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PubMed1994

The effect of temperature at which slow cooling is terminated and of thawing rate on the survival of one-cell mouse embryos frozen in dimethyl sulfoxide or 1,2-propanediol solutions.

We investigated the slow freezing of one-cell mouse embryos with either dimethyl sulfoxide (Me2SO) or 1,2-propanediol (PROH) as the cryoprotectant. One-cell embryos, collected from superovulated C57BL/6J x CBA/Ca females were exposed to 1.5 M solutions of either Me2SO or PROH. The embryos were cooled at 0.3 degrees C/min to temperatures between -10 degrees and -80 degrees C before being plunged into LN2 and then warmed at either 20 degrees C/min or 450 degrees C/min. Survival was expressed as the percentage of hatching or hatched blastocysts per frozen-thawed embryo. When the slow cooling was in 1.5 M PROH, the temperature at which survival rates after slow thawing began to increase was -35 degrees C (52.6 +/- 5.2% survival). For slow cooling in 1.5 M Me2SO this temperature was -50 degrees C (45.0 +/- 2.9% survival). The addition of sucrose to the 1.5 M PROH solution raised the temperature at which survival rates after slow thawing began to increase to -30 degrees C (54.8 +/- 3.7% survival). If slow cooling was stopped at high subzero temperatures, embryos survived better after rapid thawing than slow thawing. If slow cooling was stopped at low subzero temperatures, the survival rate was not dependent on the thawing rate if freezing was done in 1.5 M PROH. When freezing was in Me2SO solutions and to subzero temperatures of -60 degrees and -80 degrees C, slow thawing gave better survival than rapid thawing. The addition of sucrose to the Me2SO freezing solution restored the survival rates at -60 degrees and -80 degrees C. These results indicate that high rates of survival may be obtained from one-cell mouse embryos by a rapid or a slow thawing procedure, as has been found for other developmental stages. The results also indicate that PROH provides superior protection compared to Me2SO against freezing-thawing damage and that the addition of sucrose to the freezing solutions prior to freezing improves the overall survival rates. Embryos that survived freezing and developed in culture implanted and formed normal fetuses at rates similar to those of nonfrozen control embryos (60% vs 68% and 53% vs 58%, respectively.

Animals↗

PubMed1994

Human corneal studies with a vitrification solution containing dimethyl sulfoxide, formamide, and 1,2-propanediol.

We tested the tolerance of human corneas to a vitrification solution, modified VS41A, containing 3.1 M dimethyl sulfoxide, 3.1 M formamide, and 2.2 M 1,2-propanediol in a carrier solution consisting of the corneal storage medium CPTES with 2.5% w/v chondroitin sulfate. Seven human corneas were exposed for 10 min each to graded concentrations of the solution at 0 degree C, remaining in the full-strength solution for 10 min. The corneas had significantly more endothelial cell damage (P < 0.05) than seven mated control corneas, but it was minimal (4.3% cell loss). Attempts at vitrification and rewarming of three corneas exposed to the solution by this protocol, however, resulted in ice formation in the peripheral corneal stroma and severe endothelial damage. Presumably, equilibration with the cryoprotectant in the thicker periphery of the human cornea had not occurred. Ice did not form on the center of one cornea, and substantial numbers of central endothelial cells survived after vitrification in this case. Immersion of the human corneas for 25 min in each of the four graded solutions at 0 degree C was required for sufficient penetration of the cryoprotectant to allow total corneal vitrification and rewarming without ice formation. This prolonged exposure to modified VS41A caused unacceptable damage to the corneal endothelium, however. Successful vitrification of human corneas with this solution will require a safe method for obtaining corneal equilibration with the cryoprotectant.

Cornea↗

PubMed1998

Oncogenic studies with felbamate (2-phenyl-1,3-propanediol dicarbamate).

Adenoma, Liver Cell↗

PubMed1998

Acute, subchronic, and chronic toxicity studies with felbamate, 2-phenyl-1,3-propanediol dicarbamate.

Felbamate, 2-phenyl-1,3-propanediol dicarbamate, is a novel anticonvulsant that is effective against both chemically and electrically induced seizures in laboratory animals. Acute, subchronic, and chronic studies were conducted in mice, rats, and dogs to establish a preclinical safety profile for this drug. Clinical signs following single intraperitoneal doses included hypoactivity, tremors, decreased muscle tone, ataxia, prostration, and labored breathing. Death was observed after intraperitoneal but not oral administration. A consistent drug-related effect noted in all multiple-dose studies with this compound was decreased body weight and food consumption. The only other consistent change noted in multiple-dose studies with felbamate was an increase in liver weight (relative and absolute) in the rat and dog which was accompanied in some cases by increases in serum enzyme levels. No histopathological changes were observed in the liver that could explain these elevated serum enzyme levels. Based on the results of these studies it was concluded that long-term administration of felbamate in human clinical trials was warranted.

