PMID- 36583546
OWN - NLM
STAT- MEDLINE
DCOM- 20230222
LR  - 20230330
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 191
IP  - 2
DP  - 2023 Feb 17
TI  - Structure-activity relationship read-across and transcriptomics for branched 
      carboxylic acids.
PG  - 343-356
LID - 10.1093/toxsci/kfac139 [doi]
AB  - The purpose of this study was to use chemical similarity evaluations, 
      transcriptional profiling, in vitro toxicokinetic data, and physiologically based 
      pharmacokinetic (PBPK) models to support read-across for a series of branched 
      carboxylic acids using valproic acid (VPA), a known developmental toxicant, as a 
      comparator. The chemicals included 2-propylpentanoic acid (VPA), 2-ethylbutanoic 
      acid, 2-ethylhexanoic acid (EHA), 2-methylnonanoic acid, 2-hexyldecanoic acid, 
      2-propylnonanoic acid (PNA), dipentyl acetic acid or 2-pentylheptanoic acid, 
      octanoic acid (a straight chain alkyl acid), and 2-ethylhexanol. Transcriptomics 
      was evaluated in 4 cell types (A549, HepG2, MCF7, and iCell cardiomyocytes) 6 h 
      after exposure to 3 concentrations of the compounds, using the L1000 platform. 
      The transcriptional profiling data indicate that 2- or 3-carbon alkyl 
      substituents at the alpha position of the carboxylic acid (EHA and PNA) elicit a 
      transcriptional profile similar to the one elicited by VPA. The transcriptional 
      profile is different for the other chemicals tested, which provides support for 
      limiting read-across from VPA to much shorter and longer acids. Molecular docking 
      models for histone deacetylases, the putative target of VPA, provide a possible 
      mechanistic explanation for the activity cliff elucidated by transcriptomics. In 
      vitro toxicokinetic data were utilized in a PBPK model to estimate internal 
      dosimetry. The PBPK modeling data show that as the branched chain increases, 
      predicted plasma Cmax decreases. This work demonstrates how transcriptomics and 
      other mode of action-based methods can improve read-across.
CI  - (c) The Author(s) 2022. Published by Oxford University Press on behalf of the 
      Society of Toxicology. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Wu, Shengde
AU  - Wu S
AD  - Global Product Stewardship, The Procter and Gamble Company, Mason, Ohio 45040, 
      USA.
FAU - Ellison, Corie
AU  - Ellison C
AD  - Global Product Stewardship, The Procter and Gamble Company, Mason, Ohio 45040, 
      USA.
FAU - Naciff, Jorge
AU  - Naciff J
AD  - Global Product Stewardship, The Procter and Gamble Company, Mason, Ohio 45040, 
      USA.
FAU - Karb, Michael
AU  - Karb M
AD  - Global Product Stewardship, The Procter and Gamble Company, Mason, Ohio 45040, 
      USA.
FAU - Obringer, Cindy
AU  - Obringer C
AD  - Global Product Stewardship, The Procter and Gamble Company, Mason, Ohio 45040, 
      USA.
FAU - Yan, Gang
AU  - Yan G
AUID- ORCID: 0000-0001-5648-7653
AD  - Global Product Stewardship, The Procter and Gamble Company, Mason, Ohio 45040, 
      USA.
FAU - Shan, Yuqing
AU  - Shan Y
AD  - Global Product Stewardship, The Procter and Gamble Company, Mason, Ohio 45040, 
      USA.
FAU - Smith, Alex
AU  - Smith A
AD  - Global Product Stewardship, The Procter and Gamble Company, Mason, Ohio 45040, 
      USA.
FAU - Wang, Xiaohong
AU  - Wang X
AD  - Global Product Stewardship, The Procter and Gamble Company, Mason, Ohio 45040, 
      USA.
FAU - Daston, George P
AU  - Daston GP
AD  - Global Product Stewardship, The Procter and Gamble Company, Mason, Ohio 45040, 
      USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Carboxylic Acids)
RN  - 614OI1Z5WI (Valproic Acid)
SB  - IM
MH  - *Carboxylic Acids/toxicity
MH  - Molecular Docking Simulation
MH  - *Transcriptome
MH  - Valproic Acid/toxicity
MH  - Structure-Activity Relationship
OTO - NOTNLM
OT  - 2-ethylhexanoic acid
OT  - branched-alkyl carboxylic acids
OT  - read-across
OT  - structure-activity relationship (SAR)
OT  - valproic acid
EDAT- 2022/12/31 06:00
MHDA- 2023/02/22 06:00
CRDT- 2022/12/30 08:03
PHST- 2022/12/31 06:00 [pubmed]
PHST- 2023/02/22 06:00 [medline]
PHST- 2022/12/30 08:03 [entrez]
AID - 6965632 [pii]
AID - 10.1093/toxsci/kfac139 [doi]
PST - ppublish
SO  - Toxicol Sci. 2023 Feb 17;191(2):343-356. doi: 10.1093/toxsci/kfac139.