Cell Biology and Toxicology

, Volume 29, Issue 4, pp 283–291 | Cite as

Mechanism of metolachlor action due to alterations in cell cycle progression

  • Dana M. Lowry
  • Donovan Greiner
  • Michelle Fretheim
  • Macy Ubben
  • Kavita R. Dhanwada
Original Research


Metolachlor, a commonly used herbicide in the Midwestern USA, functions by inhibiting chlorophyll and protein synthesis in target plants. Herbicide exposure has led to detrimental effects in several organisms, affecting their growth and behavior; however, its mechanism of action in nontarget organisms is not yet clear. The EPA does not currently have enforceable regulations for maximal limits allowed in drinking water. Previous growth studies from our lab have demonstrated that increasing metolachlor concentrations and increasing time of exposure results in decreased growth of liver cells. The objective of this study was to elucidate a mechanism for this decrease of HepG2 cell growth after herbicide exposure. Results show that metolachlor at environmentally relevant levels (50–100 ppb) that previously led to decreased cell number does not lead to cell death by either necrosis or apoptosis. However, it was demonstrated that the levels of the retinoblastoma protein including two of its hyperphosphorylated forms are decreased in metolachlor exposed cells possibly leading to cell cycle arrest. The levels of another protein involved in cell cycle progression, p53, a mediator in the DNA damage response of cells, was not significantly altered except at the highest level of metolachlor (1,000 ppb) and after a 72-h exposure. These results suggest that the decrease in cell number after low-level metolachlor exposure is most likely due to an alteration in the cell cycle and not due to cell death in human liver cells.


Herbicides Metolachlor HepG2 Cell cycle Retinoblastoma protein 



The work performed by student authors’ satisfied requirements for undergraduate research at the University of Northern Iowa. Retinoblastoma protein ELISA analysis was performed by D. Lowry, p53 analysis was completed by D. Greiner, apoptosis analysis was performed by M. Fretheim, and cytotoxicity analysis was performed by M. Ubben. All four students were completing either their BS (DL) or BA in Biology (DG, MF, and MU). Funds were provided by Summer Undergraduate Research Program from the College of Humanities, Arts and Sciences at the University of Northern Iowa as well as a grant to K. R. Dhanwada from the Center for Health Effects of Environmental Contamination at the University of Iowa. The authors would especially like to thank Dr. David McClenahan for his assistance throughout the project and for insight during the preparation of the manuscript as well as Dr. Tilahun Abebe for editing assistance with the final manuscript.


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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Dana M. Lowry
    • 1
  • Donovan Greiner
    • 1
  • Michelle Fretheim
    • 1
  • Macy Ubben
    • 1
  • Kavita R. Dhanwada
    • 1
  1. 1.Department of BiologyUniversity of Northern IowaCedar FallsUSA

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