Enhanced proliferative response of hepatocytes to combined inhalation and oral exposures to N,N-dimethylformamide in male rats

Abstract

Male Wistar rats were exposed by inhalation to N,N-dimethylformamide (DMF) at 0 (control), 200 or 400 ppm (v/v) for 6 hr/day, 5 days/week and 4 weeks, and each inhalation group received DMF-formulated drinking water at 0, 800, 1,600 or 3,200 ppm (w/w) for 24 hr/day, 7 days/week and 4 weeks. Both the combined inhalation and oral exposures and the single-route exposure through inhalation or ingestion induced centrilobular hypertrophy and single-cell necrosis of hepatocytes, increased plasma levels of alanine aminotransferase (ALT), increased percentage of proliferating cell nuclear antigen (PCNA)-positive hepatocytes without glutathione-S-transferase placental form (GST-P)-positive liver foci, and increased relative liver weight. Those hepatic parameters of the DMF-induced effects were classified into hypertrophic, necrotic and proliferative responses according to the pathological characteristics of affected liver. While magnitudes of the hypertrophic and necrotic responses were linearly increased with an increase in amounts of DMF uptake in the single-route exposure groups, those dose-response relationships tended to level off in the combined-exposure groups. Saturation of the hypertrophic and necrotic responses at high dose levels might be attributed to suppression of the metabolic conversion of DMF to its toxic metabolites. Percentage of PCNA-stained hepatocytes classified as the proliferative response was increased more steeply in the combined-exposure groups than in the single-route exposure groups. It was suggested that the proliferative response of hepatocytes to the combined exposures would be greater than that which would be expected under an assumption of additivity for the component proliferative responses to the single-route exposures through inhalation and ingestion.

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A Luminescent Metal–Organic Framework as a Turn‐On Sensor for DMF Vapor

“…[4l] Recent studies have suggested that serious health concerns are associated with DMF exposure both through skin contact and inhalation in various industries, such as the production of synthetic fibers, films, and coatings, and leather tanning. Studies of exposed workers [7] and animal experiments [8] have confirmed the hepatotoxicity of DMF; other toxic effects have been suggested including embryotoxicity [9] and carcinogenesis. [10] Because of the large population at risk…”

Oxidative stress‐related DNA damage and homologous recombination repairing induced by N,N‐dimethylformamide

“…Overall, two hotspots of DMF studies can be concluded: one is related to the target organ liver, and the other is associated with biological metabolism. The most common toxic endpoints or pathology markers detected on DMF‐induced hepatotoxicity include liver function abnormality, serum enzymatic activity, the incidence of hepatocellular adenoma and liver cell necrosis (Fleming et al ., ; Lynch et al ., ; Ohbayashi et al ., ; Hamada et al ., ; Ohbayashi et al ., ). However, the potential mechanism of hepatotoxicity has not yet been clearly investigated.…”

“…Toxicological data available for DMF are mainly focused on animal inhalation or oral exposure, and epidemiological research in the last few decades (Table ) (Fleming et al ., ; Fiorito et al ., ; Nomiyama et al ., ; Lynch et al ., ; Senoh et al ., ; Chang et al ., ; Senoh et al ., ; Ohbayashi et al ., ; Ohbayashi et al ., ; Hamada et al ., ; Rui et al ., 2011). Overall, two hotspots of DMF studies can be concluded: one is related to the target organ liver, and the other is associated with biological metabolism.…”