WO2022080804A1 - 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 바이오마커 조성물 및 이를 이용한 예후 예측방법 - Google Patents

미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 바이오마커 조성물 및 이를 이용한 예후 예측방법 Download PDF

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WO2022080804A1
WO2022080804A1 PCT/KR2021/013992 KR2021013992W WO2022080804A1 WO 2022080804 A1 WO2022080804 A1 WO 2022080804A1 KR 2021013992 W KR2021013992 W KR 2021013992W WO 2022080804 A1 WO2022080804 A1 WO 2022080804A1
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receptor
protein
gene
alpha
subfamily
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French (fr)
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김진수
김현기
자히르자베리아
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한국원자력의학원
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Priority to EP21880451.6A priority Critical patent/EP4186983A1/en
Priority to US18/027,639 priority patent/US20230383346A1/en
Publication of WO2022080804A1 publication Critical patent/WO2022080804A1/ko

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    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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    • C12Q2600/158—Expression markers
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    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to a biomarker composition for predicting the prognosis of brain disease induced by microplastic exposure and use thereof.
  • Autism is a neurodevelopmental disorder that impairs the ability to communicate and understand social interactions. Although the cause of this symptom is not yet clear, some researchers speculate that it is a genetic developmental disorder rather than an emotional cause. The incidence rate is 1 in 1000, and the male to female ratio is about 4:1 in the United States. According to a 2011 survey, the prevalence of autism in Korea was over 2%, drawing attention. Autism is generally referred to as 'Autism Spectrum Disorder' or 'Autism Spectrum Disorder', and this disorder is divided into three categories in academic circles.
  • Plastic has contributed greatly to modern people's affluent daily life and industrial development due to its excellent function and low price. Although it has been reported as a cause that threatens human health, the effect of microplastics on brain diseases has not been studied.
  • An object of the present invention is to provide a biomarker composition for predicting the prognosis of a brain disease induced by microplastic exposure and a method for predicting the prognosis of a brain disease using the same.
  • the present invention provides Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated) protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member
  • the present invention provides Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated) protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member
  • the present invention provides Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D) from a biological sample isolated from an individual.
  • Tceanc transcription elongation factor A N-terminal and central domain containing
  • Mx1 MX dynamin like GTPase 1
  • Ms4a6d membrane-spanning 4-domains, subfamily A, member 6D
  • Arc activity regulated cytoskeletal-associated protein
  • Olfr912 olfactory receptor 912
  • Casc5 kinetochore scaffold 1
  • Egr3 Early growth response 3
  • Gm11565 predicted gene 11565
  • Gabra6 gamma-aminobutyric acid (GABA)) A receptor, subunit alpha 6
  • Cdkn1a cyclin-dependent kinase inhibitor 1A (P21)
  • Egr1 early growth response 1
  • Zfp184 zincc finger protein 184 (Kruppel-like)
  • Ms4a14 membrane-spanning 4-domains) , subfamily A, member 14
  • Tas2r121 taste receptor, type 2, member 121
  • AB124611 cDNA sequence AB124611
  • Irs4 insulin receptor substrate 4
  • Fut2 fucosyltransferase 2
  • Gm10754 predicted gene 10754
  • Rgs21 regulator of
  • It provides a method for predicting brain disease prognosis induced by microplastic exposure, comprising comparing the mRNA expression level of the gene or the expression level of the protein encoded by the gene with a control.
  • An object of the present invention is to provide a biomarker composition for predicting the prognosis of a brain disease induced by microplastics in a gene whose expression level is confirmed in an individual, and a brain disease prognosis prediction method using the same.
  • FIG. 1 is a schematic diagram showing the brain tissue penetration process of orally administered polyethylene microspheres and the results of confirming whether polyethylene microspheres penetrate into the brain tissue of a mouse animal model to which polyethylene microspheres are orally administered.
  • Figure 2 is a 3-chamber experiment (change in sociality), Y-maze (cognition and obsessive compulsive disorder), marble-burying behavior study (obsessive compulsive disorder) and nestlet to confirm whether a mouse animal model exposed to polyethylene microspheres develops autism. This is the result of performing the shredding test (obsessive-compulsive disorder).
