NJCA
  • Users Online: 99
  • Print this page
  • Email this page
  • Email this page
  • Facebook
  • Twitter


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 3  |  Page : 108-110

Propylthiouracil-induced histological changes in the placenta of swiss albino mice


1 Assistant Professor, Department of Anatomy, Shri Ram Murti Smarak Institute of Medical Sciences, Bareilly, Uttar Pradesh, India
2 Professor and Head, Department of Anatomy, Heritage Institute of Medical Sciences, Varanasi, Uttar Pradesh, India

Date of Submission14-Jul-2020
Date of Decision29-Jul-2020
Date of Acceptance23-Sep-2020
Date of Web Publication15-Oct-2020

Correspondence Address:
Samta Tiwari
Department of Anatomy, Shri Ram Murti Smarak Institute of Medical Sciences, Bareilly - 243 202, Uttar Pradesh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/NJCA.NJCA_34_20

Rights and Permissions
  Abstract 


Introduction: Propylthiouracil, an antithyroid drug, is used to treat hyperthyroidism in early pregnancy as drug of choice. Maternal and fetal morbidities and mortalities occur, if hyperthyroidism is not treated during pregnancy. Aim: The teratogenic potential of propylthiouracil is studied by observing the placental changes in Swiss albino mice, in the light of present research. Materials and Methods: 100 mg/kg body weight/day of propylthiouracil was given orally to pregnant Swiss albino mice (treated group) during early gestational period (6, 7, and 8th days of gestation), while control pregnant mice were given the same volume of distilled water orally for the same duration. The pregnant mice of all groups were sacrificed on 18th day of gestation and placentae were collected. The placentae were grossly examined, formalin fixed, and processed for histological study with H and E staining. Results: Histological examination shows edematous spaces and degenerated normal architecture of the various zones, i.e., labyrinthine, junctional, and basal zones. There was increase in the thickness of chorioallantoic plate and degeneration of giant cell trophoblasts and sinusoids. Conclusion: It was found that the propylthiouracil had a teratogenic effect; therefore, it should be used cautiously during pregnancy to avoid risk of congenital malformations.

Keywords: Giant cells, malformations, placentae, propylthiouracil, teratogenic potential


How to cite this article:
Tiwari S, Pandey S K. Propylthiouracil-induced histological changes in the placenta of swiss albino mice. Natl J Clin Anat 2020;9:108-10

How to cite this URL:
Tiwari S, Pandey S K. Propylthiouracil-induced histological changes in the placenta of swiss albino mice. Natl J Clin Anat [serial online] 2020 [cited 2020 Nov 25];9:108-10. Available from: http://www.njca.info/text.asp?2020/9/3/108/298165




  Introduction Top


Teratology is the study of various structural, behavioral, functional, and metabolic disorders present at birth. These teratogens may be any infectious agent, physical agent, chemical agent, and/or hormones. Hence, it is difficult to identify the exact agent from this plethora and prevent the congenital malformations.

Hyperthyroidism, if not treated or inadequately treated during pregnancy, will cause serious complications such as fetal death, prematurity, and/or growth restriction along with maternal hypertension.[1],[2] Antithyroid drugs, thionamides (carbimazole/methimazole), or thiourea derivative (propylthiouracil) is used in the treatment of Grave's disease, one of the common causes of hyperthyroidism in pregnancy.[3],[4] The drug of choice in treating Grave's disease during the first trimester of pregnancy is propylthiouracil.

As the documented research reports showed lesser association of fetal anomalies with propylthiouracil, it is considered as safer drug than methimazole, in the first trimester of pregnancy.[1],[5] However, few cases of fetal anomalies have been associated with prenatal use of propylthiouracil.[6],[7],[8] Extensive formal studies of teratogenicity of antithyroid drugs have not been performed as compared to its widespread usage in pregnancy.[9] Hence, this study is conducted to find out some conclusive evidence regarding teratogenic potential of propylthiouracil by studying the placental changes in pregnant mice, when drug is given during organogenesis period of gestation.


  Materials and Methods Top


The study was conducted in the Teratology Laboratory of Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi, U.P., India, after obtaining prior approval from the Institutional Ethical Committee.

In this study, twenty-one female Swiss albino mice, nearly 6 weeks of age and weighing about 20–25 g (average body weight), were used. In the departmental animal house, these were housed separately in plastic cages under optimal conditions for survival of Swiss albino mice. The study animals were given pelleted diet and tap water as per need.

Mating was facilitated by keeping female mice in the cages containing male mice of the same stock in the ratio of 2:1 during night. Then, next morning, if vaginal plug is present, it indicates day 0 of gestation. Two groups of pregnant mice were studied, i.e., control and treated. 2 mg of the drug (100 mg/kg body weight/day) was administered by oral gavages to the treated group on 6, 7, and 8th days of gestation, while the same volume of distilled water was given to control group for similar duration and by same route.