Administration, Oral↗

PubMed2002

Bulk chemicals from biotechnology: the case of 1,3-propanediol production and the new trends.

The need for a sustainable resource supply, the rapid advances in plant biotechnology and microbial genetics and the strategic shift of major chemical companies into the area of life sciences are some of the driving forces for renewed interest in producing bulk chemicals from renewable resources by biological processes. The microbial production of 1,3-propanediol as briefly reviewed in this article and compared with the competing chemical processes demonstrates the promise and constraints of bioprocesses for bulk chemicals. The new concept of biorefinery and biocommodity engineering and future research needs in this area are also outlined.

Bacteria↗

PubMed1991

Effects of isomeric 2-(arylmethylamino)-1,3-propanediols (AMAPs) and clinically established agents on macromolecular synthesis in P388 and MCF-7 cells.

The in vitro effects of the 2-(arylmethylamino)-1,3-propanediols (AMAPs) on macromolecular synthesis have been examined using the murine leukemia, P388, and the human mammary adenocarcinoma, MCF-7, under conditions of short-term drug exposure. AMAPs that were observed to inhibit macromolecular synthesis produced nearly equipotent inhibition of DNA and RNA synthesis. Equivalent inhibition of protein synthesis generally required significantly greater concentrations of AMAP. There is a general correlation between inhibition of polynucleotide synthesis and in vivo antitumor activity. The effects of four clinical candidate AMAPs (crisnatol, 773U82, 502U83, and 7U85) on macromolecular synthesis were further compared with those of actinomycin D, doxorubicin, mitoxantrone, etoposide, amsacrine, and cisplatin in MCF-7 cells. The pattern of AMAP action was most similar to that observed for doxorubicin and mitoxantrone. Finally, the effects of these four AMAPs on the size, specific activity, and rate of incorporation of [3H]-dTTP into DNA of MCF-7 cells synchronized by pretreatment with hydroxyurea was determined. It was found that DNA synthesis was inhibited by AMAPs independent of inhibition of the uptake, phosphorylation, or retention of the metabolic precursors. These results support the theory that antitumor AMAPs interfere with the normal functioning of enzymes, such as topoisomerase II or DNA and RNA polymerases, which interact with DNA.

Animals↗

PubMed1995

Possible etiologic agents for toxic oil syndrome: fatty acid esters of 3-(N-phenylamino)-1,2-propanediol.

The etiologic agent(s) that was responsible for the 1981 toxic oil syndrome [TOS] epidemic in Spain has not been identified. Liquid chromatography combined with atmospheric pressure ionization tandem mass spectrometry was used for the analysis of oils associated with TOS. Analyses focused on measuring 3-(N-phenylamino)-1,2-propanediol [PAP], the 3-oleyl ester of PAP [MEPAP], and the 1,2-di-oleyl ester of PAP [DEPAP]. DEPAP and MEPAP were found more frequently and at higher concentrations in TOS case-associated oils than in control oils with odds ratios of 13.7 (95% CI 5.0-38) and 21.9 (95% 6.1-78), respectively. Other fatty acid esters of PAP are also likely to be present in the TOS case-associated oils. More significantly, DEPAP and MEPAP were found in aniline-denatured rapeseed oil refined at ITH, the oil refining company with the clearest link to TOS cases, yet these PAP esters were not detected in unrefined aniline-denatured samples of rapeseed oil delivered to ITH. These results show that the esters of PAP were products of the ITH refining process and were not formed spontaneously during storage. PAP esters were not detected in samples of other aniline-denatured rapeseed oils that were refined elsewhere, and which were not associated with illness. These findings provide strong support for the hypothesis that one or more of the fatty acid esters of PAP were the etiologic agents for TOS.

Aniline Compounds↗

PubMed1992

Enhancement of 1,3-propanediol production by cofermentation in Escherichia coli expressing Klebsiella pneumoniae dha regulon genes.

