The Influence of Tellurium and Folic Acid Administration on Coping Behavioural Parameters in Maturing Rats: Transgenerational Effects

Special Article - Social Behavior

Austin Anthropol. 2019; 3(2): 1009.

The Influence of Tellurium and Folic Acid Administration on Coping Behavioural Parameters in Maturing Rats: Transgenerational Effects

Ratti SG1, Sacchi OJ2 and Alvarez EO1*

¹Laboratory of Experimental Neuropsychopharmacology, National University of Cuyo, Argentina

²Institute of Medicine and Experimental Biology of Cuyo (IMBECU)-CONICET, Argentina

*Corresponding author: Edgardo O Alvarez, Laboratory of Experimental Neuropsychopharmacology, National University of Cuyo, Faculty of Medical Sciences, Mendoza 5500, Argentina

Received: October 03, 2019; Accepted: October 25, 2019; Published: November 01, 2019


A previous study of our laboratory have shown that Tellurium (Te), a metalloid with low concentrations in soil and water in the earth, is able to modify important behavioural parameters related to cognitive functions when administered orally in maturing rats. Exposition of chronic non-toxic doses of Te affected spontaneous lateralized exploration, social interaction behaviour, and survival responses in the treated rats. Te effects were blocked by the simultaneous administration of folic acid, a well-known methyl group donor in the cell, suggesting an epigenetic mode of action of Te. Te behavioural effects on the second generation (F1) still were found in the next third generation (F2). In order to evaluate if these transgenerational behavioural alterations in F2 were depending on DNA methylating mechanisms, as observed in the F1 generation, F1 rats were mated at 90 days of age. Two groups of animals in the F2 offspring were formed; one treated with and the other not treated with folic acid. Results showed that the untreated folic acid F2 maturing rats, conserved the same pattern of behavioural alterations than its parents (F1), in spite that they were not exposed to Te. Those F2 animals treated with folic acid, instead recovered the normal behavioural responses in the three tests performed to evaluate coping behaviour. Results suggest that the molecular mechanism of Te is dependent on DNA methylating reactions, which is one of the molecular processes of epigenetic modulation in mammals.

Keywords: Tellurium; Lateralized behaviours; Epigenetic changes; Folic acid; Transgenerational effects


Tellurium (Te) is an inorganic trace element occupying position 16 in the periodic table of elements and is one representative of a group of inorganic chemicals classified as metalloid [1]. The most abundant chemical form in nature is the oxyanion (TeO3)2-, which reacts with many other elements, being relatively stable. Perhaps the most notorious application of Te in the early medicine of 1900 was its recognized toxicity to microbial and other microorganism agents leading to its applications in human beings for treating bacterial infections before antibiotics appeared in the health history of microbial control [2,3]. Unfortunately, the common side effect of an intense garlic odor in breath and urine of patients was an important handicap in those early medicinal treatments [4]. Although the first impression about Te in the scientific community was centered on its toxic effects, some isolated descriptions after exposition to compounds containing the metalloid put the first notion that Te in biological systems could have additional biological actions other than the obvious antiseptic properties. The most early notorious description about additional biologic effects of Te was a report about a chemist synthesizing batches of TeO2, who by unadvertised inhalation of dust in the preparation, suffered later of depression with sustained periods of sleeping in addition to garlic breath odor [5], suggesting that the nervous system showed some selective sensitivity to the metalloid in the body. Several decades later, it was found that Te inhibits the enzyme squalene epoxidase resulting in blockade of cholesterol synthesis in peripheral nerves [6,7]. Demyelination, as the Te consequent effect of cholesterol decrease, leaded to repression of the expression of mRNA for myelin specific proteins [8,9].

