**3.6. Distribution of immunohistochemical staining for AVP**

152 Neuroendocrinology and Behavior

Treatment Initial body weight (g) Total body water (mL) Total body water (%W)

62.97 ±2.55

61.09 ±5.28

64.89 ±1.23

67.59 ±1.36

pre-formed water via food and drink.

55.79 ±2.74

48.38 ±5.87

61.30 ±9.28

60.50 ±9.99

117.44 ±3.66

134.41 ±19.37

120.37 ±16.85

128.25 ±18.67

Cd-exposed Meriones.

Control

Cd-exposed

Deprived wa

Deprived water

and Cd-exposed

Meriones

ter Meriones

Meriones

Water influx mL

10.90 ±3.63

10.04 ±3.08

�� ⃰⃰ 2.17 ±0.23

�� ⃰⃰ 1.73 ±0.50 Water efflux mL

10.27 ±3.66

9.34 ±3.04

�� ⃰⃰ 1.93 ±0.56

�� ⃰⃰ 1.81 ±0.76 Water influx ml Kg -0.82 d -1

63.83 ±22.70

50.50 ±11.12

� ⃰⃰ 12.48 ±1.27

� ⃰⃰ 9.32 ±2.11

**Table 1.** Effects of Cd exposure on water metabolism (Total Body Water, Water influx, Water efflux, and Water Turnover Rates (WTR)and urinary and plasma osmolalities ) in adult *Meriones shawi* male under hydrated or deprived water conditions. Data are expressed as mean ± SEM from 6 animals in each group. ⃰⃰ p <0.01significantly different from controls C.� p<0.05; ��p<0.01 signifficantly different from

Total body water content in control group was 55.79 ± 2.74 (expressed by % of body weight). Throughout the experiments, body water was not significantly altered in any group. In animals having free access to water, water enters through metabolic water production and

The value of water influx was 10.90 ± 3.63 ml/ 63.83 ± 22.79 ml.Kg-0.82 .d-1. This water influx (Fin) was not significantly affected in the group treated with Cd in comparison to control group. The loss of water via excretion (urine and fecal) and evaporation was Fout =10.27 ± 3.66 ml/60.16 22.79 ml.kg-0.82.d-1. Water fluxes rate were equal (Fin = Fout). This indicates that animals were in water equilibrium. After, one week of Cd exposure, water flux rates

Water efflux mL.Kg-0.82 d -1

60.16 ±22.79

47.11 ±11.53

� ⃰⃰ 11.96 ±3.34

� ⃰⃰ 9.62 ±3.28 WTR in (% body water d -1)

17.36 ±6.44

15.51 ±4.55

�� ⃰⃰ 3.18 ±1.06

�� ⃰⃰ 2.45 ±0.73 WTR out (% body water d -1)

16.37 ±6.43

14.43 ±4.52

�� ⃰⃰ 3.12 ±0.67

�� ⃰⃰ 2.66 ±1.09 Urinary osmolality mOs/kg

H20

1100 ± 2

1600 ± 1.9\*\*

> �� ⃰⃰ 1700 ±1.9

> �� ⃰⃰ 1162 ±2

Plasma osmolality (mOs/kg

H20)

307.6 ± 4.2

332 ± 3

345 ± 3

307.6 ± 4.2

In control *Meriones shawi*, AVP immunostaining was found to be homogeneously distributed in the large magnocellular neurons of SON (Fig. 2) and PVN (Fig. 3). In agreement with previous, in the absence of Cd ingestion, there was a significant compensatory increase in AVP immunostaining by the SON of deprived animals following eight days of water restriction (Fig. 2C) and two weeks (Fig. 2D) compared to controls animals (fig 2A and B). This increase in AVP immunostaining was also observed in PVN respectively after eight days and two weeks of water restriction (Fig. 3C) and (Fig. 3D) compared respectively to controls animals (fig 3a and B).

Similarly to what was observed for AVP immunostaining in deprived animals without Cd, AVP immunoreactivity is strongly increased in SON following eight days of water restriction (Fig. 2E) and PVN (Fig. 2F) compared to controls animals respectively (Fig.2A) and (Fig.3A). The increase of AVP immunostaining became more important by prolonged experiment for two weeks respectively in SON (Fig. 2F) and PVN (Fig. 3F).