1,3-Propanediol (1,3-PD) is an intermediate in chemical and polymer synthesis. We have previously expressed the genes of a biochemical pathway responsible for 1,3-PD production, the dha regulon of Klebsiella pneumoniae, in Escherichia coli. An analysis of the maximum theoretical yield of 1,3-PD from glycerol indicates that the yield can be improved by the cofermentation of sugars, provided that kinetic constraints are overcome. The yield of 1,3-PD from glycerol was improved from 0.46 mol/mol with glycerol alone to 0.63 mol/mol with glucose cofermentation and 0.55 mol/mol with xylose cofermentation. The engineered E. coli also provides a model system for the study of metabolic pathway engineering.

Acetates↗

PubMed1999

The acute pathology of fatty acid anilides and linoleic diester of 3-phenylamino-1,2-propanediol in mice: possible implication as aetiologic agents for the toxic oil syndrome.

Two groups of compounds, the fatty acid anilides and the mono- and diester of 3-phenylamino-1,2-propanediol (PAP) are suspected as aetiologic agents for the toxic oil syndrome (TOS). Intraperitoneal administration of oleoyl and linoleoyl anilides in mice caused severe weight loss followed by death in 50% of the animals and histopathological changes mainly to the lungs. Linoleic diester of PAP led to weight loss, haemorrhage, congestion and emphysema in the lungs and an increase in blood eosinophilia. Although not producing the full spectrum of symptoms the effects of the substances resemble the acute human disease. Possibly, the two groups of substances led together to the full spectrum of disease manifestations seen in TOS.

Anilides↗

PubMed2002

Study of two-stage processes for the microbial production of 1,3-propanediol from glucose.

The microbial production of 1,3-propanediol (1,3-PD) from glucose was studied in a two-stage fermentation process on a laboratory scale. In the first stage, glucose was converted to glycerol either by the osmotolerant yeast Pichia farinosa or by a recombinant Escherichia coli strain. In the second stage, glycerol in the broth from the first stage was converted to 1,3-PD by Klebsiella pneumoniae. The culture broth from P. farinosa was shown to contain toxic metabolites that strongly impair the growth of K. pneumoniae and the formation of 1,3-PD. Recombinant E. coli is more suitable than P. farinosa for producing glycerol in the first stage. The fermentation pattern from glycerol can be significantly altered by the presence of acetate, leading to a significant reduction of PD yield in the second stage. However, in the recombinant E. coli culture acetate formation can be prevented by fed-batch cultivation under limiting glucose supply, resulting in an effective production of 1,3-PD in the second stage with a productivity of 2.0 g l(-1) h(-1) and a high yield (0.53 g/g) close to that of glycerol fermentation in a synthetic medium. The overall 1,3-PD yield from glucose in the two stage-process with E. coli and K. pneumoniae reached 0.17 g/g.

Anaerobiosis↗

PubMed2003

Microbial fed-batch production of 1,3-propanediol by Klebsiella pneumoniae under micro-aerobic conditions.

The microbial production of 1,3-propanediol (1,3-PD) by Klebsiella pneumoniae under micro-aerobic conditions was investigated in this study. The experimental results of batch fermentation showed that the final concentration and yield of 1,3-PD on glycerol under micro-aerobic conditions approached values achieved under anaerobic conditions. However, less ethanol was produced under microaerobic than anaerobic conditions at the end of fermentation. The batch micro-aerobic fermentation time was markedly shorter than that of anaerobic fermentation. This led to an increment of productivity of 1,3-PD. For instance, the concentration, molar yield, and productivity of 1,3-PD of batch micro-aerobic fermentation by K. pneumoniae DSM 2026 were 17.65 g/l, 56.13%, and 2.94 g l(-1) h(-1), respectively, with a fermentation time of 6 h and an initial glycerol concentration of 40 g/l. Compared with DSM 2026, the microbial growth of K. pneumoniae AS 1.1736 was slow and the concentration of 1,3-PD was low under the same conditions. Furthermore, the microbial growth in fed-batch fermentation by K. pneumoniae DSM 2026 was faster under micro-aerobic than anaerobic conditions. The concentration, molar yield, and productivity of 1,3-PD in fed-batch fermentation under micro-aerobic conditions were 59.50 g/l, 51.75%, and 1.57 g l(-1) h(-1), respectively. The volumetric productivity of 1,3-PD under microaerobic conditions was almost twice that of anaerobic fed-batch fermentation, at 1.57 and 0.80 g l(-1) h(-1), respectively.

Aerobiosis↗

PubMed2006

Fermentation of 1,3-propanediol by a lactate deficient mutant of Klebsiella oxytoca under microaerobic conditions.

