Reduction in weight gain in sheep , hen , broiler chicks  and rabbits  treated with cassava or cyanide have been reported in a concentration-dependent manner. Avais et al.  also reported an insignificant effect of cyanide on feed intake in cyanide-treated rats. However, the high nutritional value of cassava has been reported, having 112 calories per 100 gram compared to sweet potatoes and beets having 76 calories per 100 grams and 44 calories per 100 grams respectively . Its ability to provide high calories has made it an important crop for developing countries. Consumption of high calories diet has been associated with weight gain and obesity. For instance, dietary energy density was associated with higher body mass index, waist circumference, elevated fasting insulin, metabolic syndrome in U.S. adults . Normal-weight persons have also been shown to have diets with a lower energy density than obese persons . The increase in weight gain by CD in the present study could thus be partly associated to its high calories as previously reported. While the discrepancy in our observation of high weight gain and the reduction in weight gain reported by others [33, 35, 36] cannot be convincingly justified at the moment, we speculate that the dosage of the cassava administered, species of animals, the geographical effect on different cassava samples and processing methods could be culpable.
Consumption of foods with low energy density (kcal/g) has been said to reduce energy intake and has been recommended for weight management. For instance, men and women with low-energy-dense diet had a lower energy intake (approximately 425 and 275 kcal/d less) than did those with a high-energy-dense diet, even though they consumed more food (approximately 400 and 300 g/d more, respectively). Moreover, persons with high fruits and vegetable intake had the lowest energy density values and the lowest obesity prevalence . In this study, we investigated if supplementation of CD with anti-oxidants having negligible energy density will increase feed consumption and also reduce the bodyweight of rats as noted in humans by Ledikwe et al.  and Mendoza et al. . We observed an increase in body weights of rats that received melatonin and vitamin C supplements in addition to CD throughout the experimental period. We also found that the feed intake was higher in rats that received cassava but lower or unchanged in rats that received melatonin and/or vitamin C with(out) cassava at weeks 1 and 4. Contrarily, the feed intake was higher in rats that received melatonin and vitamin C supplements in addition to cassava at week 2, and also higher in all groups (except in those that received 40% CD) at week 3. Thus, our study suggests that the effect of energy density on weight gain and feed consumption are time-dependent.
Is the cassava-induced increase in body weight related to alteration in thyroid functions? It has been reported that cyanide causes a reduction in the growth rate of hens by inhibiting intra-thyroidal stimulating hormone and thereby causing a reduction in thyroxine level which is necessary for growth . In a Mozambique rural population affected by spastic paraparesis, the anti-thyroid effect of thiocyanate from cassava-derived cyanide exposure manifested as decrease in serum T4 but increase in serum T3, T3/T4 ratio and TSH . Thiocyanate also inhibited sodium-iodide symporter, thus reducing the transport of iodine from circulation into thyroid follicular cells which will impair thyroid hormone synthesis . In weaned mice, thiocyanate decreased thyroid T3, T4 and iodine contents but increased plasma TSH with corresponding hyperthrophy of the thyroid gland, all of which followed recovery after thiocyanate withdrawal . Fresh cassava root-induced elevation of serum thiocyanate was accompanied with no change in thyroid gland size, and thus no goiter . However, our own study disagrees with these previous studies and showed hyperthyroid effect of CD, as we noticed increase in the plasma T3 and T4 without any corresponding change in the TSH. Our study partly agrees with that of Adeniyi et al.  that also noticed cyanide-induced hyperthyroidism, but slightly disagrees with their study as our own hyperthyroidism is independent on thyrotropin like theirs. Adeniyi et al.  treated male Wistar rats with hexacyanoferrate III solution for 56 days and reported significant increase in the levels of thyroid hormones (T3 and T4) but reduction in TSH, while the thyroid gland showed marked epithelial hyperplasia with cellular degeneration and scanty cytoplasm. We therefore speculate that the increase in weight gain elicited by CD in our study is related to hyperthyroidism-induced increase in feed intake in the rats.