**Figure 1.** Effects of Cd exposure on water Water influx and efflux in adult *Meriones shawi* male under hydrated or deprived water conditions. Data are expressed as mean ± SEM from 6 animals in each group.

However, AVP immunostaining from deprived water animals in the presence of Cd was markedly and significantly lower in SON (Fig. 2G) than in deprived water animals but not treated with Cd for a week (Fig. 2C). This decrease of AVP immunostaining becomes more important following two weeks of treatment (Fig. 2H) in comparison in two weeks deprived water animals not treated with Cd (Fig. 2D). Similar effect of AVP depletion in SON was also observed in PVN in simultaneously deprived water group and Cd-exposed Meriones during eight days (Fig. 3G) and two weeks (Fig. 3H) in comparison to those eight days deprived water group and two weeks deprived water groups and not treated with Cd.

Effect of Cadmium Contaminated Diet in Controlling Water Behavior by *Meriones shawi* 155

**Figure 3.** Effect of Cd exposure on AVP immunoreactivity distribution in the hypothalamic

(D). Scale bars =100 µm*.*

**3.7. Effect of Cd on water metabolism** 

paraventricular nuclei (NPV) in *Meriones shawi.* Control group (A,B) *,* eight days deprived-water group (C ), two weeks deprived-water group (D), Eight days Cd-exposed group E, two weeks Cd-exposed group ( F ), 8 days Cd-exposed and also deprived water group (G), two weeks Cd-exposed and also deprived water group (H).Water deprivation increased the immunohistochemical signal in NPV nuclei (C); this increase became more important following two weeks of water deprivation (D) . Similar effect was observed when Meriones are exposed to Cd following one week (E) and two weeks (F). However, Exposure to Cd causes a decrease in immunoreactivity of vasopressin at NPV by Meriones deprived water for a week (G) compared to those water deprived group but not treated with Cd (C). This decrease was also observed after two weeks of treatment (H) as compared to water deprived Meriones

*Meriones shawi,* success dry and wet seasons by stimulating anti-diuretic and diuretic systems alternately. The maintenance of tonicity of body fluids by within a very narrow physiological range is made possible by well-developed homeostatic mechanisms that control the intake and loss of water [2, 37]. This capacity was also observed when *Meriones shawi* was treated with Cd under various conditions of water deprivation. *Meriones shawi* are able to maintain body water (55.79 %) status under water deprivation conditions. The absence of change in hematocrit value observed by deprived water groups treated or not with Cd (45%) suggests that regulatory processes occur, resulting in the maintenance of body water content and increase in urine concentration [38-39]. Whether in nature or under

**Figure 2.** Effect of Cd exposure on AVP immunoreactivity distribution in the hypothalamic supraoptic nuclei (NSO) in *Meriones shawi.* Control group (A,B) *,* eight days deprived-water group (C ), two weeks deprived-water group (D), Eight days Cd-exposed group E, two weeks Cd-exposed group ( F ), 8 days Cdexposed and also deprived water group (G), two weeks Cd-exposed and also deprived water group (H).Water deprivation increased the immunohistochemical signal in SON nuclei (C); this increase became more important following two weeks of water deprivation (D) . Similar effect was observed when Meriones are exposed to Cd following one week (E) and two weeks (F). However, Exposure to Cd causes a decrease in immunoreactivity of vasopressin at SON by Meriones deprived water for a week (G) compared to those water deprived group but not treated with Cd (C). This decrease was also observed after two weeks of treatment (H) as compared to water deprived Meriones (D). Scale bars =100 µm*.*

with Cd.