Biological effects of Te are not selectively restricted to peripheral nerves in the nervous system. In vitro cultures of astrocytes isolated from rat hippocampal structure, the incubation with tellurium tetrachloride and diphenyl ditelluride caused marked cytotoxicity [10]. It is reasonable to think that the adverse effect of Te in animals was related to the exposition dose. At lower doses, other biologic effects were apparent connected to brain functions. Thus, contrary to what it was expected in rats exposed to Te several behavioural parameters related to exploration and motivation, important responses for proper adaptation of animals to environmental changes (coping behaviour), were not affected in treated rats. Even in some tests, behavioural responses were positively increased, such as the number of entries and permanency in the fear-inducing arm of the elevated plus-maze, suggesting a decrease in emotionality and an increase in motivation [11]. In some other studies, beneficial nontoxic actions of Te in animals have been reported using ammonium trichloro(dioxoethylene-O,O’) tellurate (AS101) which was able to induce hair growth in nude mice and also in teenagers with alopecia [12]. In addition, this same molecular complex gives protection and restoration of dopaminergic neurotransmission of neurons in a model of Parkinson’s disease [13], suggesting that the metalloid is acting on important biochemical pathways regulating cell natural homeostasis.

At even lower doses of Te exposition (less than 0.5μg/L) surprising well defined behavioural effects related to cognition have been found in maturing rats [14-17] putting in perspective that the biological effects of the trace element strongly depend on the amount of exposition to animals.

Contrary to the idea that Te is a foreign external inorganic element and as such it should not normally be present in living beings, there is evidence supporting the opposing concept. Te has been found in appreciable amounts in bone tissue in humans [18]. Its presence also has been detected in blood and urine [19,20]. In addition, Te was found to form structural part of some amino-acids, such as tellurocysteine and telluromethionine in some bacterial proteins [21,22], yeast and fungi [23,24], suggesting some possible biological role for the metalloid.

Previous work in our laboratory have shown that Te administered in a chronic regimen at the non-toxic dose of 0.3μg/L in drinking water to maturing rats, inhibited the natural lateralized exploration in a novel environment; the social interaction response in an intruder/ resident conflict, and the survival response in a forced swimming test [14,15,25]. Although it is not completely clear the intrinsic molecular mechanism by which Te is affecting these behavioural responses, considering that Te is transported in the red blood cells [26], it can cross the brain barrier easily and it can reach in theory many neuronal regions. It was not surprising to find in the hippocampal structure of rats treated with this trace element, a decrease of the cytosine methylation pattern of DNA, clearly suggesting an epigenetic modulation of behavioural responses of animals [15]. Epigenetic processes have been recognized to participate in several biologic functions of organisms, but particularly remarking is that they preferentially affect brain processes in mammals [27-29]. Additional support to the participation of Te in the transgenerational decrease of methylated cytosine of hippocampal DNA was the observation that a complete blocking of the trace element inhibitory effects on behaviours was found in Te treated animals with folic acid, a wellknown methylating agent [30].

Epigenetic mechanisms have the property that after the primary inducing environmental stimulus, changes are inheritable persisting to the next generations [31,32]. Female rats treated with Te in the F1 generation, allowed to mature without any treatment until they reach 90 days old, and mated with normal males, the next generation (F2) still presented the modified behaviours previously observed in their parents, e.g. the Te biological changes persisted across generations, just as it would be expected to an epigenetic effect for this trace element [25]. This evidence suggests that permanency of the blocked behavioural responses in the F2 offspring might be due to hypomethylation state of hippocampal DNA. However, the possibility that folic acid administered in the F2 rat generation might provoke reversion of the Te biological effects is an aspect not been investigated so far. Thus, the objective of this work was to evaluate if treatment with folic acid in the third generation of animals, whose parents have been exposed to Te, the modified behavioural responses can return to normality.

Materials and Methods


Rats of a Holzman-derived colony, weighing 250-300 g, 90 days old and maintained in thermoregulated (22-24oC) and controlled light conditions (06.00 on- 20.00 h off) were used. Standard rat chow and water were available ad libitum for control animals. For experimental rats, K2TeO3 (0.39μg/L), or folic acid (0.16gr/L), were given in the drinking water.


Potassium Tellurite (K2TeO3, Tetrahedron Reactivos Analíticos, Argentina) and folic acid (Parafarm, Droguería Saporiti S.A.C.I.F.I.A., Argentina) were used.

Experimental design

The general experimental protocol used in the present work was described previously [25]. Briefly, chronic exposition to Te, beginning from fertilization of the mother rat up to prepuberal maturation stages of litter rats was applied. From 35 day-old up to 90 day-old, the trace element treated animals (F1) remained at rest without any further treatment (Figure 1). At 90 days of age, female F1 generation rats were mated with normal male animals giving the next F2 generation.