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. 2024 Jul 1;7(6):926–935. doi: 10.1002/ame2.12459

Development of an animal model of hypothyroxinemia during pregnancy in Wistar rats

Wei Wei 1, Aihua Liu 2, Min Liu 3, Mingfeng Li 3, Xinghan Wu 3, Chuan Qin 1,3,✉, Zhongyan Shan 4,✉, Ling Zhang 3,✉
PMCID: PMC11680470  PMID: 38946346

Abstract

Background

Hypothyroxinemia is a subclinical thyroid hormone deficiency in which the mother has inadequate levels of T4 during pregnancy. The fetus relies entirely on the mother's T4 hormone level for early neurodevelopment. Isolated maternal hypothyroxinemia (IMH) in the first trimester of pregnancy can lead to lower intelligence, lower motor scores, and a higher risk of mental illness in descendants. Here, we focus on the autism‐like behavior of IMH offspring.

Methods

The animals were administered 1 ppm of propylthiouracil (PTU) for 9 weeks. Then, the concentrations of T3, T4, and thyroid‐stimulating hormone (TSH) were detected using enzyme‐linked immunosorbent assay (ELISA) to verify the developed animal model of IMH. We performed four behavioral experiments, including the marble burying test, open‐field test, three‐chamber sociability test, and Morris water maze, to explore the autistic‐like behavior of 40‐day‐old offspring rats.

Results

The ELISA test showed that the serum T3 and TSH concentrations in the model group were normal compared with the negative control group, whereas the T4 concentration decreased. In the behavioral experiments, the number of hidden marbles in the offspring of IMH increased significantly, the frequency of entering the central compartment decreased, and the social ratio decreased significantly.

Conclusion

The animal model of IMH was developed by the administration of 1 ppm of PTU for 9 weeks, and there were autistic‐like behavior changes such as anxiety, weakened social ability, and repeated stereotyping in the IMH offspring by 40 days.

Keywords: autism, hypothyroxinemia during pregnancy, IMH animal model, offspring development, T4

We developed an animal model of hypothyroidism in pregnancy by administering 1 ppm of propylthiouracil in groups. Enzyme‐linked immunosorbent assay and behavioral experiments were performed to verify results. The results confirmed that the offspring rats exhibited autism‐like changes at 40 days, providing model support for subsequent exploration of molecular mechanisms.

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1. INTRODUCTION

Hypothyroidism can be divided into clinical hypothyroidism, subclinical hypothyroidism, and isolated maternal hypothyroxinemia (IMH) based on the degree of hypothyroidism. 1 IMH generally refers to abnormal free T4 concentration in the lower 2.5–5th percentile of a given population in conjunction with a normal maternal thyroid‐stimulating hormone (TSH) concentration. 1 , 2 Epidemiological studies have shown that offspring whose mothers suffered from hypothyroxinemia during pregnancy have lower intelligence scores and lower motor scores, and they are at risk of autism, attention deficit hyperactivity disorder, bipolar disorder (BP), and other psychiatric disorders. 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 The incidence of premature birth, abortion, preeclampsia, low birth weight, and fetal death increased significantly. 2 , 11 At present, there are three kinds of animal models of hypothyroidism. One of them is modeling by thyroidectomy, which is generally used for animal research on diseases with severe thyroid hormone deficiency. Propylthiouracil (PTU), generally used to treat hyperthyroidism, can inhibit the peroxidase system in thyroid cells so that the iodide ingested by thyroid cells cannot be oxidized into active iodine. These factors cause a decrease in thyroid T3 transformation and T4. Previously, animal disease models of hypothyroidism were developed by PTU administration at different concentrations; 1–10 ppm concentration can cause thyroid hormone deficiency at different degrees. 12 , 13 To reduce the effect of drugs on the body and interference with experimental research, we used the lowest concentration to develop the IMH model. Gilbert found that hypothyroidism can occur in Long‐Evans rats administered 1 ppm of PTU for 7 weeks. Therefore, based on this, we found that the animal model of IMH can be successfully developed by administering 1 ppm of PTU for 9 weeks through preexperimental exploration. 14 Thus, we adopted this method to develop the animal model.