However, AVP immunostaining from deprived water animals in the presence of Cd was markedly and significantly lower in SON (Fig. 2G) than in deprived water animals but not treated with Cd for a week (Fig. 2C). This decrease of AVP immunostaining becomes more important following two weeks of treatment (Fig. 2H) in comparison in two weeks deprived water animals not treated with Cd (Fig. 2D). Similar effect of AVP depletion in SON was also observed in PVN in simultaneously deprived water group and Cd-exposed Meriones during eight days (Fig. 3G) and two weeks (Fig. 3H) in comparison to those eight days deprived water group and two weeks deprived water groups and not treated

**Figure 2.** Effect of Cd exposure on AVP immunoreactivity distribution in the hypothalamic supraoptic nuclei (NSO) in *Meriones shawi.* Control group (A,B) *,* eight days deprived-water group (C ), two weeks deprived-water group (D), Eight days Cd-exposed group E, two weeks Cd-exposed group ( F ), 8 days Cdexposed and also deprived water group (G), two weeks Cd-exposed and also deprived water group (H).Water deprivation increased the immunohistochemical signal in SON nuclei (C); this increase became more important following two weeks of water deprivation (D) . Similar effect was observed when Meriones are exposed to Cd following one week (E) and two weeks (F). However, Exposure to Cd causes a decrease in immunoreactivity of vasopressin at SON by Meriones deprived water for a week (G) compared to those water deprived group but not treated with Cd (C). This decrease was also observed after two

weeks of treatment (H) as compared to water deprived Meriones (D). Scale bars =100 µm*.*

**Figure 3.** Effect of Cd exposure on AVP immunoreactivity distribution in the hypothalamic paraventricular nuclei (NPV) in *Meriones shawi.* Control group (A,B) *,* eight days deprived-water group (C ), two weeks deprived-water group (D), Eight days Cd-exposed group E, two weeks Cd-exposed group ( F ), 8 days Cd-exposed and also deprived water group (G), two weeks Cd-exposed and also deprived water group (H).Water deprivation increased the immunohistochemical signal in NPV nuclei (C); this increase became more important following two weeks of water deprivation (D) . Similar effect was observed when Meriones are exposed to Cd following one week (E) and two weeks (F). However, Exposure to Cd causes a decrease in immunoreactivity of vasopressin at NPV by Meriones deprived water for a week (G) compared to those water deprived group but not treated with Cd (C). This decrease was also observed after two weeks of treatment (H) as compared to water deprived Meriones (D). Scale bars =100 µm*.*

#### **3.7. Effect of Cd on water metabolism**

*Meriones shawi,* success dry and wet seasons by stimulating anti-diuretic and diuretic systems alternately. The maintenance of tonicity of body fluids by within a very narrow physiological range is made possible by well-developed homeostatic mechanisms that control the intake and loss of water [2, 37]. This capacity was also observed when *Meriones shawi* was treated with Cd under various conditions of water deprivation. *Meriones shawi* are able to maintain body water (55.79 %) status under water deprivation conditions. The absence of change in hematocrit value observed by deprived water groups treated or not with Cd (45%) suggests that regulatory processes occur, resulting in the maintenance of body water content and increase in urine concentration [38-39]. Whether in nature or under laboratory conditions, control groups were in water equilibrium (water influx = water efflux) [32]. The value of water influx was 10.90 ± 3.63 ml/ 63.83 ± 22.79 ml.Kg-0.82 .d-1 (figure 1). This water influx (Fin) was not significantly affected in the group treated with Cd in comparison to control group. The loss of water via excretion (urine and fecal) and evaporation was Fout =10.27 ± 3.66 ml./60.16 ± 22.79 ml.kg-0.82.d-1. Water fluxes rate were equal (Fin = Fout). This indicates that animals were in water equilibrium. After, one week of Cd exposure, water flux rates were not significantly affected in the group treated with Cd in comparison to control group and water equilibrium was maintained throughout the experiment. Following one week of dehydration, the water influx rates was significantly decreased from about 5 times in Meriones treated or not with Cd (p<0.01). Cd exposure appears not to impair this capacity during our experiment. However in water deprived animals there was a lower rate of water influx and efflux compared to controls. This low rate of water influx and efflux was similar in water deprived animals and treated with Cd simultaneously (water metabolism are shown in table 1).

