e3 gene expressions although no significant eye histopathological change was observed. This study illustrates for the first time the more serious visual system impairment of 6PPD compared to 6PPDQ, with thyroid signaling disruption being a contributing factor, while other important toxic targets still require further research.

Previous studies have demonstrated the reproductive toxicity of trifluorostrobin (TRI) in male organisms. However, the underlying mechanisms of TRI responsible for testicular damage and hormonal disruption remain elusive. This study elucidated the male reproductive toxicity of TRI at the molecular level under environmentally relevant concentrations and its associations with gut microbiota dysbiosis. The rats were administered TRI (1.5, 15, and 75 mg/kg of body weight/day) continuously via gavage for 90 days. Exposure to 15 mg/kg (below the no-observed adverse effect level (NOAEL) of 30 mg/kg) and 75 mg/kg TRI damaged testicular tissue, reduced sperm count, and lowered serum hormone and total cholesterol levels. Transcriptomics analysis combined with molecular docking simulations and cell proliferation assays showed that exposure to TRI led to testicular damage by inhibiting the expression of cholesterol receptor genes, which, in turn, disrupted steroid hormone biosynthesis. Furthermore, exposure to TRI resulted in a marked decline in the relative abundance of the probiotic bacteria. Consistently, significant reductions in the relative abundance of short-chain fatty acids (SCFAs), retinoic acids, and steroid hormones in the gut were observed. Additionally, a significant correlation was observed between the relative abundance of Parabacteroides and serum testosterone levels, a vital biomarker for reproductive toxicity monitoring. These findings shed light on the mode of action of TRI-induced male reproductive toxicity and highlight the link between testicular injury and gut microbiota.

As a phenylpyrazole insecticide, flufiprole is an important substitute for fipronil in the agricultural field of China. However, its bioaccumulation and metabolism in terrestrial organisms especially in the lizards living in the agricultural area have rarely been investigated. As an ectothermic animal, lizards are also sensitive to temperature changes. Considering global warming, this study measured bioaccumulation, metabolism, and hepatotoxicity of flufiprole in the Chinese native lizard (Eremias argus) under different temperature stresses. Lizards exposed to flufiprole-contaminated soil adsorbed flufiprole through the skin and flufiprole was preferred to accumulate in lizard liver and brain. The oxidation product fipronil sulfone was the main metabolite of flufiprole in both lizard liver and human liver microsomes, which were mainly metabolized by lizard CYP3A19 or human CYP3A4. The fipronil sulfone concentration increased with increased temperature in lizard tissues. In addition, more serious oxidative damage was shown under higher temperature as the glutathione (GSH), malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in lizards increased with increased temperature after flufiprole exposure. Flufiprole exposure also induced lizard liver lesions, and these lesions became more serious in the higher-temperature groups. This study provided new insights into the risk assessment of flufiprole in lizards under global warming.