Klebsiella oxytoca M5al is an excellent 1,3-propanediol (1,3-PD) producer, but too much lactic acid yielded greatly lessened the fermentation efficiency for 1,3-PD. To counteract the disadvantage, four lactate deficient mutants were obtained by knocking out the ldhA gene of lactate dehydrogenase (LDH) of K. oxytoca M5al. The LDH activities of the four mutants were from 3.85 to 6.92% of the parental strain. The fed-batch fermentation of 1,3-PD by mutant LDH3, whose LDH activity is the lowest, was studied. The results showed that higher 1,3-PD concentration, productivity, and molar conversion rate from glycerol to 1,3-PD can be gained than those of the wild type strain and no lactic acid is produced under both anaerobic and microaerobic conditions. Sucrose fed during the fermentation increased the conversion and sucrose added at the beginning increased the productivity. In fed-batch fermentation with sucrose as cosubstrate under microaerobic conditions, the 1,3-PD concentration, conversion, and productivity were improved significantly to 83.56 g l-1, 0.62 mol mol-1, and 1.61 g l(-1) h-1, respectively. Furthermore, 60.11 g l(-1) 2,3-butanediol was also formed as major byproduct in the broth.

Aerobiosis↗

PubMed1999

Microbial production of 1,3-propanediol.

1,3-Propanediol (1,3-PD) production by fermentation of glycerol was described in 1881 but little attention was paid to this microbial route for over a century. Glycerol conversion to 1,3-PD can be carried out by Clostridia as well as Enterobacteriaceae. The main intermediate of the oxidative pathway is pyruvate, the further utilization of which produces CO2, H2, acetate, butyrate, ethanol, butanol and 2,3-butanediol. In addition, lactate and succinate are generated. The yield of 1,3-PD per glycerol is determined by the availability of NADH2, which is mainly affected by the product distribution (of the oxidative pathway) and depends first of all on the microorganism used but also on the process conditions (type of fermentation, substrate excess, various inhibitions). In the past decade, research to produce 1,3-PD microbially was considerably expanded as the diol can be used for various polycondensates. In particular, polyesters with useful properties can be manufactured. A prerequisite for making a "green" polyester is a most cost-effective production of 1,3-PD, which, in practical terms, can only be achieved by using an alternative substrate, such as glucose instead of glycerol. Therefore, great efforts are now being made to combine the pathway from glucose to glycerol successfully with the bacterial route from glycerol to 1,3-PD. Thus, 1,3-PD may become the first bulk chemical produced by a genetically engineered microorganism.

Adenosine Triphosphate↗

PubMed2003

The effect of carbon sources and lactate dehydrogenase deletion on 1,2-propanediol production in Escherichia coli.

In previous studies, we showed that cofactor manipulations can potentially be used as a tool in metabolic engineering. In this study, sugars similar to glucose, that can feed into glycolysis and pyruvate production, but with different oxidation states, were used as substrates. This provided a simple way of testing the effect of manipulating the NADH/NAD+ ratio or the availability of NADH on the metabolic patterns of Escherichia coli under anaerobic conditions and on the production of 1,2-propanediol (1,2-PD), which requires NADH for its synthesis. Production of 1,2-PD was achieved by overexpressing the two enzymes methylglyoxal synthase from Clostridium acetobutylicum and glycerol dehydrogenase from E. coli. In addition, the effect of eliminating a pathway competing for NADH by using a ldh(-) strain (without lactate dehydrogenase activity) on the production of 1,2-PD was investigated. The oxidation state of the carbon source significantly affected the yield of metabolites, such as ethanol, acetate and lactate. However, feeding a more reduced carbon source did not increase the yield of 1,2-PD. The production of 1,2-PD with glucose as the carbon source was improved by the incorporation of a ldh(-) mutation. The results of these experiments indicate that our current 1,2-PD production system is not limited by NADH, but rather by the pathways following the formation of methylglyoxal.

Carbon↗

PubMed2005

Multiple growth inhibition of Klebsiella pneumoniae in 1,3-propanediol fermentation.

The inhibition of substrate and product on the growth of Klebsiella pneumoniae in anaerobic and aerobic batch fermentation for the production of 1,3-propanediol was studied. The cells under anaerobic conditions had a higher maximum specific growth rate of 0.19 h(-1) and lower tolerance to 110 g glycerol l(-1), compared to the maximum specific growth rate of 0.17 h(-1) and tolerance to 133 g glycerol l(-1) under aerobic conditions. Acetate was the main inhibitory metabolite during the fermentation under anaerobic conditions, with lactate and ethanol the next most inhibitory. The critical concentrations of acetate, lactate and ethanol were assessed to be 15, 19, 26 g l(-1), respectively. However, cells grown under aerobic conditions were more resistant to acetate and lactate but less resistant to ethanol. The critical concentrations of acetate, lactate and ethanol were assessed to be 24, 26, and 17 g l(-1), respectively.