Autism spectrum disorder is a heterogeneous neurodevelopmental disorder that occurs in early childhood; the central characteristics are social communication barriers, narrow interests, and repetitive stereotyped behavior. However, we are unsure whether hypothyroxinemia leads to abnormal development in offspring's mental health, and its molecular mechanism is still unclear. 15 , 16 It has been found that the decrease in brain‐derived neurotrophic factor (BDNF) in the IMH offspring induced the upregulation of DNA methylation in BDNF promoter. 17 Román et al. found that the risk of autism in 6‐year‐old children was associated with severe hypothyroxinemia. 18 The age contrast between rats and humans shows that rats aged about 40 days are equivalent to human adolescence. Therefore, to explore whether the offspring during adolescence has autism‐like symptoms, 40‐day‐old offspring of IMH rats were used for the behavior tests.

2. MATERIALS AND METHODS

In this study, the animal model of hypothyroxinemia during pregnancy involving PTU administration (1 ppm) and model verification was developed. Model verification includes two parts: enzyme‐linked immunosorbent assay (ELISA) to verify serum thyroid function level and behavioral test to verify behavior phenotype (Figure 1).

FIGURE 1.

FIGURE 1

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Experimental operation flow.

2.1. Experimental animals

Specific pathogen‐free Wistar rats (8 weeks old, 16 females and 8 males), weighing about 220 g, were purchased from Beijing Huafukang Technology Co., Ltd. (Beijing, China). The experimental animals were kept in the animal room (temperature, 24 ± 2°C; relative humidity, 55%–65%; 12‐h light–dark condition) of the Institute of Medical Experimental Animals, Chinese Academy of Medical Sciences. A free diet, drinking water, and adaptive feeding were provided for 2 weeks. Animal experiments were approved by the Committee for the Use and Management of Laboratory Animals of the China Academy of Medical Sciences (QC0029).

2.2. Drugs and reagents

The drugs and reagents used were PTU (HY‐B0346, MedChemExpress, Monmouth Junction, NJ, USA), radioimmunoprecipitation assay lysis buffer (P00BB, Beyotime Biotechnology, Shanghai, China), protease inhibitor (78 443, Thermo Fisher, Waltham, MA, USA), phosphatase inhibitor (Thermo Fisher, no.: 78429), thyroid hormone ELISA kit (JM‐01989R1, Jing Mei Biotechnology, Jiangsu, China), thyroid‐stimulating hormone ELISA kit (JM‐10912R1, Jing Mei Biotechnology), triiodothyronine ELISA kit (JM‐10838R1, Jing Mei Biotechnology).

2.3. Major instruments

The instruments and software used in this analysis are as follows: open‐field test recording software EthoVision XT software, three‐chamber sociability test recording software Visu Track animal behavior program, ultrasonic crusher (Q700, serial number: 125278 U‐02‐22), ELISA gel electrophoresis (Bio‐Rad, Shanghai, China).

2.4. Experimental methods

2.4.1. Modeling

After 2 weeks of adaptive feeding, 16 female Wistar rats were divided into a negative control (NC) group (N = 8) and a model control (MC) group (N = 8). The MC group rats were treated with 1 ppm of PTU for 9 weeks. 19 , 20 , 21 , 22 The NC group rats were administered sterilized water.

2.4.2. Blood sampling from the posterior orbital venous plexus and model verification

After 9 weeks of PTU administration, the blood sample was obtained from the orbital venous plexus to validate the model. The rat was anesthetized intraperitoneally with 350 mg/kg of tribromoethanol. Then, the degree of anesthesia was determined. When its righting reflex disappeared, the whiskers were cut off to avoid hemolysis. Then, using one hand, both sides of the orbit were gently pressed to expose the eyeball fully. The heparin‐treated capillaries were contracted (measuring 1–2 cm) to rotate and pierce at 45° to the rat's face from the inside of the eyeball to the eyelid until resistance was broken. Blood was collected in an Eppendorf tube and centrifuged at 4°C and 5000 rpm for 20 min. Finally, the samples were stored in a refrigerator at −80°C.

T3, T4, and TSH concentrations were measured using the total triiodothyronine ELISA kit, the thyroid hormone ELISA kit, and the thyroid‐stimulating hormone ELISA kit. If only the concentration of T4 was decreased and the concentration of T3 and TSH were in the normal range, as stated earlier, the IMH animal model was developed successfully.

