International Journal of Toxicology最新文献

Recombinant human lactoferrin (rhLF) is of commercial interest for immune support as a food ingredient. The objective was to evaluate the immunogenicity/alloimmunization potential of Helaina rhLF (effera™) from K. phaffii over a 28-day period compared to bovine LF (bLF). Study 1 was a randomized, double-blind, parallel arm, controlled trial where 66 healthy adults were randomly allocated to 1 of 3 groups: high-dose rhLF (3.4 g/d), low-dose rhLF (0.34 g/d), or bLF (3.4 g/d). Participants completed a 28-day supplementation period with follow-up visits on Days 28, 56, and 84. Study 2 was a 12-week observational study with no intervention that enrolled 24 healthy adults. In both studies, serum was obtained for analysis of anti-LF antibody levels as the primary endpoint. In Study 1, change from baseline to Day 56 in serum anti-bLF antibodies in the bLF group (least squares geometric mean and 95% confidence interval for the post/pre ratio: 3.01; 2.08, 4.35) was greater than the changes in serum anti-hLF antibodies in the low-dose rhLF (1.07; 0.77, 1.49; P < 0.001) and high-dose rhLF (1.02; 0.62, 1.70; P < 0.001) groups. The rhLF groups had similar changes to the observational study, indicating no change in anti-hLF antibodies and no evidence of alloimmunization following ingestion. Changes in safety outcomes were similar between groups and within normal ranges. These results show that under the conditions of the protocol, no increased anti-hLF antibodies or adverse events were identified following ingestion of effera™ as a food ingredient at an intake level up to 3.4 g/d in healthy adults (clinicaltrials.gov: NCT06012669).

The long-term effect of fluoridated water consumption during development on the velocity of nerve impulse conduction in the sciatic nerve of rats was assessed. Thirty male Wistar rats, 21 days old, were randomly assigned to five groups. Three groups were given fluoridated water ad libitum (as the only source) at different concentrations (10, 100, and 150 ppm), designated as groups F10, F100, and F150, respectively. The study included a control group (C) that received fluoridated water at the maximum level established by the World Health Organization (1.5 ppm of fluorides) and another group that received deionized water (DW). The animals were treated until they reached 90 days of age. Electrophysiological recordings were performed on the rats' sciatic nerves to determine nerve conduction velocity, and blood plasma was extracted for fluoride concentration analysis. The study found that the F150 group had a lower nerve impulse conduction velocity in the sciatic nerve compared to the C group (P = 0.0015). Additionally, there was a negative correlation between the concentration of fluorides in plasma and the nerve conduction velocity (r = -0.5132, P = 0.0037). These findings indicate that chronic consumption of high concentrations of fluoride leads to a decrease in nerve conduction velocity. This, in conjunction with potential alterations in the central nervous system, may explain the deficits in learning and memory tests that have been documented in numerous studies evaluating individuals exposed to fluoride consumption. These results provide valuable information for understanding the effects and action mechanisms of fluoride in exposed individuals.

Nanoplastics (NPx) can enter living organisms, including humans, through ecosystems, inhalation, and dermal contact and can be found from the intestine to the brain. However, it is unclear whether NPx accumulates and affects the dopamine system. In this study, we investigated the effects of NPx on the dopamine system in cultured murine cerebral cortex neurons. Cultured cerebrocortical neurons were treated with 100 nm NPx at the following concentrations for 24 h: 1.896 × 10⁵, 3.791 × 10⁶, 7.583 × 10⁷, 1.571 × 10⁹, 3.033 × 10¹⁰, and 3.033 × 10¹¹ particles/mL. Dopamine-associated proteins were analyzed using immunofluorescence staining. NPx treatment induced its accumulation in neurons in a dose-dependent manner and increased the levels of dopamine receptors D1 and D2 and their co-expression. However, NPx treatment did not affect the levels of other dopamine receptors, dopamine transporters, tyrosine hydroxylase, and microtubule-associated protein 2, or synaptophysin in neuronal structures. This study demonstrated that NPx is a potential modulator of the dopamine system via its receptors rather than its synthesis and reuptake in neurons and may be associated with dopamine-based psychiatric disorders.

Endocrine-disrupting chemicals (EDCs) play an important role in the incidence of type-2 diabetes. Di-2-ethyl hexyl Phthalate (DEHP) is one of the endocrine-disrupting chemicals used as a plasticizer to impart flexibility and softness to plastic-containing materials. Mono-2-ethylhexyl Phthalate (MEHP), a DEHP's primary metabolite, is preferentially absorbed once metabolized. A previous study from our laboratory showed that DEHP and MEHP altered the key proteins such as insulin receptor (INSR) and glucose transporter-4 (GLUT4) in L6 myotubes. In a sequel to the previous study, the present study hypothesized that DEHP and its metabolite MEHP may alter the Insr and Glut4 gene expression in L6 myotubes. Therefore, to find out the molecular mechanism behind the decreased INSR and GLUT4 protein levels in the previous study, the direct effect of DEHP and its metabolite MEHP in regulating Insr and Glut4 gene transcription in L6 myotubes was studied. The L6 myotubes were exposed to 50 and 100 μM DEHP and MEHP for 24 h, followed by insulin stimulation for 20 min. We observed decreased Insr and Glut4 mRNA levels in DEHP and MEHP-treated groups. Western blot data showed decreased protein levels of MEF2A and MyoD in treated groups. ChIP assay detected a decreased association of MEF2A and MyoD to the Glut4 gene promoter and HMGA1 to the Insr gene promoter. The study revealed that DEHP and MEHP diminished the Insr and Glut4 gene expression through weakened interaction of their transcription factors on the respective promoter.

