toxicological impact of exposure to 2,3,7,8-

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*Corresponding author: Email: [email protected];

Annual Research & Review in Biology4(8): 1278-1289, 2014

SCIENCEDOMAIN internationalwww.sciencedomain.org

Toxicological Impact of Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on Some

Hormonal Profiles and HematologicalParameters in Goats

Azza M. Mohamed1*, A. O. Hegab2, Jehad M. Yousef1

and Manal E. A. El H alwagy1

1Biochemistry Department, Faculty of Science for Girls, King Abdulaziz University, Saudi Arabia.2Biology Department, Faculty of Science, Taif University, Saudi Arabia.

Authors’ contributions

This work was carried out in collaboration between all authors. Author AMM designed thestudy and wrote the first draft of the manuscript, author AOH wrote the protocol and

performed the statistical analysis, author JMY managed the biochemical analyses of thestudy and author MEAEH managed the literature searches. All authors read and approved

the final manuscript

Received 28th August 2013Accepted 23rd October 2013Published 2nd January 2014

ABSTRACT

Female Baladi goats were used to investigate the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on some serum hormones and blood features.Animals were divided into two groups, group 1: served as control, group 2: animals wereorally administered with three repeated doses (0.23µg/Kg body weight) of TCDD with 2days interval between dosing.Results revealed that exposure to TCDD induced reduction in serum estradiol,progesterone and prolactin levels and elevation in glucocorticoid hormone cortisolthroughout the different studied periods (48h, 96h and 16 days commenced the lastintoxicated dose). The adverse impact of TCDD on goat reproductive hormones wasconfirmed by histopatholgical observations on their uteri and ovaries after 16 dayscommenced the last intoxicated dose. Intoxication of goats with TCDD showed alsomarked decreases in hemoglobin (Hb) concentration, red blood cell count (RBC), packedcell volume (PCV), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH)

Original Research Article

Annual Research & Review in Biology, 4(8): 1278-1289, 2014

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and mean corpuscular hemoglobin concentrations (MCHC) compared with normal healthygroup. Pronounced decreases in total white blood cells (WBC) count as well as in itsdifferential percentages namely lymphocytes, monocytes and eosinophils were alsonoticed in intoxicated animals compared with normal ones, while the percentage ofneutrophils showed significant increase.In conclusion, the results of this study indicated that oral exposure of female goats torepeated doses of TCDD caused endocrine disruption which may lead to adverse impacton their reproductive performance. Moreover, toxicity of TCDD inducedimmunosuppressive effect and anemia as indicated by its deleterious action on differenthematological parameters.

Keywords: Female goats; tetrachlorodibenzo-p-dioxin; hormones; hematological parameters.

1. INTRODUCTION

Endocrine disrupters (EDs) are pollutants that can act as agonists or antagonists to naturalhormones. EDs have been intensively studied for their actions as estrogen mimetic whereinthey work by binding to the estrogen receptor, thus affecting estrogen-regulated cellular andreproductive processes [1].

Dioxins are a class of persistent polyhalogenated aromatic hydrocarbons (PHAHs) of whichpolychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), haveidentified as among the most globally distributed potent environmental pollutants [2]. Dioxinsare unwanted by products of many industrial processes and mainly come from industrial airemissions, waste incineration and combustion of fuels [3]. Moreover, they are slowlydegraded in environment and hence remain as persistent and toxic contaminants for longtime. Humans are exposed to dioxins through diet, particularly fish products, meat and fattymilk and [4]. TCDD has been reported to accumulate in body due to its lipophilic properties,slow metabolism and excretion [5].

Based on biochemical and toxic responses, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) isconsidered one of the most potent members of PCDDs group and a model compound forstudy of the mechanisms of PCDDs [6]. The compound is often referred simply as dioxin.

Exposure to acute and chronic toxic levels of TCDD in various animal species and man,causes a wide-variety of adverse effects in a tissue and species specific manner, includinghepato-toxicity, carcinogenicity, teratogenicity, interference with lipid metabolism, reductionof bone strength, neurobehavioral effects, endocrine disruption, wasting syndrome, thymicatrophy, developmental and reproductive toxicity and immunosuppression [7 -10]. Previousstudies on female reproductive system of nonhuman primates indicated that exposure toTCDD leads to long - term adverse effects on pregnancy and ovarian function [11-12] and ithas been implicated in development of endometriosis [13] and abortion [14].

Therefore, the aim of this study was to demonstrate the reproductive toxicity andhematotoxicity induced by TCDD on some serum hormones, blood features andhistomorphologic phenotypes of uteri and ovaries in female goats.


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2. MATERIALS AND METHODS

2.1 Chemicals

All chemicals used in the current investigation were of high analytical grade and products ofthe Sigma and Merck companies (USA). TCDD (>99 % pure) was purchased from the UFAOil Institute (Ufa, Russia). It was mixed with corn oil. The mixture was stirred using amagnetic stirrer before dosing.