Effect of Cadmium Contaminated Diet in Controlling Water Behavior by *Meriones shawi* 157

concentrated urine [8]. Water loss was also limited by the lowered faecal water loss achieved by the production of very dry feces. In deprived water Meriones we show that water intake was provided from preformed water of food and by metabolic water production as described by Speakman [48] and King and Bradshaw [49]. Our findings are in agreement with previous reports showing that renal concentrating mechanisms are the first line of defense against water depletion [4, 12, 50]. It is well established that modifications of serum osmolality during depletion are detected via osmoreceptors by magnocellular mainly located in the hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN) in the brain [39, 51]. These neurons increase their electrophysiological activity during water restriction leading to an increase of AVP synthesis [52- 53] (and facilitates sustained antidiuresis [54] (De Mota et al. 2004). In contrast to what was observed in the laboratory rat where dehydration causes a dramatic depletion of hypothalamic AVP immunoreactivity in both SON and PVN [55- 56], water restriction induced in our model an increase in expression of AVP. This increase becomes

Interestingly, the ability of acute systemic dehydration to produce AVP in both SON and PVN in *Meriones shawi* deprived water and not treated with Cd, was also observed while treating Meriones with Cd but not deprived water. We hypothesized that potential effects of Cd might include exaggerated synthesis of AVP during Cd exposure in our model *Meriones shawi* and support the idea of an increase of AVP as result of Cd intoxication (see figure 2 and 3). These findings suggest that Cd ingestion has potential effects on the vasopressinergic system that responds with elevated synthesis of AVP under stimulated conditions [57]. A large number of studies have demonstrated that Cd exposure produce marked

The current study is the first to explore the potential impact of Cd exposure on the magnocellular neuroendocrine system responsible for hydromineral balance. In this paper, we shown an involvement of the hypothalamo-vasopressinergic system of AVP, wish plays a fundamental role in the maintenance of body fluid homeostasis, in the protective reactions of the organism during Cd exposure in *Meriones shawi* by secreting arginine-vasopressin in response to a variety of physiological stimuli, including osmotic [61-63] and nonosmotic stimuli [64, 65]. In support of this, we found that water metabolism was identical in both groups of deprived water *Meriones* and treated *Meriones* with Cd respectively. In contrast, the adaptive response of vasopressin enhancement secretion in both SON and PVN under stimulated conditions as dehydration or Cd exposure in *Meriones shawi,* was attenuated in Meriones simultaneously exposed to Cd and dehydration of water, as compared to deprived water but not treated with Cd group. Our results show an inhibitory effect of Cd exposure on AVP immunoreactivity in both SON and PVN in response to acute water restriction in adult male *Meriones.* We hypothesized that potential effects of Cd might modifies vasopressinergic system which is amplified under water restriction, where AVP neurons are under constant stimulation and suggested that vasopressinergic system is subtly disrupted. Similar effect of AVP depletion in both SON and PVN, produced by Cd ingestion in deprived water was also

more important with time of restriction water.

neuroendocrine changes in animals [58- 59] and human [60].

The urinary osmolality (UO) in the control *Meriones* group was around 1100 mOsm.Kg-1.H20. The mean value increased significantly from 1100 mOsm Kg-1H20/ to 1600 mOsm.Kg-1 H20 following one week of water restriction. This value not change when animals were exposed to Cd [40]. The plasma osmolality (PO) was around 270 mOsm.Kg-1. It was not changed in all groups following one and two weeks of experiment. Hematocrit was around (44.32 ± 1.08 %). It did not change in any treatment condition as compared to day 1. All these results are shown in table 1.

In spite of the variations in water metabolism, all animals were in water equilibrium, at the end of experimentation. All these results indicate that even under the most stringent conditions *Meriones shawi* has a strong capacity to maintain a homeostasis state. It seems evident that water restriction induced a pronounced body mass loss in animals after eight days of treatment without available drinking water. This indicates a depletion of reserves of endogenous metabolic water supplies as an alternative to fresh water [9]. Although changes in body mass in Cd-exposed animals are assumed to be due to reduction of daily consumption of food, this decrease of food uptake became larger in animals both deprived water and treated with Cd. This is in agreement with the findings of Pettersen et al. [41] who demonstrated that rats exposed to Cd become anorexic. An important finding in this study, described by other authors Woltowski et al. [42] and Leffel et al. [43] was the early occurrence of Cd induced hepatic damage manifested by lower liver weight, which was explained by the high level of Cd found in livers of exposed animals. As shown by Sudo et al. [44] Cd preferentially localizes in hepatocytes after administration, and its concentration may exceed the capacity of intracellular constituents, mainly metallothioneins (MTs) to bind Cd [45]. MT-bound Cd then appears in the blood plasma [44] and is efficiently filtered through the glomeruli, and subsequently taken up by the tubules leading to its accumulation in kidney [46-47].

