PMID- 35089383
OWN - NLM
STAT- MEDLINE
DCOM- 20220329
LR  - 20220329
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Linking)
VI  - 96
IP  - 3
DP  - 2022 Mar
TI  - In vitro and in silico approach to study the hormonal activities of the 
      alternative plasticizer tri-(2-ethylhexyl) trimellitate TEHTM and its 
      metabolites.
PG  - 899-918
LID - 10.1007/s00204-022-03230-4 [doi]
AB  - Tri-(2-ethylhexyl) trimellitate (TEHTM) is a plasticizer for polyvinyl chloride 
      (PVC) material used in medical devices. It is an alternative to di-(2-ethylhexyl) 
      phthalate (DEHP), a well-known reprotoxic and endocrine disruptor. As 
      plasticizers are known to easily migrate when in contact with fatty biological 
      fluids, patient exposure to TEHTM is highly probable. However, there is currently 
      no data on the potential endocrine-disrupting effects of its human metabolites. 
      To evaluate the effects of TEHTM metabolites on endocrine activity, they were 
      first synthesized and their effects on estrogen, androgen and thyroid receptors, 
      as well as steroid synthesis, were investigated by combining in vitro and in 
      silico approaches. Among the primary metabolites, only 4-MEHTM 
      (4-mono-(2-ethylhexyl) trimellitate) showed agonist activities on ERs and TRs, 
      while three diesters were TR antagonists at non-cytotoxic concentrations. These 
      results were completed by docking experiments which specified the ER and TR 
      isoforms involved. A mixture of 2/1-MEHTM significantly increased the estradiol 
      level and reduced the testosterone level in H295R cell culture supernatants. The 
      oxidized secondary metabolites of TEHTM had no effect on ER, AR, TR receptors or 
      on steroid hormone synthesis. Among the fourteen metabolites, these data showed 
      that two of them (4-MEHTM and 2/1-MEHTM) induced effect on hormonal activities in 
      vitro. However, by comparing the concentrations of the primary metabolites found 
      in human urine with the active concentrations determined in bioassays, it can be 
      suggested that the metabolites will not be active with regard to estrogen, 
      androgen, thyroid receptors and steroidogenesis-mediated effects.
CI  - (c) 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, 
      part of Springer Nature.
FAU - Dahbi, Laurence
AU  - Dahbi L
AD  - Derttech "Packtox", NUTOX, INSERM U1231, Universite Bourgogne Franche-Comte, 
      21000, Dijon, France.
FAU - Farce, Amaury
AU  - Farce A
AD  - Universite de Lille, CHU Lille, U1286-INFINITE-Institute for Translational 
      Research in Inflammation, 59000, Lille, France.
FAU - Kambia, Nicolas
AU  - Kambia N
AD  - Universite de Lille, CHU Lille, ULR 7365 GRITA-Groupe de Recherche sur les formes 
      Injectables et les Technologies Associees, 59000, Lille, France.
FAU - Severin, Isabelle
AU  - Severin I
AD  - Derttech "Packtox", NUTOX, INSERM U1231, Universite Bourgogne Franche-Comte, 
      21000, Dijon, France.
FAU - Dine, Thierry
AU  - Dine T
AD  - Universite de Lille, CHU Lille, ULR 7365 GRITA-Groupe de Recherche sur les formes 
      Injectables et les Technologies Associees, 59000, Lille, France.
FAU - Moreau, Emmanuel
AU  - Moreau E
AD  - Universite Clermont Auvergne, INSERM U1240, Imagerie Moleculaire et Strategies 
      Theranostiques, 63000, Clermont-Ferrand, France.
FAU - Sautou, Valerie
AU  - Sautou V
AD  - Universite Clermont Auvergne, CHU Clermont Ferrand, Clermont Auvergne INP, CNRS, 
      ICCF, 63000, Clermont-Ferrand, France.
FAU - Chagnon, Marie-Christine
AU  - Chagnon MC
AUID- ORCID: 0000-0003-1275-657X
AD  - Derttech "Packtox", NUTOX, INSERM U1231, Universite Bourgogne Franche-Comte, 
      21000, Dijon, France. Marie-Christine.Chagnon@u-bourgogne.fr.
LA  - eng
PT  - Journal Article
DEP - 20220128
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 0 (Benzoates)
RN  - 0 (Endocrine Disruptors)
RN  - 0 (Plasticizers)
RN  - 0 (Receptors, Androgen)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Receptors, Thyroid Hormone)
RN  - 3319-31-1 (tri-(2-ethylhexyl)trimellitate)
RN  - 3XMK78S47O (Testosterone)
RN  - 4TI98Z838E (Estradiol)
SB  - IM
MH  - Benzoates/metabolism/*toxicity
MH  - Cell Line, Tumor
MH  - Computer Simulation
MH  - Endocrine Disruptors/metabolism/*toxicity
MH  - Estradiol/metabolism
MH  - Humans
MH  - Molecular Docking Simulation
MH  - Plasticizers/metabolism/*toxicity
MH  - Receptors, Androgen/drug effects/metabolism
MH  - Receptors, Estrogen/drug effects/metabolism
MH  - Receptors, Thyroid Hormone/drug effects/metabolism
MH  - Testosterone/metabolism
OTO - NOTNLM
OT  - In silico
OT  - Medical devices
OT  - Steroidogenesis
OT  - T-screen assay
OT  - TEHTM
OT  - hER and hAR reporter gene assays
EDAT- 2022/01/29 06:00
MHDA- 2022/03/30 06:00
CRDT- 2022/01/28 12:12
PHST- 2021/08/17 00:00 [received]
PHST- 2022/01/12 00:00 [accepted]
PHST- 2022/01/29 06:00 [pubmed]
PHST- 2022/03/30 06:00 [medline]
PHST- 2022/01/28 12:12 [entrez]
AID - 10.1007/s00204-022-03230-4 [pii]
AID - 10.1007/s00204-022-03230-4 [doi]
PST - ppublish
SO  - Arch Toxicol. 2022 Mar;96(3):899-918. doi: 10.1007/s00204-022-03230-4. Epub 2022 
      Jan 28.