2.2 Experimental Animals

The study protocol was approved by the Animal Experiment local ethics Committee. Eightmature female baladi goats (2-2.5 years old and 20-25 kg) were obtained from NationalResearch Centre Experimental Farm (Abu Rawash, Giza, Egypt). The animals were fed oncommercial diet and water ad libitum.

2.3 Experimental Design

Animals were divided into two groups, each consisting of four animals, G1: Normalhealthy animals. G2: Animals administered three repeated doses of TCDD with two daysintervals. TCDD was given orally at a dose of 0.23µg/Kg body weight (equivalent to 1/3 ofLD50 of TCDD) [15]. Blood samples were collected from each animal of both control andTCDD intoxicated groups after 48 h, 96 h and 16 days commenced the last intoxicated doseinto sterilized tubes for serum separation and into tubes containing heparin for determinationof hematological parameters. Serum was separated by centrifugation at 3000× g for 10minutes and used for biochemical serum analysis. At the end of experimental period (16days) all animals were slaughtered, the uterus and ovary from each animal was collected forhistopathological examination.

2.4 Haematological Evaluation

Haematological parameters including, white blood cells (WBC) count and differentialpercentages, red blood cells (RBC) count, haemoglobin (Hb), packed cell volume (PCV),mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration,(MCHC) and mean corpuscular volume (MCV) were determined using auto- analyzer(Abbott Diagnostics, USA).

2.5 Biochemical Serum Analysis

2.5.1 Hormonal assay

Serum estradiol, progesterone, prolactin and cortisol were assayed using availablecommercial Radioimmunoassay (RIA) kits according to the manufacturer’s instructions.

2.6 Histopathological Examination

A small specimens of ovaries and uterus were fixed by 4% formalin and then embeddedinto paraffin, sectioned for 5–6-μm thick, and mounted on the glass microscope slides using


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standard histopathological techniques. The sections were stained with hematoxylin-eosinand examined by light microscopy [16].

2.7 Statistical Analysis

The obtained data were computed and statistically analyzed according to Snedecor andCochran [17]. Data were analyzed by comparing values obtained from animals after thestudied intoxicated periods (48h, 96h and 16 days) in an intoxicated group with the valuesfor individual controls. Results are expressed as mean ± S.D. The significant differencesamong values were analyzed using analysis of variance (one-way Anova) coupled with post-hoc (LSD). Results were considered significant at P< 0.05.

3. RESULTS

3.1 Clinical Signs

The Clinical symptoms of intoxicated goats with repeated oral dose of dioxin during dioxiningestion till the end of experimental period (16 days) were general weakness, loss ofappetites, weight loss, diarrhea. Respiratory manifestations were in the form of continuousnasal discharge and cough.

3.2 Hormonal Profiles and Histo-pathological Examination

Figs. (1 and 2) summarize the adverse effect of TCDD on some hormones in serum offemale goats. The results revealed marked reduction in serum estradiol (Fig. 1) andprogesterone (Fig. 2) levels during the different exposure periods of goats to TCDD (48h, 96h and 16 days after the last intoxicated dose) compared with control healthy animals. Theresult also demonstrated that exposure to TCDD led to significant a reduction in the serumprolactin level, and an increase in the serum level of glucocorticoid steroid hormone,cortisol, during the same exposure periods of goats to this toxin compared with normal ones(Fig. 2). Histopathological observation showed that TCDD induced degenerative changesin uteri of intoxicated goats as observed by a decrease in the number of glands in theendometrium associated with infiltration of reactive inflammatory cells (Fig. 3). The ovariesof intoxicated goats also showed degenerative ovarian follicle (Fig. 4).

3.3 Haematological Parameters

The effect of oral administration of TCDD on blood features of goats was illustrated in Fig. 5.Significant decreases in Hb concentration, RBCs count, PCV, MCV, MCH and MCHC wererecorded after the studied exposure periods compared with normal healthy group.Pronounced decreases in total WBCs count as well as in its differential percentages namelylymphocytes, monocytes and eosinophils were also noticed in intoxicated animals comparedwith normal ones, while the percentage of neutrophils showed significant increase (Fig. 6).


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Fig. 1. Serum estradiol level in normal and TCDD-intoxicated goatsValues are expressed as mean ± SD of 4 animals. Estradiol is expressed in pg/ml, a P ≤ 0.001, bP ≤0.01 compared with normal group; *P ≤ 0.001 compared with TCDD intoxicated group 48 h after the

last intoxicated dose.