The presence of polystyrene plastics in the human testis has raised concerns, yet their biological activity remains poorly characterized. This study aimed to investigate the biological effects and potential regulatory genes of polystyrene nanoplastics on spermatocyte line, GC-2spd(ts). After a 24-h exposure to polystyrene nanoplastics, the results indicated cell membrane disruption, impairment of mitochondrial membrane potential, increased levels of reactive oxygen species (ROS), and induced DNA damage. Furthermore, a comprehensive transcriptomic analysis was conducted, revealing differential gene expression patterns in GC-2spd(ts) cells in response to polystyrene nanoplastics. A total of 134 differentially expressed genes (DEGs) were identified, with 48 genes upregulated and 86 genes downregulated. The Gene Ontology analysis highlighted the involvement of these genes in various spermatogenesis-related biological processes, including acrosome reaction, sperm mitochondrial organization, sperm annulus, and outer acrosomal membrane. Subsequently, the quantification of gene expression through qRT-PCR identified five key genes (NSUN7, SEPTIN4, TRIM36, EQTN, and SYT8) screened from the DEGs. In conclusion, this study provides valuable insights into the biological effects of polystyrene nanoplastics on mouse spermatocytes using comprehensive transcriptomic analysis, contributing to the establishment of a foundation for future investigations into these relevant pathways.

Drug development is a lengthy process that promotes and protects the health and safety of future patients. Nonclinical safety studies follow essentially similar designs that fulfill regulatory requirements but are amended based on factors including the mechanism of action, class of molecule, and route of administration. Clinical observations, clinical pathology, and macroscopic pathology in dose range-finding (DRF) studies generally provide sufficient information to select doses for pivotal studies by most delivery routes. Inhaled drug candidates are recognized for producing adverse effects on the respiratory system at the microscopic level that may otherwise be unpredictable; therefore, unlike other routes of administration, inhalation DRF studies typically include histopathology of the respiratory tract. Histopathology evaluations can add several weeks to the Investigational New Drug (IND) application timeline along with additional costs but have been considered necessary to support accurate dose selection for adequate safety margins, thereby potentially avoiding additional studies and animal usage by ensuring achievement of a NOAEL in the pivotal studies. Therefore, DRF inhalation studies initiated from 2018 to 2021 at Labcorp were reviewed to determine whether inclusion of histopathology on preliminary inhalation studies was necessary for subsequent dose selection. Histopathology findings in the DRF impacted dose selection in pivotal inhalation studies for approximately 45% of rat and dog studies. This review identified histopathology findings in rat and dog that support continued inclusion of respiratory tract histopathology in DRF studies. Future investigations will evaluate potential surrogate endpoints for these findings, which could reduce nonclinical drug development timelines by several weeks.

The skin is the largest organ in the body and the only one to come into contact with solar UV radiation (UVR). UVA (320-400 nm) is a significant contributor to UV-related skin damage. The UVA spectrum makes up over 95% of solar-UV energy reaching the earth's surface causing the majority of the visible signs of skin photoaging. Many consumer products also emit UVA, including nail dryers. There have been sporadic reports suggesting that these units may be contributing to skin cancer incidence. This notion was recently bolstered by a finding that nail dryer-irradiated mammalian skin cells develop a mutational signature consistent with UVA exposure. This report was surprising considering the comparatively low level of UVA to which the skin is exposed during nail treatments. In this research, we investigated how UVA-emitting devices caused cytotoxic/genotoxic impact after only low levels of UVA exposure. Our data showed that levels of UVA in the unit are highly variable and location dependent. We confirm previous reports that using prolonged exposure protocols could induce significant levels of DNA damage. It was also determined that UV-induced DNA damage only partially correlated with the level of UVA fluency. On investigation, we found that the unit had a rapid increase in internal temperature when in use. Exposing human cells to these elevated temperatures acted synergistically with UVA to magnify the cytotoxic and genotoxic impact of UV irradiation.

This is the 12th in a series of salary surveys conducted at approximately 3-year intervals for toxicologists that began in 1988. Previous salary surveys were conducted in 1988,¹ 1991,² 1995,³ 1998,⁴ 2001,⁵ 2004,⁶ 2007 (which was posted electronically, but not published), 2012,⁷ 2016,⁸ 2020,⁹ and 2022.¹⁰ In addition to presenting the 2024 results, herein we are providing additional data and an analysis of the trends for employment and pay in toxicology over the last 37 years.