Does cassava and its cyanide cause oxidative stress? Serum thiocyanate is a stable metabolite and a useful biomarker of cyanide exposure , whose implications in oxidative stress have been well-documented . For instance, prolonged sub-lethal cyanide administration caused a decline in superoxide dismutase activity in red blood cells and catalase activities in some tissues of cyanide-toxified rats [45–47]. Cyanide intoxication has been linked to increasing lipid peroxidation leading to the production of malondialdehyde (MDA) which is a pro-oxidant that causes oxidative stress [46, 48]. Hariharakrishnan et al.  also reported that various concentrations of cyanide caused cytotoxicity in Rhesus monkey kidney epithelial cells, which was accompanied by elevation of MDA, reactive oxygen species (ROS), reactive nitrogen species (RNS), and diminished cellular antioxidant status (reduced glutathione, glutathione peroxidase, superoxide dismutase and catalase). Increase in serum aminotransferases (aspartate and alanine aminotransferase) have also been observed following cyanide exposure indicating damage to the cell membrane of the liver . In the present study, we observed that both doses of CD increased thiocyanate and reduced the total antioxidant capacity (TAC). These observations suggest that CD has pro-oxidant effect and are in agreement with previous studies cited in this paragraph.
Is there a link between the cassava-induced hyperthyroidism and oxidative stress? The involvement of ROS and oxidative stress in the development of hyperthyroidism and autoimmune diseases like Graves’ disease has been well documented. For instance, hyperthyroidism increases oxygen consumption, dysfunction in the mitochondrial respiratory chain, elevated intracellular adenosine triphosphate consumption and increased ROS production [51, 52]. Genesis of Graves’ disease and its orbitopathy , in addition to hyperthyroidism-induced damage such as thyrotoxic myopathy and cardiomyopathy  have been strongly linked to oxidative stress. Untreated hyperthyroidism also reportedly increased oxidative stress parameters, while restoration of euthyroidism with antithyroid drug reversed the biochemical abnormalities associated with oxidative stress . In fact, animal and human studies suggest that increased ROS directly contribute to some clinical manifestations of the disease. Our simultaneous observation of hyperthyroidism and oxidative stress in cassava-treated rats show that there is a link between these two conditions as reported by others.
Can the oxidative stress be ameliorated by melatonin and/or vitamin C? Treatment of 24 hyperthyroid patients with propylthiouracil for 5 days combined with vitamin C for 1 month potentiated the antioxidant defense system and oxidative stress in them . Antioxidants treatment also improved clinical picture of hyperthyroid patients and led to earlier attainment of euthyroid state [57, 58]. Asayama et al.  also reported that vitamin E protects against thyroxine-induced lipid peroxidation in muscles. Similarly, we also observed in this study that melatonin and/or vitamin C ameliorates cassava-induced oxidative stress and hyperthyroidism in rats.
Exposure of dogs to cassava-borne cyanide diet for 14 weeks has been reported to elicit testicular degenerative changes and liver lesion . In our present study, the sperm count (but not other semen parameters) was increased by 80% CD, but not 40% CD, an effect that was augmented by melatonin. Combination of melatonin and vitamin C in cassava-treated rats increased the semen parameters when compared to control and CD only. Our data also showed that CD did not significantly affect testosterone and gonadotropins, neither did melatonin and/or vitamin C caused any change when administered alone or combined with cassava treatment. Though most of the semen parameters did not show significant effect in cassava-treated animals, the degeneration of the seminiferous tubules as evident from the testicular histology suggests gonadotoxicity in these animals. It also suggests that the gonadotoxic effect of cassava in male rats are independent on the hormones but might be attributed to either the direct or indirect effect of cyanide and/or its metabolite (thiocyanate) on the seminiferous tubules via induction of oxidative stress.