Cell Division↗

PubMed2006

Microbial production of 1,3-propanediol by Klebsiella pneumoniae using crude glycerol from biodiesel preparations.

1,3-Propanediol (1,3-PD) was produced by Klebsiella pneumoniae using crude glycerol obtained from biodiesel production. The 1,3-PD concentration of 51.3 g/l(-1) on crude glycerol from alkali-catalyzed methanolysis of soybean oil was comparable to that of 53 g/l(-1) on crude glycerol derived from a lipase-catalyzed process. The productivities of 1.7 g l(-1) h(-1) on crude glycerol were comparable to that of 2 g l(-1) h(-1) on pure glycerol. It could be concluded that the crude glycerol could be directly converted to 1,3-PD without any prior purification.

Bioreactors↗

PubMed2001

Absorption and effects of 3-(N-phenylamino)-1,2-propanediol esters in relation to toxic oil syndrome.

Toxic Oil Syndrome (TOS) was an epidemic disease related to the consumption of rapeseed oil denatured with aniline that made its sudden appearance in Spain in 1981. The fatty acid esters of 3-(N-phenylamino)-1,2-propanediol (PAP), which is a chemical class of by-products resulting from the reaction of aniline with oil components, have shown a strong association with TOS-related oils. These compounds also show some structural similarities to platelet-activating factor (PAF). In search of a toxic agent that could explain the widespread systemic effects observed in TOS patients, we investigated the intestinal absorption and biotransformation of the different PAP esters found in TOS-related oil samples and the possible pathophysiological effect of these mediators and their metabolic products if acting as PAF analogs. Results indicate that PAP esters are absorbed in the gastrointestinal tract and are distributed and stored in different organs, particularly in the liver and brown adipose tissue. PAP in these organs showed different patterns of fatty acids, indicating the ability of the gastrointestinal tract to modify the fatty acid composition of the parent PAP. Thus, the fatty acid profile of the PAP esters found in intestine appears to be related to the type of oil used as vehicle. Some of these PAP esters, when a long acyl chain was present in the sn-1 position of the molecule, showed an inhibitory effect on the PAF synthesis. This is an important observation in line with the systemic nature of the disease.

Adipose Tissue↗

PubMed1992

Parthenogenetic activation pattern and microtubular organization of the mouse oocyte after exposure to 1,2-propanediol.

We have studied the effect of 1,2-propanediol (PROH) on cumulus-oocyte complexes from the mouse. We determined the morphological survival rate, the pattern of parthenogenetic activation, and the microtubular and chromosomal organization. Cumulus-oocyte complexes were collected at 16 h post hCG from superovulated female hybrid mice. These cumulus-intact oocytes were exposed to 1.5 or 3 M PROH for 6, 12, or 18 min at 0, 22, or 37 degrees C. The cryoprotectant was diluted out in a 1 M sucrose solution at 22 degrees C. After 5-6 h at 37 degrees C, oocytes were denuded and examined under Nomarski optics. The results show that PROH can induce degeneration and parthenogenetic activation in the mouse oocyte in a concentration, temperature, and time-dependent way. As the activation stimulus was strengthened, an increasing proportion of oocytes shifted from parthenogenetic activation with polar body extrusion to parthenogenetic activation with polar body retention and even to immediate cleavage. Nontoxic and nonactivating conditions involved mainly exposure to 1.5 M PROH at 0 degrees C. Spindle integrity and chromosomal organization were analyzed for exposure to 1.5 and 3 M PROH for 12 min at 0 degrees C. The separate effect of cooling and exposure to 1 M sucrose were also evaluated. Microtubules were visualized by monoclonal anti-alpha-tubulin labeling followed by immunogold-silver staining. Cooling and exposure to 1 M sucrose or to 1.5 M PROH did not induce major abnormalities in the microtubular or chromosomal organization. On the other hand, a significant percentage of deformities such as spindle size reduction and loss of bipolarity were observed after exposure to 3 M PROH. The results of the present study demonstrate that the use of PROH as a single cryoprotectant for the freezing of mature unfertilized oocytes cannot be recommended in procedures involving ambient temperature or concentrations exceeding 1.5 M PROH. On the other hand, the potential beneficial effect of low temperatures may outweigh the effect of concentration at subzero temperatures and could be explored further in the tailoring of conditions for slow controlled freezing.

Animals↗