Effect of chromium administration on hypothalamic-pituitary-thyroad azis and iodine metabolism in rats

Abstract

Toxicity due to heavy metals is of major concern in Pakistan. Mercury, cadmium, chromium, arsenic, lead, zinc and copper concentrations have increased to alarming levels in the water, soil and air which have become large dumps of industrial effluents. Physiologically, heavy metals can profoundly affect the functioning of the endocrine system. In Pakistan, thyroid related diseases are also very common. Chromium in hexavalent form is highly toxic and a known carcinogen, however as opposed to the trivalent form, its toxic effects on the thyroid structure and function are relatively unexplored. Acute exposure to chromium (VI) can occur in the occupational set up. The present study was designed therefore using laboratory rats as a model system to investigate the thyroid gland structure and function and iodine metabolism following two acute intraperitoneal doses of 30 mg/kg b.w. potassium dichromate given within 48 hours. Pituitary and hypothalamic tissues were also investigated. The study employed diverse methods including: atomic absorption spectrophotometry, solidphase radioimmunoassay (RIA), RT-PCR, analytical methods for estimation of iodine, light and electron microscopy, DNA ladder assay and acridine orange staining. Results showed that in the chromium treated animals, hypothalamic clu·omium concentration increased (p < 0.05), while thyroid chromium concentration decreased (p < 0.01); however, pituitary clu·omium was only slightly elevated. Whole blood chromium concentration increased (p < 0.001) while serum chromium concentration was slightly raised (p = n.s.). Chromium excretion in the urine increased (p < 0.05). Serum FT4 and FT3 levels decreased (p < 0.01 and p < 0.001 , respectively), while serum TSH concentration increased (p < 0.01). RT-PCR indicated upregulation of TSH mRNA. Both the urine iodine and protein bound iodine levels decreased (p < 0.01; p < 0.05 respectively). Cells of the anterior pituitary showed hypertrophy with an increase in cell size (p < 0.001) but the cellular density decreased (p < 0.001). Thyroid gland showed follicular hyperplasia. The number of follicles increased (p < 0.001), however the follicular size decreased (p < 0.001). A large number of follicles were disorganized becoming irregular in shape, slu·unken or regressed, while a few were fused with the others. Necrosis was also evident in a few sections. Interfollicular x spaces widened leading to an increase of stromal tissue. Epithelial cells were desquamated and their heights increased (p < 0.001), while the nuclear size regressed (p < 0.001). The nuclei were pyknotic ranging from irregular to round, and oval or elongated. Cytoplasmic size increased (p < 0.01). Colloid retraction and resorption were frequently observed. Thyroid gland ultrastructural analysis showed disrupted basal laminae of the follicles. The follicles therefore appeared collapsed. The nuclei of the cells were pyknotic with irregular shape. Most cell organelles were deformed. The endoplasmic reticulum and Golgi apparatus were either disrupted or disorganized, while mitochondria were not abundant. Colloid droplets decreased and an increase of collagen fibers was readily noticeable. Acridine orange staining of thyroid cells demonstrated excessive dead cells. DNA ladder assay of the hypothalamus, pituitary and thyroid glands showed fragmentation of the DNA. On quantification, it was fow1d that the DNA damage occurred to the hypothalamus was 56 ± 1.78 %, to the pituitary it was 30 ± 1.26 % and to the thyroid gland it was 55 ± 1.21 %. The present study concludes that chromium in the hexavalent form is highly toxic to hypothalamic-pituitary-thyroid axis of the body. This might lead to severe and persistent hypothyroidism with drastic structural as well as functional alterations and the iodine concentration. It is suspected from the thyroid morphology that a long term or chronic, exposure could possibly result in tumor formation. Further studies are required to elucidate the mechanism of action of hexavalent or trivalent chromium at cellular and molecular levels and a complete understanding of the iodine metabolism in the case of cm"omium toxicity.