Studies on toxicodynamic of chromium with particular reference to its effect on Myometrial activity in rat

Abstract

Present study was conducted to evaluate the effect of chromium on myometrial newlineactivity in rats and the possible mechanistic pathways. The study was undertaken in three newlinephases i.e. Phase I- Biomonitoring studies; Phase II-In-vivo study on effect of chromium newlineexposure at 250 ppb, 1ppm and 10 ppm in drinking water for 90 days and, also 45 days after newlineits withdrawal; and Phase III-In-vitro study on effect of chromium on myometrial activity and newlineits mechanistic pathways. For in-vivo studies, adult female wistar rats were divided into seven newlinegroups of ten animals each. Rats of group I served as control group whereas group II, III and newlineIV were orally administered potassium dichromate at 250 ppb, 1 ppm and 10 ppm daily for newline90 days while rats of groups V, VI and VII constituted the withdrawal groups and study was newlineundertaken after 45 days of withdrawal following 90 days exposure. Cows and buffaloes newlinesuffering with different reproductive problems had higher blood levels of chromium than the newlinepermissible value of 0.5 µg/L. Highest blood levels of 1.90 ± 0.12 and 1.76 ± 0.22 µg/L were newlineobserved in cows and buffaloes having the history of repeat breeding and abortions, newlinerespectively. Highest chromium level was observed in Ganga river water (332.7 ± 34.1 µg/L) newlineand lowest (57.70 ± 5.32 µg/L) in the water samples collected from Mathura University newlineAfter 90 days of continuous exposure and 45 days of withdrawal period, no newlinesignificant effect was observed on the body weight, relative and absolute organ weights. newlineChromium-exposure resulted in significant (plt0.05) reduction in haemoglobin, TEC, TLC newlineand MCV values. Plasma BUN and creatinine levels were significantly (plt0.05) increased in newlinechromium treated rats of group III and IV as compared to the control group. Significant newline(plt0.05) increase in ALT activity and bilirubin levels in rats of group II and group III newlineindicated chromium-induced hepatotoxicity. newlineChromium significantly (plt0.05) increased lipid peroxidation, reduced catalase newlineactivity and significantly (plt0.05) reduced in GSH and GPx activity in erythrocytes, liver and newlinekidneys in rats of chromium-treated groups. Withdrawal of chromium exposure for 45 days newlinedid not have any significant effect in restoring the MDA levels, catalase and GST activities newlineand GSH levels in rats. Thus, suggesting chromium-induced oxidative stress which is newlineirreversible up to 45 days. newlineExposure of rats to chromium at 250 ppb, 1 ppm and 10 ppm for 90 days, resulted in newlineaccumulation of significantly higher concentration of chromium in uteri and ovaries of rats of newline1 ppm and 10 ppm exposure groups but chromium levels did not significantly decline even newlineafter 45 days of withdrawal. Chromium significantly (plt0.05) decreased the blood levels of newlineiron and zinc in rats of groups II, III and IV, and also V, VI and VII. Thus, suggesting that newlinechromium exposure had long term deleterious effects on blood iron and zinc levels in rats. newlineWith the increment of chromium exposure levels, absolute tension (g), mean integral newlinetension (g) and frequency (BPM) of chromium in rat myometria increased with increase in newlinedose but the increase in tension was statistically significant only in 1 and 10 ppm exposure newlinegroups. CaCl2, KDS, oxytocin and PGF2and#945; induced maximal contractions were significantly newlinereduced in myometrium of rats of group II while significantly increased in rats of group III newlineand IV but pD2 values in chromium exposed groups were significantly lower than in control newlinegroup. Compared to the control, there was potentiation of the relaxant effect (Rmax) of newlineterbutaline in uteri of rats of groups II and III while reduction in Rmax value in rats of group newlineIV, but alterations in Rmax values were not statistically significant. newlineFollowing withdrawal of chromium exposure, spontaneous myometrial activity data newlineof the uteri of rats of groups V, VI and VII revealed that compared to groups III and IV; newlineabsolute tension (g) and mean integral tension (g) were significantly decreased in rats of newlinegroups VI and VII, respectively. Compared to the control, the Emax values of CaCl2, KDS, newlineOxytocin, PGF2and#945; and BAY K 8644 in uteri of rats of groups II, III and IV and rats of groups newlineV, VI and VII were found to be significantly reduced. The dose response curves of CaCl2, newlineOxytocin, PGF2and#945; and BAY K 8644 were found to be significantly shifted towards right in all newlinethe chromium withdrawal groups V, VI and VII as compared to the DRC of oxytocin in newlinecontrol group. newlineIn vivo studies suggest chromium significantly decreased the contractile effect of newlineCaCl2, KDS, PGF2and#945;, oxytocin, BAY K8644 at low doses while higher doses increased it. newlinePossibility of chromium inhibiting the Ca-channels and/or intracellular signaling pathways newlineinvolved in mediating contractile effects of oxytocin and PGF2and#945; cannot be ruled out. newlineThe results of the present in-vitro study suggest that chromium decreases the influx of newlineCa2+ through L-type Ca2+-channels, stimulates KATP and Kv channels and also stimulates and#946;2 newlineand and#946;3 adrenergic receptors to produce inhibitory effect on rat myometrium. newline