N-Acetyl-l-cysteine and aminooxyacetic acid differentially modulate trichloroethylene reproductive toxicity via metabolism in Wistar rats
- 18 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Archives of Toxicology
- Vol. 95 (4), 1303-1321
- https://doi.org/10.1007/s00204-021-02991-8
Abstract
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 β-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.Keywords
Funding Information
- National Institute of Environmental Health Sciences (P42ES017198, T32ES007062, P30ES017885)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD079342)
- Horace H. Rackham School of Graduate Studies, University of Michigan (Graduate Student Research Grants)
This publication has 57 references indexed in Scilit:
- 3-Nitrotyrosine: A biomarker of nitrogen free radical species modified proteins in systemic autoimmunogenic conditionsHuman Immunology, 2013
- Adverse Birth Outcomes and Maternal Exposure to Trichloroethylene and Tetrachloroethylene through Soil Vapor Intrusion in New York StateEnvironmental Health Perspectives, 2012
- Toxicological Pathology in the Rat PlacentaJournal of Toxicologic Pathology, 2011
- Trichloroethylene induces dopaminergic neurodegeneration in Fisher 344 ratsJournal of Neurochemistry, 2010
- Evidence of Autoimmune-Related Effects of Trichloroethylene Exposure from Studies in Mice and HumansEnvironmental Health Perspectives, 2009
- The use of N-acetylcysteine for the prevention of hypertension in the reduced uterine perfusion pressure model for preeclampsia in Sprague-Dawley ratsAmerican Journal of Obstetrics and Gynecology, 2005
- Induction of CYP3A1 by dexamethasone and pregnenolone-16α-carbonitrile in pregnant rat and fetal livers and placentaExperimental and Toxicologic Pathology, 2003
- Expression of cytochrome P450 (CYP) isozymes in rat placenta through pregnancyExperimental and Toxicologic Pathology, 2001
- Trichloroethylene-Induced Mouse Lung Tumors: Studies of the Mode of Action and Comparisons between SpeciesFundamental and Applied Toxicology, 1997
- Sulfoxidation of Mercapturic Acids Derived from Tri- and Tetrachloroethene by Cytochromes P450 3A: A Bioactivation Reaction in Addition to Deacetylation and Cysteine Conjugate β-Lyase Mediated CleavageChemical Research in Toxicology, 1996