Means and Methods for Assessing Increased Peroxisomal Proliferation

Abstract

The present invention pertains to the field of toxicological assessments for risk stratification of chemical compounds. Specifically, it relates to a method for diagnosing increased peroxisomal proliferation. It also relates to a method of determining whether a compound is capable of inducing such peroxisomal proliferation in a subject and to a method of identifying a drug for treating increased peroxisomal proliferation. Furthermore, the present invention relates to a data collection comprising characteristic values of at least five metabolites, a data storage medium comprising said data collection, and a system and a device for diagnosing increased peroxisomal proliferation. Finally, the present invention pertains to the use of a group of metabolites or means for the determination thereof for the manufacture of a diagnostic device or composition for diagnosing increased peroxisomal proliferation in a subject.

1 . A method for diagnosing a disorder associated with increased peroxisomal proliferation comprising:
 (a) selecting a male or female subject suspected to suffer from increased peroxisomal proliferation;   (b) obtaining a body fluid test sample from the male or female subject;   (c) determining the amount of at least five of the following analytes Coenzyme Q10, 16-Methylheptadecanoic acid, 17-Methyloctadecanoic acid, Eicosatrienoic acid (C20:3), Threonine, Proline, Tyrosine, trans-4-Hydroxyproline from the body fluid test sample from the male subject, or the amount of at least five of the following analytes Pantothenic acid, Coenzyme Q9, Glycerol, Palmitic acid (C16:0), Linoleic acid (C18:cis[9,12]2), 14-Methylhexadecanoic acid, gamma-Linolenic acid (C18:cis[6,9,12]3), 16-Methylheptadecanoic acid, Threonic acid, Cytosine, Phosphatidylcholine (C18:0/C22:6) from the body fluid test sample from the female subject;   (d) comparing the amounts determined in step (c) to corresponding reference results, wherein the reference results comprise
 (i) reference results obtained from one or more samples derived from one or more subjects which has been brought into contact with Benzylbutyl Phthalate, Fenofibrate, Clofibrate, Fenoforbrate, Diethylhexylphthalate or Wy 14643, 
 (ii) reference results obtained from one or more samples derived from one or more subjects which has not been brought into contact with Benzylbutyl Phthalate, Fenofibrate, Clofibrate, Fenoforbrate, Diethylhexylphthalate or Wy 14643, 
 (iii) reference results obtained from one or more samples derived from one or more subjects which suffers from increased peroxisomal proliferation, or 
 (iv) reference results obtained from one or more samples derived from one or more subjects known to not suffer from increased peroxisomal proliferation; and 
   (e) based on the comparison of step (d), diagnose the disorder by monitoring, confirmation, or classification of the disorder or its symptoms in the male or female subject.   
     
     
         2 . The method of  claim 1 , wherein said male or female subject has been brought into contact with a compound suspected to be capable of inducing increased peroxisomal proliferation. 
     
     
         3 . The method of  claim 2 , wherein said compound is at least one compound selected from the group consisting of: Benzylbutyl Phthalate, Fenofibrate, Clofibrate, Fenoforbrate, Diethylhexylphthalate, and Wy 14643. 
     
     
         4 . The method of  claim 1 , wherein said reference result is obtained from one or more samples derived from (i) one or more subjects which suffers from increased peroxisomal proliferation; or (ii) one or more subjects which has been brought into contact with at least one compound selected from the group consisting of: Benzylbutyl Phthalate, Fenofibrate, Clofibrate, Fenoforbrate, Diethylhexylphthalate, and Wy 14643. 
     
     
         5 . The method of  claim 4 , wherein identical amounts for the analytes in the body fluid test sample and the reference result are indicative for increased peroxisomal proliferation. 
     
     
         6 . The method of  claim 1 , wherein said reference result is obtained from one or more samples derived from (i) one or more subjects known to not suffer from increased peroxisomal proliferation; or (ii) one or more subjects which has not been brought into contact with at least one compound selected from the group consisting of: Benzylbutyl Phthalate, Fenofibrate, Clofibrate, Fenoforbrate, Diethylhexylphthalate, and Wy 14643. 
     
     
         7 . The method of  claim 6 , wherein amounts for the analytes which differ in the body fluid test sample in comparison to the reference result are indicative for increased peroxisomal proliferation. 
     
     
         8 . The method of  claim 1 , wherein indicative for increased peroxisomal proliferation are amounts of the analytes in comparison to the reference result of one or more subjects known to not suffer from increased peroxisomal proliferation which differ as follows: (i) in a body fluid sample of a male: Coenzyme Q10 decreased, 16-Methylheptadecanoic acid decreased, 17-Methyloctadecanoic acid decreased, Eicosatrienoic acid (C20:3) increased, Threonine decreased, Proline decreased, Tyrosine decreased, trans-4-Hydroxyproline decreased; and (ii) in a body fluid sample of a female subject: Pantothenic acid increased, Coenzyme Q9 increased, Glycerol increased, Palmitic acid (C16:0) increased, Linoleic acid (C18:cis[9,12]2) increased, 14-Methylhexadecanoic acid increased, gamma-Linolenic acid (C18:cis[6,9,12]3) decreased, 16-Methylheptadecanoic acid decreased, Threonic acid increased, Cytosine decreased, Phosphatidylcholine (C18:0/C22:6) decreased. 
     