On 18th day of gestation, the pregnant mice were sacrificed by cervical dislocation. The fetuses and the placentae were collected after performing laparotomy and fixed in 10% formalin solution, for 48–72 h, and then the placentae were dissected out and processed for H and E staining. The microscopic findings of the treated group were compared with the corresponding control.


  Observations and Results Top


On microscopic examination under low magnification, the treated placenta showed edematous spaces and degenerated normal architecture of the various zones of placenta, i.e., labyrinthine, junctional, and basal zones. The thickness of chorioallantoic plate and degeneration of labyrinthine zone in all the treated group was observed [Figure 1]b, as compared to their corresponding control showing normal thickness and architecture of chorioallantoic plate and labyrinthine zone respectively [Figure 1]a. On higher magnification, the treated placenta showed edematous spaces and dilatation of sinusoids with degeneration of giant cell trophoblasts in the junctional zone [Figure 2]b while corresponding control showed well developed junctional zone with abundant giant cell trophoblasts [Figure 2]a. The destruction and dilatation of sinusoids in labyrinthine zone had been also observed in treated group. [Figure 3]b while its corresponding control showed normal appearance of sinusoids in the labyrinthine zone [Figure 3]a. In oil immersion, the treated placenta showed degenerated giant cell trophoblasts and destruction of blood sinusoids in the junctional zone [Figure 4]b as compared to control showing normal appearance of giant cell trophoblasts and blood sinusoids in the junctional zone [Figure 4]a.
Figure 1: (a) Control placenta showing normal architecture of the chorioallantoic plate (CP) and labyrinthine zone (L); ×100. (b) Treated placenta showing increased thickness of chorioallantoic plate (CP), along with destructed and degenerated labyrinthine zone (L); ×100

Click here to view
Figure 2: (a) Control placenta showing well-developed junctional zone (↔) with abundant giant cell trophoblasts (←); ×400. (b) Treated placenta showing edematous spaces and dilatation of sinusoids (★) with degeneration of giant cell trophoblasts (←) in the junctional zone; ×400

Click here to view
Figure 3: (a) Control placenta showing normal appearance of sinusoids (★) in the labyrinthine zone (↔); ×400. (b) Treated placenta showing the destruction and dilatation of sinusoids (★) in labyrinthine zone (↔); ×400

Click here to view
Figure 4: (a) Control placenta showing giant cell trophoblasts (→) and blood sinusoids (★) in the junctional zone; ×1000. (b) Treated placenta showing degenerated giant cell trophoblasts (→) and destruction of blood sinusoids (★) in the junctional zone; ×1000

Click here to view



  Discussion Top


Hyperthyroidism, in pregnancy, usually in the first trimester, is treated with propylthiouracil. Propylthiouracil easily crosses the placenta; therefore, maternal treatment during pregnancy leads to considerable fetal exposure to the drug.[10] A previous study showed fetal loss associated with the use of propylthiouracil exposure during organogenesis.[4] There is risk of low birth weight and intrauterine growth retardation in female treated with propylthiouracil during pregnancy, as observed in a case–control study.[11] The gross malformations of the head and neck region such as anencephaly, cleft lip, cleft palate, ear lobe malformation, aplasia cutis congenita, and preauricular cyst/sinus have been reported by many workers in children born to women with propylthiouracil exposure during pregnancy.[11],[12],[13],[14]

In a previous human study, it has been observed that propylthiouracil causes hepatocellular type of liver injury in most cases. Histopathological findings in this study revealed hemorrhagic necrosis of parenchyma, loss of architecture of hepatic lobules, and presence of inflammatory infiltrate.[15],[16] A review article unveiled the fact that propylthiouracil is associated with vasculitis/necrotizing glomerulonephritis in human,[17] while an animal study on albino rat found histopathological changes such as dilated capillaries within the glomeruli, dilatation of tubules, and degenerated epithelium on antithyroid drug exposure.[18]

The pharmacokinetic studies show that the thyroperoxidase and myeloperoxidase system in the phagocytic cells metabolizes propylthiouracil into various oxidative metabolites such as propyluracil-2-sulfonate that oxidizes sulfhydryl groups of proteins to form sulfide compounds, probably responsible for the immunological side effects.[19] Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis is one of the associated adverse effects of propylthiouracil. Endothelial damage occurs during early phase of vasculitis and it is mainly induced via antibody-dependent cellular cytotoxicity caused by antiendothelial cell antibodies (AECA).[20]

These highly reactive oxidative intermediates and the presence of autoantibodies such as ANCA and AECA may be the probable cause of histopathological changes such as degeneration of various zones and dilatation of sinusoids in the placentae of the treated Swiss albino mice.


