PMID- 33599830
OWN - NLM
STAT- MEDLINE
DCOM- 20211103
LR  - 20220402
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Print)
IS  - 0340-5761 (Linking)
VI  - 95
IP  - 4
DP  - 2021 Apr
TI  - N-Acetyl-L-cysteine and aminooxyacetic acid differentially modulate 
      trichloroethylene reproductive toxicity via metabolism in Wistar rats.
PG  - 1303-1321
LID - 10.1007/s00204-021-02991-8 [doi]
AB  - Exposure to the industrial solvent trichloroethylene (TCE) has been associated 
      with adverse pregnancy outcomes in humans and decreased fetal weight in rats. TCE 
      kidney toxicity can occur through formation of reactive metabolites via its 
      glutathione (GSH) conjugation metabolic pathway, largely unstudied in the context 
      of pregnancy. To investigate the contribution of the GSH conjugation pathway and 
      oxidative stress to TCE toxicity during pregnancy, we exposed rats orally to 
      480 mg TCE/kg/day from gestational day (GD) 6 to GD 16 with and without 
      N-acetyl-L-cysteine (NAC) at 200 mg/kg/day or aminooxyacetic acid (AOAA) at 
      20 mg/kg/day as pre/co-treatments from GD 5-16. NAC is a reactive oxygen species 
      scavenger that modifies the GSH conjugation pathway, and AOAA is an inhibitor of 
      cysteine conjugate beta-lyase (CCBL) in the GSH conjugation pathway. TCE decreased 
      fetal weight, and this was prevented by AOAA but not NAC pre/co-treatment to TCE. 
      Although AOAA inhibited CCBL activity in maternal kidney, it did not inhibit CCBL 
      activity in maternal liver and placenta, suggesting that AOAA prevention of 
      TCE-induced decreased fetal weight was due to CCBL activity inhibition in the 
      kidneys but not liver or placenta. Unexpectedly, NAC pre/co-treatment with TCE, 
      relative to TCE treatment alone, altered placental morphology consistent with 
      delayed developmental phenotype. Immunohistochemical staining revealed that the 
      decidua basale, relative to basal and labyrinth zones, expressed the highest 
      abundance of CCBL1, flavin-containing monooxygenase 3, and cleaved caspase-3. 
      Together, the findings show the differential effects of NAC and AOAA on 
      TCE-induced pregnancy outcomes are likely attributable to TCE metabolism 
      modulation.
FAU - Su, Anthony L
AU  - Su AL
AUID- ORCID: 0000-0002-5280-6423
AD  - Department of Environmental Health Sciences, University of Michigan, 1415 
      Washington Heights, Ann Arbor, MI, 48109, USA. ansu@umich.edu.
AD  - Department of Systems Pharmacology and Translational Therapeutics, Perelman 
      School of Medicine, University of Pennsylvania, 421 Curie Blvd, Philadelphia, PA, 
      19104, USA. ansu@umich.edu.
FAU - Lash, Lawrence H
AU  - Lash LH
AUID- ORCID: 0000-0003-3239-4481
AD  - Department of Pharmacology, Wayne State University School of Medicine, 540 East 
      Canfield Avenue, Detroit, MI, 48201, USA.
FAU - Bergin, Ingrid L
AU  - Bergin IL
AUID- ORCID: 0000-0001-5436-4633
AD  - Unit for Laboratory Animal Medicine, University of Michigan Medical School, North 
      Campus Research Complex, 2800 Plymouth Rd, Ann Arbor, MI, 48109, USA.
FAU - Bjork, Faith
AU  - Bjork F
AD  - Department of Environmental Health Sciences, University of Michigan, 1415 
      Washington Heights, Ann Arbor, MI, 48109, USA.
FAU - Loch-Caruso, Rita
AU  - Loch-Caruso R
AUID- ORCID: 0000-0002-5993-2799
AD  - Department of Environmental Health Sciences, University of Michigan, 1415 
      Washington Heights, Ann Arbor, MI, 48109, USA.
LA  - eng
GR  - P42 ES017198/ES/NIEHS NIH HHS/United States
GR  - T32 HD079342/HD/NICHD NIH HHS/United States
GR  - P30 ES017885/ES/NIEHS NIH HHS/United States
GR  - T32 ES007062/ES/NIEHS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210218
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Free Radical Scavengers)
RN  - 0 (Solvents)
RN  - 14I68GI3OQ (Aminooxyacetic Acid)
RN  - 290YE8AR51 (Trichloroethylene)
RN  - GAN16C9B8O (Glutathione)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/*pharmacology
MH  - Aminooxyacetic Acid/*pharmacology
MH  - Animals
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Free Radical Scavengers/pharmacology
MH  - Glutathione/metabolism
MH  - Male
MH  - Oxidative Stress/drug effects
MH  - Placenta/drug effects
MH  - Pregnancy
MH  - Pregnancy Outcome
MH  - Rats
MH  - Rats, Wistar
MH  - Reproduction/*drug effects
MH  - Solvents/metabolism/toxicity
MH  - Trichloroethylene/metabolism/*toxicity
PMC - PMC8035313
MID - NIHMS1676126
OTO - NOTNLM
OT  - Aminooxyacetic acid (AOAA)
OT  - Cysteine conjugate beta-lyase (CCBL)
OT  - Fetal weight
OT  - N-acetyl-L-cysteine (NAC)
OT  - Trichloroethylene (TCE)
OT  - Wistar rat
COIS- Conflict of interest The authors declare that they have no conflict of interest.
EDAT- 2021/02/19 06:00
MHDA- 2021/11/04 06:00
PMCR- 2022/04/01
CRDT- 2021/02/18 12:16
PHST- 2020/09/22 00:00 [received]
PHST- 2021/01/21 00:00 [accepted]
PHST- 2021/02/19 06:00 [pubmed]
PHST- 2021/11/04 06:00 [medline]
PHST- 2021/02/18 12:16 [entrez]
PHST- 2022/04/01 00:00 [pmc-release]
AID - 10.1007/s00204-021-02991-8 [pii]
AID - 10.1007/s00204-021-02991-8 [doi]
PST - ppublish
SO  - Arch Toxicol. 2021 Apr;95(4):1303-1321. doi: 10.1007/s00204-021-02991-8. Epub 
      2021 Feb 18.