Toxicological Sciences最新文献

Tylosin, a broad-spectrum macrolide antibiotic, is used to treat chronic respiratory infectious diseases in both urban and commercial broiler chickens and laying hens in an extra-label manner. To ensure food safety and facilitate extra-label withdrawal interval (WDI) estimations, a physiologically based pharmacokinetic (PBPK) model for tylosin in broiler chickens and laying hens was developed. The model structure encompassed plasma, crop, gizzard, small intestine, colon, muscle, liver, kidney, fat, rest of body, and an integrated reproductive system consisting of the ovary and oviduct (for hens). This model adequately predicted the pharmacokinetics of tylosin in plasma, tissues, egg yolk and white under different scenarios in both broilers and layers with determination coefficients of 0.87 and 0.78, respectively. The model was converted to a user-friendly web-based interface. The estimated WDIs were 2.0, 3.0, 4.0, 2.0, and 2.0 days for eggs, kidney, liver, muscle, and fat, respectively, based on FDA tolerance after daily oral administration at 110 mg/kg tylosin via medicated water for five consecutive days in laying hens. This model provides a useful and flexible tool for food safety assessment of tylosin in chickens and lays the groundwork for extrapolating to other drugs in other poultry species.

Titanium dioxide nanoparticles (TiO2 NPs) are among the most widely produced metallic NPs due to commercial and industrial applications in products including food, cosmetics, paints, and plastics. TiO2 NPs are released into the environment posing health risks for humans and wildlife. Widespread uses have raised concerns about the potential toxicity of TiO2 NPs in reproduction. The ovary is an important endocrine organ responsible for sex steroid hormone production and folliculogenesis. NPs can reach the ovary, but limited information is available regarding NP toxicity and its effects on ovarian antral follicles. Thus, we tested the hypothesis that exposure to TiO2 NP affects sex hormone synthesis, oxidative stress, and antioxidant response in ovarian antral follicles in vitro. In addition, we characterized the NP internalization in the antral follicles over time to determine any association between NP internalization and effects on the antral follicle. Antral follicles were exposed to vehicle control or TiO2 NPs (5, 25, and 50 µg/ml) for 96 h. The lowest NP concentration (5 µg/ml) showed no internalization and no effects in antral follicles. The 25-µg/ml concentration had the highest internalization rate, leading to increased mRNA ratio of Bax to Bcl2. Interestingly, the highest concentration (50 µg/ml) showed lower internalization compared with the 25 µg/ml, with altered levels of steroidogenic involved genes and increased levels of progesterone and testosterone compared with control. In conclusion, these data suggest that TiO2 NP is internalized in antral follicles as the first step process in impairing follicle functions.

There is growing evidence that organophosphate esters (OPEs) can act as endocrine-disrupting chemicals. However, only a few studies have assessed the effects of OPE exposure on one of the most important endocrine glands in the body, the adrenal gland. Our aim was to test the effects of a mixture of OPEs detected in Canadian house dust on adrenal function in Sprague Dawley rats. Adult male and female rats (n = 15 per treatment group) were administered either a vehicle or an OPE mixture (0.048, 1.6, or 48 mg/kg bw/d) for 70 to 72 d via their diet. With OPE exposure, adrenal glands from male adult rats were reduced in weight, whereas those of female rats showed an increase in weight. This led us to investigate whether OPEs induce sex-specific effects on adrenal gland function and the mechanisms involved. Serum levels of two adrenal hormones, aldosterone and corticosterone, were decreased only in male serum samples. Serum levels of renin and adrenocorticotropic hormone, which regulate aldosterone and corticosterone synthesis, respectively, were assessed. Exposure to the OPE mixture decreased renin levels only in males. Serum biochemistry analysis revealed that triglycerides and LDL cholesterol levels were increased in males. Transcriptomic analysis revealed that the top affected pathways in male adrenal glands from all three treatment groups were related to potassium channels, which play a role in regulating aldosterone and corticosterone levels. The most affected pathways in female adrenal glands were related to cholesterol biosynthesis and immune functions. These results show that an environmentally relevant mixture of OPEs affects adrenal function and that these effects are sex specific.

