Embryonic arsenic exposure reduces intestinal cell proliferation and alters hepatic IGF mRNA expression in killifish (Fundulus heteroclitus)

ABSTRACT

Arsenic (As) is a toxicant found in food and water throughout the world, and studies suggested that exposure early in life reduces growth. Thus, the goal of this study was to examine mechanisms by which As impacted organismal growth. Killifish (Fundulus heteroclitus) were exposed to 0, 10, 50, or 200 ppb As as embryos and, after hatching, were reared in clean water for up to 40 weeks. Metabolism studies revealed that killifish biotransform As such that monomethylated and dimethylated arsenicals account for 15–17% and 45–61%, respectively, of the total metal. Growth, as measured by condition factor (CF), was significantly and dose-dependently reduced at 8 weeks of age but was similar to controls by 40 weeks. To determine mechanisms underlying the observed initial decrease, intestinal proliferation and morphology were examined. Arsenic-exposed fish exhibited significant 1.3- to 1.5-fold reduction in intestinal villus height and 1.4- to 1.6-fold decrease in proliferating cell nuclear antigen (PCNA+) intestinal cells at all weeks examined. In addition, there were significant correlations between CF, PCNA+ cells, and intestinal villus height. Upon examining whether fish might compensate for the intestinal changes, it was found that hepatic mRNA expression of insulin-like growth factor 1 (IGF-1) and its binding protein (IGFBP-1) were dose-dependently increased. These results indicate that embryonic exposure initially diminished growth, and while intestinal cell proliferation remained reduced, fish appear to compensate by enhancing transcript levels of hepatic IGF-1 and IGFBP-1.

KEYWORDS:

• Arsenic
• intestine
• IGF-1
• monomethylarsonic acid (MMA)
• stem cell
• killifish

Acknowledgments

The authors thank John Smink for his assistance with animal husbandry, Dr. William Bridges for help with statistical analyses, and Clemson University’s Histology Core facility.

Conflicts of interest

The authors declare that no conflicts of interest exist.

Data Accessibility

Data are available upon request ([email protected])

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the National Institutes of Health under Grant R03ES023930.