2.4.3. Animal mate

Sixteen female and eight male rats were used in the experiment, with two females and one male per cage (the most cost‐effective ratio). Mating occurred in the evening, and vaginal suppositories were detected before 7:00 a.m. (no more than 12 h to prevent vaginal suppositories from shedding). 19 , 20

2.4.4. Marble burying test

When the offspring rats were weaned, earmarking was carried out, and the offspring rats were grouped based on the mother rats. On the 40th day, the rats underwent a marble burying test. A transparent individual ventilated cage (IVC) (40 × 25 × 20 cm) was prepared, and the padding (10 cm thick) was placed at the bottom of the cage; 20 marble glass balls (1.5 cm in diameter) were arranged (like 4 × 5) in the cage, and the distance between the glass balls and between the glass balls and the cage wall was equal. The rats were acclimated to the new environment 10–15 min up front and then placed in the experimental cage for 30 min. The number of marbles was recorded, and two‐thirds of the glass beads were recorded as being buried. The increase in the number of burying acts compared with the NC group suggests the existence of stereotyped repetitive behavior in rats.

2.4.5. Open‐field test

A black open‐field test box (approximately 100 × 100 × 40 cm) was prepared for rats. The rat was acclimated to the environment 30 min up front, and the Super Maze/Visu Track animal behavior analysis software was used. Then, the parameters were set, the rat was placed in the center of the open‐field test box with its back to the experimenter, and the rat's movement in the box was recorded automatically within 10 min. At the end of the experiment, the rat was removed from the box, and the feces was cleaned. The residual odor was eliminated by spraying alcohol, and the rat was dried with a paper towel. Behavior index such as the time of entry into the central district, the time of stay in the central district, the ratio of the time of stay in the central district and surrounding areas, and the ratio of the times of entry into the central area and the surrounding area was analyzed.

2.4.6. Three‐chamber sociability test

In the illuminated 650 lux room, a rectangular box consisting of three chambers (each measuring 19 × 45 cm), with small arches in the partition walls, was placed. The rat was acclimated to the new environment 30 min up front, and the Visu Track animal behavior analysis software was used. On the first day of the adaptation phase, the rat was placed in a central chamber with its back to the experimenter and left to move freely for 10 min. The next day, for a social aptitude test, unfamiliar rats with the same strain, sex, and age were placed in a cylindrical cage in one lateral compartment, and another empty cage was placed on the other side. The rat was placed in the central chamber for 10 min, with its back to the experimenter. On the third day of the social novelty phase, another rat was placed in the empty cage based on the situation of the second day, and the rat's movement was also recorded for 10 min. The activity time, the frequency of entry, the ratio of duration in different chambers, and the time of entry were analyzed.

2.4.7. Morris water maze

The swimming pool (1.2–2 m diameter) was divided into four quadrants. In the first quadrant of the pool, a platform (height: 20–35 cm, diameter: 12 cm) was placed. The pool was filled with water (21–23°C) up front to approximately 1 cm over the platform, and ink was added to becloud the water until the platform could not be seen. During the training period, the rat was randomly placed in the water in the first, second, third, and fourth quadrants, with its back to the pool's edge. Then, the rat was led to the platform, made to stay for 15 s, dried, and put back into the cage. Each rat was trained thrice a day for 4 days. At the end of the training phase, the platform was removed, and the rat was placed in the pool in the third quadrant. The rat was tested for 60 s, and the time of stay in the first quadrant and the time of crossing the platform were recorded.

2.4.8. Statistical analysis

All data were tested using GraphPad PRISM, version 9.4.1, software for normal distribution; t‐tests for classification, nonparametric tests, and one‐way analysis of variance (ANOVA) were used for comparison between groups. p < 0.05 was set as the significance of the data.

3. RESULTS

3.1. Establishment of IMH animal model

After 9 weeks of PTU administration, blood samples were obtained from the orbital venous plexus. The rat serum was analyzed, and thyroid hormones, including T3, T4, and TSH, were detected using ELISA. A standard distribution test was performed, and a t‐test was performed to analyze the results. The results showed that the concentration of T4 in the MC group (N = 5) was significantly lower than that of the T4 in NC group (N = 6) (p < 0.05). Still, the concentration of T3 and TSH did not change significantly (p > 0.05) (Figure 2). The results showed that the IMH female mouse model was developed successfully.

FIGURE 2.