In order to maintain physiological serum osmolality, water intake and water loss are finely balanced by *Meriones shawi* even under water restriction and Cd exposure condition (fig 1). It appears that *Meriones shawi* are able to retain water by excretion of highly concentrated urine [8]. Water loss was also limited by the lowered faecal water loss achieved by the production of very dry feces. In deprived water Meriones we show that water intake was provided from preformed water of food and by metabolic water production as described by Speakman [48] and King and Bradshaw [49]. Our findings are in agreement with previous reports showing that renal concentrating mechanisms are the first line of defense against water depletion [4, 12, 50]. It is well established that modifications of serum osmolality during depletion are detected via osmoreceptors by magnocellular mainly located in the hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN) in the brain [39, 51]. These neurons increase their electrophysiological activity during water restriction leading to an increase of AVP synthesis [52- 53] (and facilitates sustained antidiuresis [54] (De Mota et al. 2004). In contrast to what was observed in the laboratory rat where dehydration causes a dramatic depletion of hypothalamic AVP immunoreactivity in both SON and PVN [55- 56], water restriction induced in our model an increase in expression of AVP. This increase becomes more important with time of restriction water.

156 Neuroendocrinology and Behavior

shown in table 1.

accumulation in kidney [46-47].

simultaneously (water metabolism are shown in table 1).

laboratory conditions, control groups were in water equilibrium (water influx = water efflux) [32]. The value of water influx was 10.90 ± 3.63 ml/ 63.83 ± 22.79 ml.Kg-0.82 .d-1 (figure 1). This water influx (Fin) was not significantly affected in the group treated with Cd in comparison to control group. The loss of water via excretion (urine and fecal) and evaporation was Fout =10.27 ± 3.66 ml./60.16 ± 22.79 ml.kg-0.82.d-1. Water fluxes rate were equal (Fin = Fout). This indicates that animals were in water equilibrium. After, one week of Cd exposure, water flux rates were not significantly affected in the group treated with Cd in comparison to control group and water equilibrium was maintained throughout the experiment. Following one week of dehydration, the water influx rates was significantly decreased from about 5 times in Meriones treated or not with Cd (p<0.01). Cd exposure appears not to impair this capacity during our experiment. However in water deprived animals there was a lower rate of water influx and efflux compared to controls. This low rate of water influx and efflux was similar in water deprived animals and treated with Cd

The urinary osmolality (UO) in the control *Meriones* group was around 1100 mOsm.Kg-1.H20. The mean value increased significantly from 1100 mOsm Kg-1H20/ to 1600 mOsm.Kg-1 H20 following one week of water restriction. This value not change when animals were exposed to Cd [40]. The plasma osmolality (PO) was around 270 mOsm.Kg-1. It was not changed in all groups following one and two weeks of experiment. Hematocrit was around (44.32 ± 1.08 %). It did not change in any treatment condition as compared to day 1. All these results are

In spite of the variations in water metabolism, all animals were in water equilibrium, at the end of experimentation. All these results indicate that even under the most stringent conditions *Meriones shawi* has a strong capacity to maintain a homeostasis state. It seems evident that water restriction induced a pronounced body mass loss in animals after eight days of treatment without available drinking water. This indicates a depletion of reserves of endogenous metabolic water supplies as an alternative to fresh water [9]. Although changes in body mass in Cd-exposed animals are assumed to be due to reduction of daily consumption of food, this decrease of food uptake became larger in animals both deprived water and treated with Cd. This is in agreement with the findings of Pettersen et al. [41] who demonstrated that rats exposed to Cd become anorexic. An important finding in this study, described by other authors Woltowski et al. [42] and Leffel et al. [43] was the early occurrence of Cd induced hepatic damage manifested by lower liver weight, which was explained by the high level of Cd found in livers of exposed animals. As shown by Sudo et al. [44] Cd preferentially localizes in hepatocytes after administration, and its concentration may exceed the capacity of intracellular constituents, mainly metallothioneins (MTs) to bind Cd [45]. MT-bound Cd then appears in the blood plasma [44] and is efficiently filtered through the glomeruli, and subsequently taken up by the tubules leading to its