Ozone is an urban air pollutant known to cause lung injury and altered function. Using established models of acute (0.8 ppm, 3 h) and episodic (1.5 ppm, 2 h, 2 times/wk, 6 wk) inhalation exposure, we observed distinct structural changes in the lung; whereas acutely, ozone primarily disrupts the bronchiolar epithelial barrier, episodic exposure causes airway remodeling. Herein we examined how these responses altered pulmonary function. A SCIREQ small animal ventilator was used to assess lung function; impedance was used to conditionally model resistance and elastance. Episodic, but not acute ozone exposure reduced the inherent and frequency-dependent tissue recoil (elastance) of the lung. Episodic ozone also increased central and high-frequency resistance relative to air control after methacholine challenge, indicating airway hyperresponsiveness. Pressure-volume (PV)-loops showed that episodic ozone increased maximum lung volume, whereas acute ozone decreased lung volume. Episodic ozone-induced functional changes were accompanied by increases in alveolar circularization; conversely, minimal histopathology was observed after acute exposure. However, acute ozone exposure caused increases in total phospholipids, total surfactant protein D (SP-D), and low-molecular weight SP-D in bronchoalveolar lavage fluid. Episodic ozone exposure only increased total SP-D. These findings demonstrate that acute and episodic ozone exposure caused distinct alterations in surfactant composition and pulmonary function. Whereas loss in PV-loop area following acute ozone exposure is likely driven by increases in SP-D and inflammation, emphysematous pathology and airway hyperresponsiveness after episodic ozone appear to be the result of alterations in lung structure.

MicroRNA (miRNAs) have been associated with drug-induced kidney injury (DIKI). However, there are few reports on the utility of miRNAs, when monitoring for nephrotoxicity across multiple species. The purpose of this study was to assess the value of urinary miRNA profile changes as renal safety biomarkers, when monitoring for kidney injury in investigative toxicology studies. To this end, we evaluated urine miRNA expression levels in response to amphotericin B (AmpB-induced nephrotoxicity in mice, rats and dogs. The results showed that 35 miRNAs were significantly differentially expressed across the three species in response to the induced renal injuries. Dogs showed the highest number of miRNAs with significant changes. miR-205-5p and miR-31-5p were the most consistently altered miRNA biomarkers across all three species. In rodents, these two miRNAs were the most sensitive markers and showed comparable or better sensitivities than the previously published urine protein biomarkers with the same nephrotoxicant. In dogs, none of the upregulated miRNAs were as sensitive as urine clusterin protein as observed in a previously published study with AmpB. Taken together, these miRNAs could complement the more established urinary protein biomarkers in monitoring DIKI in mice, rats and dogs. To our knowledge, this is the first report that demonstrates the comparative utility of urinary miRNAs for the early detection of DIKI across three nonclinical animal models.

There is widespread concern that environmental exposures constitute an underappreciated but significant contribution to rising rates of neurodevelopmental disorders (NDDs). There is also international consensus that regulatory frameworks for developmental neurotoxicity (DNT) testing are woefully inadequate, prompting reappraisal of DNT testing methods. One approach aims to make testing more efficient, less animal-intensive, and higher throughput, through in vitro evaluation of DNT. These new approach methodologies (NAMs) promise to accelerate and standardize DNT testing through interrogation of fundamental mechanisms of neurodevelopment. While in the early stages of development, they have significant, well-publicized shortcomings, including little to no accounting for cellular or genetic diversity, cell extrinsic signaling molecules, sex as a biological variable, developmental stage, or relevance to NDDs. One of the most advanced NAM platforms is a collection of 17 in vitro assays termed the DNT in vitro battery (IVB). While it models some aspects of neurodevelopmental processes, it fails to capture others. Proper brain ontogeny, and consequently normal behavior and cognition, relies on the integrity of fundamental mechanisms, their temporal/spatial fidelity, and the magnitude of their expression. These fundamental mechanisms are regulated by factors not considered by the DNT IVB including diverse cell types and neurotransmitters. While the DNT IVB could prove to be an important tool in DNT hazard detection, we identify key areas, including cell-extrinsic neurotransmitter signaling, diversity of neural progenitors, interneurons, and biological sex, that should be prioritized for development and inclusion in future refinements to meaningfully enhance biological coverage and relevance to human cognition and behavior.

