Project description:The main constituents of electronic cigarette liquids are nicotine, propylene glycol (PG), and vegetable glycerin (VG), together with distilled water and flavors. To assess the toxicity of PG/VG mixtures with and without nicotine as basic components of liquids used in e-cigarettes, a 90-day rat inhalation study according to the Organization for Economic Co-operation and Development test guideline 413 was conducted. Sprague-Dawley (SD) rats were nose-only exposed, 6 h/day, 5 days/week to filtered air, or nebulized vehicle (saline), or three concentrations of PG/VG (0.174 mg PG/l + 0.210 mg VG/l; 0.520 mg PG/l + 0.630 mg VG/l; 1.520 mg PG/l + 1.890 mg VG/l) – with (test item) and without (reference item) 23 µg nicotine/L. Standard toxicological endpoints were complemented by molecular analyses using transcriptomics, proteomics, and lipidomics. Compared to vehicle exposure, the tested PG/VG aerosols showed only very limited biological effects with no signs of toxicity, both for the standard toxicological endpoints (e.g., histopathology, clinical chemistry) and the systems toxicological analyses (transcriptomics, proteomics, and lipidomics). The addition of nicotine to the PG/VG aerosols (23 µg/l) resulted in effects in line with nicotine effects in previous studies. These included up-regulation of xenobiotic enzymes (Cyp1a1 and Fmo3) in the lung and metabolic effects, e.g., reduction in serum lipid concentrations and changes in the expression of metabolic enzymes in the liver. Signs of a generalized stress response to nicotine exposure such as decreased thymus weights were observed; and likely, a subset of the observed metabolic alterations was interlinked with this generalized stress response. Under the conditions of this 90-day SD rat inhalation study, no toxicologically relevant effects of PG/VG aerosols (up to 1.520 mg PG/l + 1.890 mg VG/l) were observed, and the no observed adverse effect level (NOAEL) for PG/VG/nicotine was determined to be 438/544/6.7 mg/kg/day. Further the study demonstrated how complementary systems toxicology analyses can reveal, also in the absence of observable adverse effects, subtoxic and adaptive responses to pharmacologically active compounds such as nicotine.

Project description:The main constituents of electronic cigarette liquids are nicotine, propylene glycol (PG), and vegetable glycerin (VG), together with distilled water and flavors. To assess the toxicity of PG/VG mixtures with and without nicotine as basic components of liquids used in e-cigarettes, a 90-day rat inhalation study according to the Organization for Economic Co-operation and Development test guideline 413 was conducted. Sprague-Dawley (SD) rats were nose-only exposed, 6â€‰h/day, 5 days/week to filtered air, or nebulized vehicle (saline), or three concentrations of PG/VG (0.174 mg PG/l + 0.210 mg VG/l; 0.520 mg PG/l + 0.630 mg VG/l; 1.520 mg PG/l + 1.890 mg VG/l) with (test item) and without (reference item) 23 µg nicotine/L. Standard toxicological endpoints were complemented by molecular analyses using transcriptomics, proteomics, and lipidomics. Compared to vehicle exposure, the tested PG/VG aerosols showed only very limited biological effects with no signs of toxicity, both for the standard toxicological endpoints (e.g., histopathology, clinical chemistry) and the systems toxicological analyses (transcriptomics, proteomics, and lipidomics). The addition of nicotine to the PG/VG aerosols (23 Âµg/l) resulted in effects in line with nicotine effects in previous studies. These included up-regulation of xenobiotic enzymes (Cyp1a1 and Fmo3) in the lung and metabolic effects, e.g., reduction in serum lipid concentrations and changes in the expression of metabolic enzymes in the liver. Signs of a generalized stress response to nicotine exposure such as decreased thymus weights were observed; and likely, a subset of the observed metabolic alterations was interlinked with this generalized stress response. Under the conditions of this 90-day SD rat inhalation study, no toxicologically relevant effects of PG/VG aerosols (up to 1.520 mg PG/l + 1.890 mg VG/l) were observed, and the no observed adverse effect level (NOAEL) for PG/VG/nicotine was determined to be 438/544/6.7 mg/kg/day. Further the study demonstrated how complementary systems toxicology analyses can reveal, also in the absence of observable adverse effects, subtoxic and adaptive responses to pharmacologically active compounds such as nicotine.

Project description:In a subacute study, male Wistar rats were treated daily by gavage with 800 mg/kg metformin for 1, 3, or 14 consecutive days, followed by necropsy 24h after the last application. The biguanide metformin is a widely used antidiabetic drug, which has received great interest in oncology research in recent years after an epidemiological study showed a link between metformin treatment and a reduced cancer risk in diabetic patients. Since mitochondrial metabolism has become a target for possible cancer therapeutic approaches, especially for tumors relying on oxidative metabolism, mitochondrial complex I inhibition is under discussion to be responsible for the anti-cancer effect of metformin. The known strong complex I inhibitor Rotenone has also shown anti-cancer activity, however is associated with toxic effects. Therefore, we compared metformin and phenformin, another biguanide withdrawn from the marked as antidiabetic due to safety reasons, with rotenone, to elucidate potential mechanisms rendering biguanides apparently less toxic than rotenone. In this context, various blood and tissue parameters as well as histopathology were measured and/or evaluated. Moreover, gene expression profiling was conducted in liver and heart due to the high metabolic activity and high energy demand. All investigations were based on an experimental design previously described for mechanistic investigations of the effects of rotenone. Our examinations regarding gene expression showed that 1630 transcripts were deregulated by rotenone, metformin and/or phenformin in liver, whereas 777 transcripts were deregulated in heart, indicating that the heart is less affected by these compounds. Overall, the mechanistic profile of phenformin appears to be similar to that of rotenone, yet at a quantitatively reduced level, whereas metformin displayed only transient similarities after one day of treatment. These differences are likely due to differential molecular properties of these compounds, especially concerning their effects on mitochondria: Metformin, in contrast to rotenone, requires a certain mitochondrial potential to allow accumulation in this organelle, thereby self-limiting its entry and thus ability to inhibit mitochondrial function, whereas rotenone and to some extent also phenformin can enter mitochondria freely. Thus, our more detailed molecular characterization of these compounds suggests that inhibition of mitochondrial functions can serve as target for an anti-cancer mode of action, yet should be self-limited or balanced to some extent to avoid exhaustion of all energy stores.

			Action	DRS
	20220413.sld	Other
	MS2200232_C_4h.raw	Raw
	MS2200232_M_4h.raw	Raw
	MS2200232_Y_4h.raw	Raw
	MS2200232_b_4h.msf	Msf

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Toxicological Effects and Underlying Mechanisms of Chlorination–Derived Metformin Byproducts in Escherichia coli

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