Fig. 2. Serum levels of progesterone, prolactin and cortisol hormones in normal andTCDD-intoxicated goats

Values are expressed as mean ± SD of 4animals. Progestrone and prolactin are expressed in ng/ml ,cortisol is expressed in µg/dl. aP ≤ 0.001, bP ≤ 0.01, cP ≤ 0.05 compared with normal group; *P ≤

0.001 compared with TCDD intoxicated group 48 h after the last intoxicated dose.


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Fig. 3. Toxic impact of oral repeated doses of TCDD administration on uterus offemale goats 16 days after the last intoxicated dose , (a) Section of uterus in control

goats showing large number of glands in the endometrium (b) section of uterus inintoxicated goat showing a degenerative change and a decrease in the number ofglands in the endometrium and infiltration of reactive inflammatory cells (arrows)

(H&E X 400)

Fig. 4. Toxic impact of oral repeated doses of TCDD administration on ovaries offemale goats 16 days after the last intoxicated dose , (a) Section of an ovary of

control goat showing normal ovarian follicle, (b) section of an ovary of intoxicatedgoat showing degeneration of ovarian follicle (arrow) (H&E X 400)

Fig. 5. levels of some hematological parameters in normal and TCDD-intoxicated goats(a)Hb= Haemoglobin concentration, (b) RBC= Red Blood Cell, (c) PCV= Packed Cell Volume, (d)MCH= Mean

Corpuscular Haemoglobin, (e)MCHC= Mean Corpuscular Haemoglobin Concentration, (f) MCV= MeanCorpuscular Volume. Results are expressed as mean ± SD of 4 animals. aP ≤ 0.001, bP ≤ 0.01, cP ≤ 0.05

compared with normal group . *P ≤ 0.05 compared with TCDD intoxicated group 48 h after the lastintoxicated dose.


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Fig. 6. WBCs count and differential percentages in normal and TCDD-intoxicated goats

(a) WBCs ,( b) Neutrophils , (c) lymphocytes, (d) Eosinophilis , (e), Basophilis, ( f )monocytes . Data are expressed as mean± SD of 4 animals in each group, . aP ≤ 0.001, bP ≤

0.01, cP ≤ 0.05 compared with normal group . *P ≤ 0.05, **P ≤ 0.01 compared with TCDDintoxicated group 48 h after the last intoxicated dose.

4. DISCUSSION

TCDD is the most widely studied dioxins which is a class of persistent environmentalpolyhalogenated aromatic hydrocarbons toxin (soil and sediment). TCDD bio-accumulates infish and animals which are then consumed by humans. The half-life of dioxin in the humanbody is 7–11 years [18]. Previous studies demonstrated that TCDD could induce a widespectrum of toxic responses in experimental animals including immunotoxicity, teratogenicity,carcinogenicity, and endocrine disruption [19 -20].

The current study showed that oral administration of TCDD to goats dramatically led toreduction in estradiol and progesterone levels, indicating that this pollutant had antiestrogeniceffects on goat uterine cellular function in vivo. These data are compared with previous studysuggest that the decrease in serum estradiol under the effect of dioxin may be a cause of thealterations in estradiol receptor mRNA [21 -22]. The antiestrogenic action of dioxin was foundto cause decreases in uterine weight, blocking ovulation, higher incidence of ovarian andmammary tumors, and other reproductive abnormalities [23-24]. The reduction inprogesterone level presented in the current study may be due to the decrease in estradiollevel. Estradiol normally regulates a wide variety of processes within the uterus includingwater imbibitions, proliferation and functional activity of epithelial, stromal, myometrial andvascular cells. It also stimulates increases in progesterone but previous in vitro study wasfond that dioxin inhibits these responses [25]. The majority of the effects of TCDD appear tobe mediated by their binding to a cellular protein called the aryl hydrocarbon receptor (AhR)which represses estrogen receptor function, thus inhibiting the expression of estrogenresponsive genes [26-27]. The adverse impact of TCDD on female goat hormones wassupported by histopathological study on uteri and ovaries of intoxicated animals. The resultdemonstrated that TCDD induced degenerative changes and a decrease in the number of


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glands in the endometrium associated with infiltration of reactive inflammatory cells. Theovaries of intoxicated goats also showed degenerative ovarian follicle.

The current study also revealed that administration of TCDD to goats led to significantreduction in serum prolactin. This result may indicate that the antiestrogenic impact of thispollutant affect the pituitary gland function, thus affecting the synthesis and secretion ofprolactin. On the other hand, it may consider another response resulting from decreasedestradiole level. This may be explained by the fact that endogenous steroid hormones suchas 17 ß-estradiol, affect the hypothalamus–pituitary–gonad axis by positive and negativefeedback [28]. The pituitary gland synthesizes and secretes many hormones that regulatedirectly or indirectly the physiological functions of the organism via regulating other endocrineglands [28]. Prolactin is a peptide hormone produced by pituitary gland. This hormone playimportant roles in controlling growth, osmoregulation, metabolism, reproduction anddevelopment in all vertebrates [29-32]. Studies have shown that the promoter regions ofvertebrate prolactin gene contain estrogen response elements (ERE) and the expressionand release of prolactin is modulated by estrogen [33].