FIGURE 2

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Serum T3, T4, and thyroid‐stimulating hormone (TSH) concentrations in hypothyroxinemia rats during pregnancy. Black dots represent samples from the NC (negative control) group, and red dots represent samples from the MC (model control) group. Data are presented as mean ± standard deviation. **p < 0.01.

3.2. Forty‐day data on related organs in rat

At 40 days, the rats were killed after behavioral examination. The hypothalamus, pituitary gland, and thyroid gland were excised; absorbed excess water was removed; and the rats were weighed. It was found that compared with the NC group, the weight of the thyroid decreased significantly in the MC group (p < 0.05). In contrast, the weight of the pituitary gland and the hypothalamus did not change significantly (p > 0.05). Figure 3 shows that hypothyroxinemia during pregnancy may contribute to thyroid gland dysplasia, but it has no significant effect on the appearance of the pituitary gland and the hypothalamus.

FIGURE 3.

FIGURE 3

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The ratio between thyroid, pituitary, hypothalamus, and body weight (g) in 40‐day‐old rats. Black dots represent samples from the NC (negative control) group, and red dots represent samples from the MC (model control) group. The numerical value in the figure is enlarged by the unified multiple for convenience of visualization. Data are presented as mean ± standard deviation. ****p < 0.0001.

3.3. Marble burial experiment

At 40 days, the number of marbles buried in the MC group was significantly higher than that in the NC group (p < 0.05); the results suggested that the MC rats exhibited repetitive behaviors, as shown in Figure 4.

FIGURE 4.

FIGURE 4

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Marble burial experiment. Black dots represent samples from the NC (negative control) group, and red dots represent samples from the MC (model control) group. (A) Records of the NC and MC groups before and after the marble burial experiment. (B) Strip chart of marble burial experiment. Data are presented as mean ± standard deviation. ***p < 0.001.

3.4. Open‐field test

At 40 days, the open‐field test showed that the total distance of rats in the MC group did not increase significantly compared with that in the NC group (p > 0.05). Compared with the NC group, the movement time of the MC group significantly increased (p < 0.05) and the immobility time significantly decreased (p < 0.05). The ratio of the frequency of entering the central lattice to the frequency in the surrounding lattice was reduced considerably (p < 0.05) among these groups (see Figure 5). The above results indicate that there are anxiety behavior changes in offspring of IMH rats.

FIGURE 5.

FIGURE 5

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Open‐field experiment. Black dots represent samples from the NC (negative control) group, and red dots represent samples from the MC (model control) group. (A) Open‐field test setup plot. (B) The ratio of the number of frequencies of entry between area A and area C and the ratio of frequencies of entry between area B and area C. (C) Bar chart of fixed time. (D) Bar chart of total moving distance. (E) Bar chart of total moving time. Data are presented as mean ± standard deviation. *p < 0.05 and **p < 0.01.

3.5. Three‐chamber sociability test

As shown in Figure 6, in the three‐chamber sociability test, the time of entering chamber 1 is significantly less in the MC group than in the NC group (p < 0.05). The time of entering chamber 3 increased substantially (p < 0.05). Compared with the NC group, the frequency of entering chamber 1 did not significantly increase in the MC group in the second stage (p > 0.05). In the third stage (social novelty preference test), there was no significant difference in the time social ratio of entering chamber 1 and chamber 3 (p > 0.05). It is suggested that the offspring of IMH rats tended to decrease their social ability at 40 days.

FIGURE 6.

FIGURE 6

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Statistics of three social experiment indicators. Black dots represent samples from the NC (negative control) group, and red dots represent samples from the MC (model control) group. (A) Three social experiment settings. (B) Total time for chamber 1 and chamber 3. (C) The entry time of the third stage of chamber 1. (D) The third‐stage social ratio of the three‐chamber sociability test. (E) The total time of chamber 3 during the social first period. Data are presented as mean ± standard deviation. *p < 0.05 and ***p < 0.0001 compared with the NC group.

3.6. Morris water maze

Figure 7 shows that, during the Morris water maze exercise, the MC group achieved the fastest learning speed on the third day. However, there was no improvement on the last day compared with the NC group. There was no significant difference in swimming speed between the NC and the MC groups (p > 0.05). Compared with the NC group, there was no substantial decrease in the number of platform crossings (p > 0.05) and the duration in the target quadrant (p > 0.05). The results show no spatial learning and memory impairment in the offspring of IMH model rats administered 1 ppm PTU at 40 days.

