Dietary modulations of folic acid affect the development of diethylnitrosamine induced hepatocellular carcinoma in a rat model

Abstract

The present study evaluated the role of dietary folate modulations in the development of hepatocellular carcinoma (HCC) in a rat model. Male Wistar rats were given diethylnitrosamine (DEN) carcinogen for a period of 18 weeks in addition to different folate modulations. Biochemical parameters were assayed and liver tissues were examined using various histopathological stains viz. Hematoxylin and eosin (H&E), Masson’s trichrome, Immunohistochemistry (IHC) staining for arginase-1 and α-smooth muscle actin (SMA). Serum folate and hepatic folate stores were decreased and increased in folate deficiency (FD) and folate oversupplemented (FO) group respectively. Analysis of serum liver function tests revealed deranged liver functioning in all the groups. H&E staining of rat liver demonstrated vague nodularity from 2nd to 8th week, fibrosis from 10th to 15th week, cirrhosis and HCC from 16th to 18th week. Combining the observations of H&E with IHC for arginase-1, 14 (50%), 11 (39.3%) and 17 (58.6%) rats showed HCC positivity in FN (folate normal), FD and FO diets respectively. IHC for α-SMA depicted increased staining with progression of the disease from fibrosis to cirrhosis in all the dietary groups. Collectively, findings of all the histopathological stains, revealed increase in the number of cirrhotic cases and decrease in the number of HCC cases in FD group, indicating delayed progression of HCC with FD. Moreover, FO led to more number of HCC and reduction in the number of cirrhotic cases, signifying early progression of HCC.

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Abbreviations

FA:

Folic acid

FD:

Folate deficiency

FN:

Folate normal

FO:

Folate oversupplementation

HCC:

Hepatocellular carcinoma

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. However, funding assistance provided by ICMR to the research fellow (Renuka Sharma) is fully acknowledged.

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JK, ADas, ADuseja, RS supported the conception and design of the study, acquisition/analysis and interpretation of data, drafting or revising the article critically for essential intellectual content, final approval of the version to be submitted. IN helped with microtomy and staining techniques. TA contributed in dosing and feeding related procedures of rats. Paper represents the honest work and reliable results.

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Correspondence to Jyotdeep Kaur.

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Sharma, R., Ali, T., Negi, I. et al. Dietary modulations of folic acid affect the development of diethylnitrosamine induced hepatocellular carcinoma in a rat model. J Mol Histol (2021). https://doi.org/10.1007/s10735-020-09955-9

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Keywords

  • Folate
  • Folate deficiency
  • Folate oversupplementation
  • Fibrosis
  • Cirrhosis
  • HCC