Exposure of perfluorohexane sulfonate (PFHxS) is associated with hepatomegaly and accumulation of lipids that may be mediated by nuclear receptors like peroxisome proliferator-activated receptor-α (PPARα), constitutive androstane receptor (CAR), or pregnane X receptor (PXR). This study tested the hypotheses that: 1) PFHxS causes changes in liver by activating PPARα, CAR or PXR, and 2) there is a species difference in PPARα activity by PFHxS. Wild-type, Ppara-null, and PPARA-humanized mice were fed either a control diet, or one containing 2.2 mg PFHxS/kg diet or 25.8 mg PFHxS/kg diet for either seven or twenty-eight days, and target gene expression was examined. Relative liver weights were similar after seven days with either 2.2 or 25.8 mg PFHxS/kg dietary exposure compared to controls. Relative liver weights were higher after treatment for twenty-eight days in all three genotypes fed 25.8 mg PFHxS/kg diet compared to controls. The concentration of PFHxS was dose-dependently increased in serum and liver compared to controls. PFHxS exposure of 2.2 and 25.8 mg PFHxS/kg diet caused an increase in expression of PPARα target genes in wild-type mice and this effect was not observed in similarly treated Ppara-null mice or PPARA-humanized mice. Administration of PFHxS caused increased expression of the CAR target gene Cyp2b10 in all three genotypes at both timepoints, and the PXR target gene Cyp3a11 in all three genotypes after twenty-eight days. Exposure to PFHxS can increase liver weight due in part to the activation of mouse, but not human, PPARα. Activation of CAR and PXR by PFHxS also likely contributes to the observed hepatomegaly in all three genotypes.

Formaldehyde (FA) is a common chemical linked to respiratory problems such as airway hyperresponsiveness and pulmonary inflammation. Due to its toxicological effects and ease of mass production, FA is also recognized as a significant chemical threat by the U.S. Department of Homeland Security. This study investigates the role of mast cells in the pulmonary inflammatory response to acute high dose FA exposure. Using wild type (C57BL/6J) and mast cell-deficient (KitW-sh) mouse models, we assessed the impact of oropharyngeal aspiration of FA on lung pathology. Our findings reveal that C57BL/6J mice experienced significant increases in cellular infiltration, altered immune cell populations, and changes in lipid mediator profiles. In contrast, KitW-sh mice exhibited significantly reduced inflammatory responses. Notably, the presence of mast cells was associated with enhanced dendritic cell migration and differential production of bioactive lipid mediators, such as specialized pro-resolving mediators and pro-inflammatory leukotrienes in C57BL/6J mice. These results highlight the crucial role of mast cells in the immune response to formaldehyde and suggest they could be therapeutic targets for treating FA-induced lung inflammation.

An overdose of acetaminophen (APAP) is the leading cause of drug-induced hepatotoxicity and acute liver failure (ALF) in the United States. It is established that the predominant mode of hepatocyte cell death after an APAP overdose is through necrosis, and it is now recognized that this occurs through regulated pathways involving RIP kinases. These kinases, along with the pseudo-kinase MLKL are central players in classical necroptotic cell death. Despite the skepticism regarding the role of necroptosis in APAP-induced liver injury, recent research demonstrating necroptosis-independent roles for MLKL led us to re-examine the role of this pseudo-kinase in APAP pathophysiology. Treatment of Mlkl-/-mice with a moderate (300 mg/kg) overdose of APAP resulted in an exacerbation of liver injury at 6- and 12-hours post-APAP as evidenced by elevated plasma alanine aminotransferase activities, and extensive necrosis accompanied by diminished glutathione levels. Interestingly, these differences between Mlkl-/- and wild type mice were negated at the 24-hour mark, previously scrutinized by others. At 6 and 12 hours post APAP, Mlkl-/- mice exhibited augmented translocation of AIF and Endonuclease G without affecting JNK activation, suggesting enhanced mitochondrial permeability transition in the absence of MLKL. Lack of MLKL also impacted autophagy, the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, with decreased levels of p62 and LC3B and increased expression of CHOP and GRP78 at 6 hours post APAP. In essence, our findings illuminate a noncanonical role for MLKL in the early phases of APAP-induced liver injury, warranting further exploration of its influence on APAP pathophysiology.

Formation of the placenta during gestation is required to support fetal growth and development. Derived from the placenta, trophoblast cells express nuclear and membrane-bound receptors. Among these receptors is the epidermal growth factor receptor (EGFR) which plays a key role in placental development. Activation of EGFR-mediated signaling in trophoblast cells regulates critical processes, such as proliferation, differentiation, invasion, and fusion during pregnancy, making it essential for normal placental formation. Dysfunction of EGFR in placental trophoblast cells has been associated with adverse pregnancy outcomes, including intrauterine growth restriction, preeclampsia, and preterm birth. Ubiquitous environmental chemicals, like polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorine pesticides, and bisphenols, have been reported to modulate EGFR signaling pathways, potentially contributing to placental dysfunction. This review explores the pivotal role of EGFR signaling in placental development and function, with a focus on how environmental chemicals interfere with EGFR-mediated pathways and placental cell functions as well as their implications for pregnancy outcomes. Findings presented herein underscore the need for further research into the effects of exposure to environmental chemicals on modulating EGFR signaling pathways in the context of placental health.