FIGURE 7.

FIGURE 7

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The data from the Morris water maze experiment were analyzed. Black dots represent samples from the NC (negative control) group, and red dots represent samples from the MC (model control) group. (A) Morris water maze setup. (B) Learning speed during the water maze exercise phase. (C) Number of runs across the platform during the water maze exploration phase. (D) Target quadrant time during the water maze exploration phase. (E) Swimming speed during the water maze exploration phase. Data are presented as mean ± standard deviation.

4. DISCUSSION

Since the research on the influence of the thyroid hormone on brain development in the 1920s, 23 the importance of the thyroid hormone has been evident. People's understanding of diseases is more divided and profound. Exploring many aspects and fields, IMH in pregnancy with hypothyroidism is a subclinical disease with insignificant body surface characteristics and imperceptible influence. It is generally believed that T4 is the main form of existence, and T3 is the main form of function. But surprisingly, only decreased T4 during pregnancy can lead to brain development defects in future generations. 24 , 25 , 26 This is attributed to changes in maternal hormone levels during pregnancy, such as increased maternal human chorionic gonadotropin, stimulating TH secretion. Estrogen synthesizes thyroid‐binding globulin, which leads to increased TH binding. The activity of deiodinase increased, and the metabolic rate of TH increased. Finally, the renal clearance rate of iodine increased. 27 , 28 These are the reasons for T4 deficiency. However, before the thyroid gland develops in the fetus, the fetus depends entirely for its survival on the mother TH. Before birth, maternal thyroid hormone plays a vital role in fetal development. 29 , 30 This reveals the critical role of T4 in neurodevelopment and the deep‐seated regulatory mechanism. 29 , 31 , 32 , 33 , 34 After decades of concerted efforts by scientists, the effects of simple hypothyroxinemia in pregnancy included adverse pregnancy outcomes (preterm birth, miscarriage, dystocia, macrosomia, etc.), poor neurocognitive outcomes in school‐age children, and impaired mental development in children associated with psychiatric disorders in offspring (BP, autism, anxiety, etc.). 35 , 36 , 37 , 38 , 39 Among these findings, T4 deficiency in the second and third trimesters had no effect. At present, the main concern regarding hypothyroidism is the need to prevent hypothyroidism during pregnancy. The main clinical manifestations of autism are repetitive movements, impaired social skills, and language communication barriers.

Therefore, we developed an animal model of IMH in pregnancy involving PTU administration to inhibit thyroid peroxidase and the synthesis of thyroid hormone; then the open‐field test to detect anxiety, the marble burying test to detect stereotyped repetitive behavior, and the three‐chamber sociability test to observe the autism‐like behavior of offspring were performed.

5. CONCLUSIONS

This study detected autism‐like behavioral changes that occurred in IMH rats after 40 days. The age control relationship suggests that in human beings, if the mother suffers from uncomplicated hypothyroidism during pregnancy, the offspring will experience mental development disorders similar to autism when they are aged 11–12 years. Further research is needed to explore whether IMH is necessary for intervention treatment.

AUTHOR CONTRIBUTIONS

The concept was developed by Zhongyan Shan and Chuan Qin. Zhongyan Shan and Ling Zhang modified the article. Wei Wei wrote the manuscript, drew the figures, and edited the paper. Min Liu, Mingfeng Li, and Xinghan Wu contributed to the experiments. All authors contributed to manuscript revision and read and approved the submitted version.

FUNDING INFORMATION

This study was supported by the CAMS Innovation Fund for Medical Science (2021‐I2M‐1‐034) and the National Natural Science Foundation of China (grant number: 81700697).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

Animal experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Laboratory Animal Science of CAMS&PUMC (QC22009).

Wei W, Liu A, Liu M, et al. Development of an animal model of hypothyroxinemia during pregnancy in Wistar rats. Anim Models Exp Med. 2024;7:926‐935. doi: 10.1002/ame2.12459

Wei Wei and Aihua Liu have contributed equally to this work and should be considered co‐first authors.

Chuan Qin, Zhongyan Shan, and Ling Zhang have contributed equally to this work.

Contributor Information

Chuan Qin, Email: qinchuan@pumc.edu.cn.

Zhongyan Shan, Email: cmushanzhongyan@163.com.

Ling Zhang, Email: zhangling@cnilas.org.

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