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22대 대한민국 국회 국회정보길라잡이 국회의원검색
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Abstract 8

I. 서론 10

1. 연구배경 10

2. 연구가설 13

II. 연구 방법 15

1. 동물모델 15

(1) 실험동물 15

(2) 시험물질 제조 및 투여 16

2. 뇌 조직 homogenate 제조 및 total protein 정량 17

3. 혈청 및 전제 뇌 조직 내 IgG isotype 농도 분석 18

4. 혈청 내 IgE 농도 분석 19

5. 뇌 조직 내 싸이토카인 농도 분석 20

6. Brain derived neutrophic factor 농도 분석 21

7. 혈청 내 norepinephrine 농도 분석 22

8. 통계분석 24

III. 결과 25

1. 연구대상 신생자 개요 25

2. 혈청 내 IgG isotype 및 IgE 농도 평가 27

3. Whole brain 조직 중 IgG isotype 농도 평가 30

4. Whole brain 조직 중 각종 싸이토카인 농도 평가 32

5. Whole brain 내 brain derived neutrophic factor 농도 평가 36

6. 혈청 중 norepinephrine 농도 평가 38

IV. 고찰 40

V. 결론 48

참고문헌 51

표목차

Table 1. Number of mouse studied from gestational day 8 to postnatal day 21. 26

Table 2. Level of serum IgG isotype and IgE (mean±SE) for postnatal day 21 mice exposed to lead or mercury from gestational day 8 to postnatal day 21. 29

Table 3. Level of IgG isotype deposited in whole brain perfused (mean±SE) for postnatal day 21 mice exposed to lead or mercury from gestational day 8 to postnatal day 21. 31

Table 4. Level of various cytokines (pg/㎎ protein) in the whole brain of postnatal day 21 mice exposed to lead or mercury from gestational day 8 to postnatal day 21. 34

Table 5. Characteristics of antibodies and various cytokines in the serum and whole brain of postnatal day 21 mice exposed to lead or mercury from gestational day 8 to postnatal day 21. 47

그림목차

Figure 1. Pathogenesis of autism-like behavior in BTBR mice involving environmental stressors. 14

Figure 2. Level of IL-4/IFN-g ratio in the whole brain of postnatal day 21 mice exposed to lead or mercury from gestational day 8 to postnatal day 21. 35

Figure 3. Level of brain derived neutrophic factor (mean±SE) in whole brain of postnatal day 21 mice exposed to lead or mercury... 37

Figure 4. Level of serum norepinephrine (mean±SE) for postnatal day 21 mice exposed to lead or mercury from gestational day 8 to postnatal day 21. Statistical significances : *, figure with same... 39

초록보기

 Autism or autism spectrum disorder (ASD) is a neuro developmental disorder which has been persistently increasing over the last decade and its etiology is uncertain. Neuroinflammational process in brain is hypothetically suggested to play a role for induction of autism, but no systemic investigation has been undertaken. Using BTBR T+tf/J mice which is considered optimal for autism investigation based on its neuroanatomical or behavioral evaluation, effect of heavy metal lead and mercury exposure on autoimmune-prone neuroinflammational pathogenesis in BTBR mice was evaluated and compared with FVB mice, a control strain because of its positive social behaviors.

BTBR and FVB mouse were exposed orally to lead acetate (0.1 mM), mercury chloride (0.01 mM), both lead (0.05 mM) and mercury (0.005 mM), or distilled water from gestational day 8 to postnatal day 21. Number of neonatal mice studied was 116 (female, 56; male, 60) and 125 (female, 69; male, 56) for BTBR and FVB, respectively. Levels of serum IgG isotypes, IgE and norepinephrine were determined, and levels of brain-derived neutrophic factor (BDNF), interleukin (IL)-4, IL-6, IL-18, IL-33, and interferon-γ, and IgG isotye deposited in whole brains were evaluated.

Concerning the elevated IgG1/IgG2a ratio, an indicator for skewedness toward type-2 helper T cell reactivities, the ratio was higher in BTBR mice than FVB mice in which both were not exposed to metals. Regardless of strain, mice concurrently exposed to lead or mercury demonstrated significantly higher IgG1/IgG2a ratio than the mice intaken distilled water. Serum IgE level was also significantly higher in BTBR mice exposed to the metals than FVB mice exposed to the metals. Regarding IgG isotype deposit in whole brain, IgG1/IgG2a ratio was higher in BTBR male mice group exposed to lead or lead and mercury mixture than FVB male mice group exposed to the above metals. Two pro-inflammatory cytokines, IL-18 and IL-33, were downregulated in BTBR mice exposed to the metals when compared with those of no metal-administered control BTBR mice, but FVB mice exhibited the opposite results. BDNF level was higher in the BRBR mice group administered with lead than the mice group with distilled water, which was not observed in FVB mice. Lead-treated groups both in BTBR and FVB mice has higher serum norepinephrine level compared to its corresponding control group.

Overall, this study suggest that metal exposure, especially lead, induce a certain neurotoxicological effect on autistic prone BTBR mice, which could be involved with occurrence of ASD.

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