In order to maintain physiological serum osmolality, water intake and water loss are finely balanced by *Meriones shawi* even under water restriction and Cd exposure condition (fig 1). It appears that *Meriones shawi* are able to retain water by excretion of highly Interestingly, the ability of acute systemic dehydration to produce AVP in both SON and PVN in *Meriones shawi* deprived water and not treated with Cd, was also observed while treating Meriones with Cd but not deprived water. We hypothesized that potential effects of Cd might include exaggerated synthesis of AVP during Cd exposure in our model *Meriones shawi* and support the idea of an increase of AVP as result of Cd intoxication (see figure 2 and 3). These findings suggest that Cd ingestion has potential effects on the vasopressinergic system that responds with elevated synthesis of AVP under stimulated conditions [57]. A large number of studies have demonstrated that Cd exposure produce marked neuroendocrine changes in animals [58- 59] and human [60].

The current study is the first to explore the potential impact of Cd exposure on the magnocellular neuroendocrine system responsible for hydromineral balance. In this paper, we shown an involvement of the hypothalamo-vasopressinergic system of AVP, wish plays a fundamental role in the maintenance of body fluid homeostasis, in the protective reactions of the organism during Cd exposure in *Meriones shawi* by secreting arginine-vasopressin in response to a variety of physiological stimuli, including osmotic [61-63] and nonosmotic stimuli [64, 65]. In support of this, we found that water metabolism was identical in both groups of deprived water *Meriones* and treated *Meriones* with Cd respectively. In contrast, the adaptive response of vasopressin enhancement secretion in both SON and PVN under stimulated conditions as dehydration or Cd exposure in *Meriones shawi,* was attenuated in Meriones simultaneously exposed to Cd and dehydration of water, as compared to deprived water but not treated with Cd group. Our results show an inhibitory effect of Cd exposure on AVP immunoreactivity in both SON and PVN in response to acute water restriction in adult male *Meriones.* We hypothesized that potential effects of Cd might modifies vasopressinergic system which is amplified under water restriction, where AVP neurons are under constant stimulation and suggested that vasopressinergic system is subtly disrupted. Similar effect of AVP depletion in both SON and PVN, produced by Cd ingestion in deprived water was also observed in deprived water laboratory rats treated by an organochlorine pollutant (polychlorinated biphenyls (PCBs) during 15 days [66]. According to these authors, the AVP decline was attributable to specific effects of overt toxicity and/or malaise oral of PCBs on vasopressinergic hypothalamic cells function. In combination with the efficacy of *in vitro* application, these data are consistent with direct actions on components of the hypothalamo-neurohypophysial system present within the SON [67-68]. PCBs has been reported to inhibit nitric oxide synthase activity. It is noteworthy that the inhibition of nitric oxide production in SON tissue punches produces a virtually identical, selective effect on dehydration stimulated intranuclear AVP release *in vitro* [69] and has been reported to exaggerate pituitary depletion of AVP in the intact deprived water rat [70] .

Effect of Cadmium Contaminated Diet in Controlling Water Behavior by *Meriones shawi* 159

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Most strikingly, vasopressin is recognized as circulating hormone. Its actions were essentially confined to peripheral organs. However, currently AVP have been shown to be released in the brain as chemical messengers. AVP, like many peptides, when released within the brain, plays an important role in social behaviour. In rats, AVP is implicated in paternal behaviors, such as grooming, crouching over and contacting pups. AVP is also important for partner preference and pair bonding, particularly for males in a variety of species. It has been shown that AVP has powerful influences on complex behaviours [71]. Disruption of vasopressinergic system has been linked to several neurobehavioural disorders including prader-Willi syndrome, affective disorders, obsessive-compulsive disorder and polymorphisms of V1a vasopressin receptor have been linked to autism [72].
