Fluoride induced tissue hypercalcemia, IL-17 mediated inflammation and apoptosis lead to cardiomyopathy: Ultrastructural and biochemical findings

Toxicology. 2018 Aug 1;406-407:44-57. doi: 10.1016/j.tox.2018.05.012. Epub 2018 May 22.

Abstract

An increased prevalence of cardiac complications has been observed in residents of fluorosis endemic areas chronically exposed to fluoride. Fluoride induces soft tissue injury due to oxidative stress, lipid peroxidation (LPO) and mitochondriopathy. It was hypothesized that chronic fluoride exposure induces apoptosis in cardiomyocytes due to inflammation, lysis of extra cellular matrix and altered calcium metabolism. This study was planned to evaluate the effects of chronic fluoride exposure and the mechanism of action in the cardiac muscle. Fifteen week old male Wistar rats were administered a human equivalent dose of fluoride (50 and 100 ppm ad-libitum, HED = 5 & 10 ppm in human) for 75-days. After 75-days of fluoride exposure, the animals were euthanized and fluoride, oxidative stress (SOD, GPX, Catalase activities) and LPO were measured. Histopathological and ultrastructural pathological examinations were conducted on the cardiac tissues using light, atomic force and electron microscopies. The cardiac tissues were also assessed for apoptosis (TUNEL/Caspase assays), and tissue calcium levels (Alizarin-assay and SEM-EDX). Tissue inflammation and expression of IL-17, MMP-9, Caspase-3 and Bcl-2 were evaluated. In the fluoride exposed groups, a significant (≤0.05) increase in levels of oxidative stress, LPO and apoptosis were observed. The IL-17, MMP-9 and Caspase-3 were significantly (≤0.05) higher in the cardiac muscle after chronic fluoride exposure. The fluoride seems to have induced inflammation in the cardiac tissues, as well as an increase in tissue calcium (≤0.05). There was significant damage to cardiac muscle fibres including, thinning, distortion and neo-vasculogenesis following chronic fluoride exposure. Mitochondriopathy, lysis of ground substance, oedema, and hyper-vacuolation was seen in fluoride treated groups. Remarkable levels of distortion and bending in Z band were observed under the AFM. Many of these observed changes mimic those occurring in cardiomegaly, cardiac hypertrophy and cardiomyopathies.

Keywords: Apoptosis; Atomic force microscopy (AFM); Cardiomyopathies; Cardiotoxicity; Fluoride toxicity; Inflammation; Interleukin-17; MMP-9; SEM-EDX; Ultrastructure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cardiomyopathies / chemically induced
  • Cardiomyopathies / metabolism*
  • Cardiomyopathies / pathology
  • Fluorides / toxicity*
  • Hypercalcemia / chemically induced
  • Hypercalcemia / metabolism*
  • Hypercalcemia / pathology
  • Inflammation Mediators / metabolism*
  • Interleukin-17 / metabolism*
  • Male
  • Myocardium / metabolism
  • Myocardium / ultrastructure
  • Random Allocation
  • Rats
  • Rats, Wistar

Substances

  • Inflammation Mediators
  • Interleukin-17
  • Fluorides