The current result also showed significant elevation in the serum level of glucocorticoidsteroid hormone, cortisol, which was more pronounced after 16 days commenced the lastintoxicated TCDD dose. This result is coped with [34] who reported marked increase cortisollevel in animals exposed to TCDD toxicity which may be related to that TCDD could stimulate.cortisol biosynthesis [35]. Previous authors stated that elevated cortisol level inducedoxidative stress through depletion cellular glutathione, which is an important substrate inantioxidant defense [36].

Haematological indices are very important in assessing infection, organ function, and manydiseases in animals by comparing their levels in the blood with reference values [37]. Thepresent study showed that oral administration of TCDD to goats could induce haematotoxicityas shown by its deteriorating effect on different hematological parameters during the studieddifferent exposure periods. Result showed that oral exposure of goats to TCDD led tooccurrence of anemia as indicated by significant decrease in RBCs count, HB concentation,PCV and MCV. This effect was more severe on 16 days after the last dose administrationcompared with control. Similar results were reported by Funseth and IIback [38] who foundsignificantly decreased in RBCs count in the TCDD treated rats on day 28. In this respect,Viluksela et al. [39] mentioned that the highest mortality rates recorded in rats treated withmixture of four chlorinated dibenzo-p-dioxins was related to wasting, hemorrhage, andanemia, in addition to prothrombin times were prolonged and platelet counts were decreasedin some rats receiving high doses. Some authors attributed the induced anemia by TCDDtoxicity to apoptic cell death in circulating erythrocytes which coupled with the inability of bonemarrow to compensate the increased rate of destruction due to myelotoxic effect of TCDDon bone marrow [40]. In this context, the same authors found that TCDD caused decreasesin total number of hematopoietic cells in bone marrow. Anemia could also be attributed toTCDD induced oxidative stress through its effect on AhR mediated pathway, leading toinduction of α-aminolevulinic acid synthetase which is the initial and rate limiting enzyme inheme synthesis [41].

The current study also showed that oral exposure of goats to TCDD has suppressing effecton leukocyte production as indicated by marked decrease in total WBCs count as well asin its differentia percentages namely lymphocytes, monocytes and eosinophils, while thepercentage of neutrophils showed significant increase. The deviation in leukocyte counts wassevere after 16 days commenced the last intoxicated dose. This result is coped with Abd El-


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Nasser et al. [40] who demonstrated that oral exposure to TCDD resulted in severedecreases in leukocyte counts as well as in the percentages of lymphocytes, monocytes andeosinophils. The toxic effects of TCDD on total and differential leukocytes was previouslyexplained by some mechanisms. Murante and Gasiewicz [42] reported that TCDD affectsthe proliferation and/or differentiation processes of hemopoietic stem cells in bone marrow asit has a myelotoxic effects, thus it reduced the capacity of bone marrow to generate pro-lymphocytes. Also, it was found that marrow apoptosis and hypoplasia of bone marrow cellsare the major mechanisms of TCDD toxicity induced leucopenia [43]. In addition, Donald etal. [44] attributed this condition to immune suppressive effect of TCDD on bone marrow stemcells by mechanism mediated directly or indirectly through estrogenic action. Moreover, it wasfound that TCDD-treated hematopoietic stem cells almost lost long-term reconstitution activity[45]. Beside, some authors declared that TCDD has direct effect on the functional AhR thatis expressed by bone marrow stromal cells and plays an important role in the support anddirection of lymphopoiesis [43]. The authors added that TCDD treatment could alterlymphopoietic development, resulting in decrease of the total number of hematopoietic cellsand lymphocytes.

Neutrophilia recorded in this study during the term of TCDD exposure was not related todirect effect rather than as a compensatory response to the recoded lymphopenia. Byexamining the bone marrow in rats intoxicated with TCDD, Abd El-Nasser et al. [40]observed that significant decreases in lymphocytic, eosinophillic, and megakaryocyticseries, while neutrophillic series including myeloblast, metamyeloblast, promyloblast,segmented and band cell series showed significant increase.

5. CONCLUSION

The results of this study indicate that oral exposure of female goats to TCDD was found tohave antiestrogenic effect and induced adverse effects on progesterone and prolactin. Sucheffect may lead to endocrine disruption and subsequently affect the reproductiveperformance of animals. Moreover, this pollutant showed immunosupressive effect indicatedby its deleterious action on hematological parameters.

COMPETING INTERESTS

Authors have declared that no competing interests exist.

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