  Conclusion Top


It is not possible to extrapolate animal data directly to humans and it indicates the need for careful monitoring of the drug. To conclude, propylthiouracil was found to be teratogenic in the present animal study based on various microscopic findings when used at a dose of 100 mg/kg of body weight, during early stage of gestation (organogenesis period). Although the antenatal use of propylthiouracil may lead to increased risk of fetal malformations, its use in pregnancy cannot be completely avoided because of the lack of safer alternative drugs. Hence, hyperthyroidism in pregnancy (especially during first trimester) should be managed with lowest possible effective dose of propylthiouracil until its safety is established in a large randomized trial study having long-term follow-up or the discovery of a new safer alternative.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Chan GW, Mandel SJ. Therapy insight: Management of Graves' disease during pregnancy. Nat Clin Pract Endocrinol Metab 2007;3:470-8.  Back to cited text no. 1
    
2.
Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein IL, et al. The role of propylthiouracil in the management of Graves' disease in adults: Report of a meeting jointly sponsored by the American thyroid association and the food and drug administration. Thyroid 2009;19:673-4.  Back to cited text no. 2
    
3.
Patil-Sisodia K, Mestman JH. Graves hyperthyroidism and pregnancy: A clinical update. Endocr Pract 2010;16:118-29.  Back to cited text no. 3
    
4.
Benavides VC, Mallela MK, Booth CJ, Wendler CC, Rivkees SA. Propylthiouracil is teratogenic in murine embryos. PLoS One 2012;7:e35213.  Back to cited text no. 4
    
5.
Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001;86:2354-9.  Back to cited text no. 5
    
6.
Herbst A, Selenkew H. Hyperthyroidism during pregnancy. N Engl J Med 1965;273:627-33.  Back to cited text no. 6
    
7.
Pearce SH. Spontaneous reporting of adverse reactions to carbimazole and propylthiouracil in the UK. Clin Endocrinol (Oxf) 2004;61:589-94.  Back to cited text no. 7
    
8.
Briggs GG, Freeman RK, Yaffe SJ. Propylthiouracil. Drugs in Pregnancy and Lactation. In: 7th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2005. p. 1365-70.  Back to cited text no. 8
    
9.
Koren G, Soldin O. Therapeutic drug monitoring of antithyroid drugs in pregnancy: The knowledge gaps. Ther Drug Monit 2006;28:12-3.  Back to cited text no. 9
    
10.
Mortimer RH, Cannell GR, Addison RS, Johnson LP, Roberts MS, Bernus I. Methimazole and propylthiouracil equally cross the perfused human term placental lobule. J Clin Endocrinol Metab 1997;82:3099-102.  Back to cited text no. 10
    
11.
Chen CH, Xirasagar S, Lin CC, Wang LH, Kou YR, Lin HC. Risk of adverse perinatal outcomes with antithyroid treatment during pregnancy: A nationwide population-based study. BJOG 2011;118:1365-73.  Back to cited text no. 11
    
12.
Momotani N, Ito K, Hamada N, Ban Y, Nishikawa Y, Mimura T. Maternal hyperthyroidism and congenital malformation in the offspring. Clin Endocrinol (Oxf) 1984;20:695-700.  Back to cited text no. 12
    
13.
Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K, et al. Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation. J Clin Endocrinol Metab 2012;97:2396-403.  Back to cited text no. 13
    
14.
Andersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregnancy use of antithyroid drugs: A danish nationwide study. J Clin Endocrinol Metab 2013;98:4373-81.  Back to cited text no. 14
    
15.
Carrion AF, Czul F, Arosemena LR, Selvaggi G, Garcia MT, Tekin A, et al. Propylthiouracil-induced acute liver failure: Role of liver transplantation. Int J Endocrinol 2010;2010:910636.  Back to cited text no. 15
    
16.
Heidari R, Niknahad H, Jamshidzadeh A, Abdoli N. Factors affecting drug-induced liver injury: Antithyroid drugs as instances. Clin Mol Hepatol 2014;20:237-48.  Back to cited text no. 16
    
17.
John R, Herzenberg AM. Renal toxicity of therapeutic drugs. J Clin Pathol 2009;62:505-15.  Back to cited text no. 17
    
18.
Gazia MA. Antithyroid drug or hypothyroidism causes cellular damage in the renal cortex of adult male albino rats; A histological and immunohistochemical study. Egypt J Histol 2013;36:636-45.  Back to cited text no. 18
    
19.
Schmiedeberg von S, Hanten U, Goebel C, Schuppe H-C, Uetrecht J, Gleichmann. T cells ignore the parent drug propylthiouracil but are sensitized to a reactive metabolite generated in vivo. Clin Immunol Immunopathol 1996;80:162-70.  Back to cited text no. 19
    
20.
Yu F, Zhao MH, Zhang YK, Zhang Y, Wang HY. Anti-endothelial cell antibodies (AECA) in patients with propylthiouracil (PTU) induced ANCA positive vasculitis are associated with disease activity. Clin Exp Immunol 2005;139:569-74.  Back to cited text no. 20
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and Me...
Observations and...
Discussion
Conclusion
References
Article Figures

 Article Access Statistics
    Viewed162    
    Printed4    
    Emailed0    
    PDF Downloaded9    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]