     
         9 . The method of  claim 1 , wherein said increased peroxisomal proliferation results in a predisposition for at least one disorder or disease selected from the group consisting of: cancer, thyroid disorders, reproductive dysfunction, skeletal and cardiac myopathies, and dysfunction of the immune system. 
     
     
         10 . The method of  claim 1 , wherein said determining the amount of analytes comprises mass spectrometry (MS). 
     
     
         11 . The method of  claim 10 , wherein said mass spectrometry is liquid chromatography (LC)-MS or gas chromatography (GC)-MS. 
     
     
         12 . The method of  claim 1 , wherein said subject is a mammal. 
     
     
         13 . The method of  claim 11 , wherein the method is automated. 
     
     
         14 . The method of  claim 13 , wherein the method comprises computer assisted data processing. 
     
     
         15 . A method for diagnosing a disorder associated with increased peroxisomal proliferation comprising:
 (a) selecting a male or female subject suspected to suffer from increased peroxisomal proliferation;   (b) obtaining a body fluid test sample from the male or female subject;   (c) determining the amount of at least five of the following analytes Coenzyme Q10, 16-Methylheptadecanoic acid, 17-Methyloctadecanoic acid, Eicosatrienoic acid (C20:3), Threonine, Proline, Tyrosine, trans-4-Hydroxyproline from the body fluid test sample from the male subject, or the amount of at least five of the following analytes Pantothenic acid, Coenzyme Q9, Glycerol, Palmitic acid (C16:0), Linoleic acid (C18:cis[9,12]2), 14-Methylhexadecanoic acid, gamma-Linolenic acid (C18:cis[6,9,12]3), 16-Methylheptadecanoic acid, Threonic acid, Cytosine, Phosphatidylcholine (C18:0/C22:6) from the body fluid test sample from the female subject.   
     
     
         16 . The method of  claim 15 , wherein said male or female subject has been brought into contact with a compound suspected to be capable of inducing increased peroxisomal proliferation. 
     
     
         17 . The method of  claim 16 , wherein said compound is at least one compound selected from the group consisting of: Benzylbutyl Phthalate, Fenofibrate, Clofibrate, Fenoforbrate, Diethylhexylphthalate, and Wy 14643. 
     
     
         18 . The method of  claim 15 , wherein reference results are obtained from one or more samples derived from (i) one or more subjects which suffers from increased peroxisomal proliferation; or (ii) one or more subjects which has been brought into contact with at least one compound selected from the group consisting of: Benzylbutyl Phthalate, Fenofibrate, Clofibrate, Fenoforbrate, Diethylhexylphthalate, and Wy 14643. 
     
     
         19 . The method of  claim 18 , wherein identical amounts for the analytes in the body fluid test sample and corresponding reference results are indicative for increased peroxisomal proliferation. 
     
     
         20 . The method of  claim 15 , wherein reference results are obtained from one or more samples derived from (i) one or more subjects known to not suffer from increased peroxisomal proliferation; or (ii) one or more subjects which has not been brought into contact with at least one compound selected from the group consisting of: Benzylbutyl Phthalate, Fenofibrate, Clofibrate, Fenoforbrate, Diethylhexylphthalate, and Wy 14643. 
     
     
         21 . The method of  claim 20 , wherein amounts for the analytes which differ in the body fluid test sample relative to corresponding reference results are indicative for increased peroxisomal proliferation. 
     
     
         22 . The method of  claim 20 , wherein indicative for increased peroxisomal proliferation are amounts of the analytes relative to corresponding reference results of one or more subjects known to not suffer from increased peroxisomal proliferation which differ as follows: (i) in a body fluid sample of a male: Coenzyme Q10 decreased, 16-Methylheptadecanoic acid decreased, 17-Methyloctadecanoic acid decreased, Eicosatrienoic acid (C20:3) increased, Threonine decreased, Proline decreased, Tyrosine decreased, trans-4-Hydroxyproline decreased; and (ii) in a body fluid sample of a female subject: Pantothenic acid increased, Coenzyme Q9 increased, Glycerol increased, Palmitic acid (C16:0) increased, Linoleic acid (C18:cis[9,12]2) increased, 14-Methylhexadecanoic acid increased, gamma-Linolenic acid (C18:cis[6,9,12]3) decreased, 16-Methylheptadecanoic acid decreased, Threonic acid increased, Cytosine decreased, Phosphatidylcholine (C18:0/C22:6) decreased. 
     
     
         23 . The method of  claim 15 , wherein said increased peroxisomal proliferation results in a predisposition for at least one disorder or disease selected from the group consisting of: cancer, thyroid disorders, reproductive dysfunction, skeletal and cardiac myopathies, and dysfunction of the immune system. 
     
     
         24 . The method of  claim 15 , wherein said determining the amount of analytes comprises mass spectrometry (MS). 
     
     
         25 . The method of  claim 24 , wherein said mass spectrometry is liquid chromatography (LC)-MS or gas chromatography (GC)-MS. 
     
     
         26 . The method of  claim 15 , wherein said subject is a mammal. 
     
     
         27 . The method of  claim 25 , wherein the method is automated. 
     
     
         28 . The method of  claim 27 , wherein the method comprises computer assisted data processing.