Fetal origin of adverse pregnancy outcome

The water disinfectant by-product chloroacetonitrile induces oxidative stress and apoptosis in mouse fetal brain

Ahmed E. Ahmed, Sam Jacob, Gerald A. Campbell, Hassan M. Harirah, J. Regino Perez-Polo, Kenneth M. Johnson

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Epidemiological studies indicate a relationship between water disinfectant by-products (DBP) and adverse pregnancy outcomes (APO) including neural tube defects. These studies suggest that fetal brain may be vulnerable to DBP during early stages of development. Therefore, we examined several molecular markers commonly known to indicate chemical-induced neurotoxicity during fetal brain development following prenatal exposure to the DBP; chloroacetonitrile (CAN). Pregnant mice, at gestation day 6 (GD6), were treated with a daily oral dose of CAN (25 mg/kg). At GD12, two groups of animals were treated with an i.v. tracer dose of [2-14C]-CAN. These animals were sacrificed at 1 and 24 h after treatment and processed for quantitative in situ micro-whole-body autoradiography. The remaining groups of animals continued to receive CAN. At GD18, control and treated animals were weighed, anesthetized, and fetuses were obtained and their brains were removed for biochemical and immunohistochemical analyses. Whole-body autoradiography studies indicate a significant uptake and retention of [2-14C]-CAN/metabolites (M) in fetal brain (cerebral cortex, hippocampus, cerebellum) at 1 and 24 h. There was a 20% reduction in body weight and a 22% reduction in brain weight of fetuses exposed to CAN compared to controls. A significant increase in oxidative stress markers was observed in various fetal brain regions in animals exposed to CAN compared to controls. This was indicated by a 3- to 4-fold decrease in the ratio of the reduced to oxidized form of glutathione (GSH/GSSG), increased lipid peroxidation (1.3-fold), and increased 8-hydroxy-2-deoxyguanosine levels (1.4-fold). Cupric silver staining indicated a significant increase in the number of degenerating neurons in cortical regions in exposed animals. In animals exposed to CAN there was increase in nuclear DNA fragmentation (TUNEL staining) detected in the cerebral cortex and cerebellum (2-fold increase in apoptotic indices). Caspase-3 activity in cerebral cortex and cerebellum of treated animals were also increased (1.7- and 1.5-fold, respectively). In conclusion, this study indicates that CAN/M crossed the placenta and accumulated in fetal brain tissues where it caused oxidative stress and neuronal apoptosis. These events could predispose the fetus to altered brain development leading to APO as well as behavioral and learning and memory deficits.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalDevelopmental Brain Research
Volume159
Issue number1
DOIs
StatePublished - Sep 8 2005

Fingerprint

Disinfectants
Pregnancy Outcome
Oxidative Stress
Apoptosis
Water
Brain
Fetus
Cerebral Cortex
Cerebellum
Glutathione Disulfide
Autoradiography
chloroacetonitrile
Silver Staining
Neural Tube Defects
Memory Disorders
In Situ Nick-End Labeling
DNA Fragmentation
Fetal Development
Caspase 3
Placenta

Keywords

  • Adverse pregnancy outcome
  • Apoptosis
  • Chloroacetonitrile
  • Neurotoxicity
  • Oxidative stress
  • Water disinfectant by-product

ASJC Scopus subject areas

  • Developmental Biology
  • Developmental Neuroscience

Cite this

Fetal origin of adverse pregnancy outcome : The water disinfectant by-product chloroacetonitrile induces oxidative stress and apoptosis in mouse fetal brain. / Ahmed, Ahmed E.; Jacob, Sam; Campbell, Gerald A.; Harirah, Hassan M.; Perez-Polo, J. Regino; Johnson, Kenneth M.

In: Developmental Brain Research, Vol. 159, No. 1, 08.09.2005, p. 1-11.

Research output: Contribution to journalArticle

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