  • the present inventors studied the risk that may appear when polystyrene microspheres (PS), a type of microplastic, are ingested in vivo, as microplastics with a diameter of less than 5 mm are recognized as a new environmental and human health risk factor.
  • Biomarker composition for predicting the prognosis of brain diseases induced by microplastics by confirming that PS absorbed into the body penetrates the brain tissue and changes the gene expression level in the brain tissue The present invention was completed to provide
  • the present invention provides Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated) protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member
  • the Tceanc transcription elongation factor A N-terminal and central domain containing
  • Mx1 MX dynamin like GTPase 1
  • Ms4a6d membrane-spanning 4-domains, subfamily A, member 6D
  • Arc activity regulated cytoskeletal -associated protein
  • Olfr912 olfactory receptor 912
  • Casc5 kinetochore scaffold 1
  • Egr3 Early growth response 3
  • Gm11565 predicted gene 11565
  • Gabra6 gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6)
  • Cdkn1a cyclin-dependent kinase inhibitor 1A (P21)
  • Egr1 early growth response 1
  • Zfp184 zinc finger protein 184 (Kruppel-like)
  • Ms4a14 membrane-spanning 4-domains, subfamily A, member 14
  • Tas2r121 taste receptor
  • the Ptpn20 protein tyrosine phosphatase, non-receptor type 20
  • Tex14 testis expressed gene 14
  • Bhlhe23 basic helix-loop-helix family, member e23
  • Loxl2 lysyl oxidase like 2
  • Rora RAR- related orphan receptor alpha
  • Nrap nebulin-related anchoring protein
  • Olfr435 olfactory receptor 435
  • Htr2a (5-hydroxytryptamine (serotonin) receptor 2A)
  • Fcer1g Fc receptor, IgE, high affinity I, gamma polypeptide
  • Ecscr endothelial cell surface expressed chemotaxis and apoptosis regulator
  • Lrrk2 leucine-rich repeat kinase 2
  • Ddx51 DEAD box helicase 51
  • Olfr1284 olfactory receptor 1284
  • Stfa2l1 stef
  • the microplastic exposure may be selected from the group consisting of oral exposure, inhalation exposure and transdermal exposure.
  • the microplastic is polystyrene, polypropylene, polyethylene, polyamide (Polyamide, PA), acrylonitrile-butadiene-styrene (ABS), polytetrafluoroethylene (PTFE), cellulose acetate (Cellulose Acetate, CA), polycarbonate (PC), polymethyl methacrylate (PMMA), polyvinyl chloride (PVC), polyethylene terephthalate (PET), acrylic (Acrylic), melamine It may be one selected from the group consisting of resin and polyurethane (PU).
  • the microplastic may contain harmful substances that are eluted and desorbed from the plastic.
  • the harmful substances eluted from the plastic may be selected from the group consisting of mineral oil, styrene dimer, trimer perfluorinated compound, sterilization preservative, polyols, acrylates, phenols, melamine and nitrosamines.
  • the harmful substances desorbed from the plastic are heavy metals, sterilizing preservatives, phthalates, bisphenol A, perfluorinated compounds, PCBs (Polychlorinated biphenyls), DDTs (, HCH (Hexachlorocyclohexane), polycyclic aromatic hydrocarbons (PAHs), aliphatic hydrocarbons, nonylphenol, Lubricating Oil, Pharmaceutical, CBZ(Carbamazepine), 4MBC(4-MethylBenzylidene Camphor), TCS(TriCloSan), EE2(17 ⁇ -Ethinyl Estradiol), (SDZ(Sulfadiazine), AMX(Amoxicillin), TC(Tetracycline), CIP(Ciproxacin) And it may be one selected from the group consisting of Trimethoprim (TMP).
  • TMP Trimethoprim
  • the microplastic is a plasticizer, flame retardant, stabilizer, antioxidant, UV stabilizer, heat stabilizer, slip agent, lubricant, antistatic agent, curing agent, foaming agent, biocide, water-soluble colorant, organic pigment, inorganic pigment, special effect added to plastic It may include one or two or more from the group of additives consisting of colorants, fillers and enhancers.
  • the brain disease may be selected from the group consisting of schizophrenia, frontal lobe epilepsy, autism and attention deficit hyperactivity disorder (ADHD).
  • ADHD attention deficit hyperactivity disorder
  • the present invention provides Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated) protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member
  • the kit may be an RT-PCR kit, a DNA chip kit, or a protein chip kit, but is not limited thereto.
  • the present invention provides Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor , subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member
  • the method for measuring the mRNA expression level is RT-PCR, competitive RT-PCR (Competitive RT-PCR), real-time RT-PCR (Real-time RT-PCR), RNase protection assay (RPA; RNase protection assay), Northern Blue It may be to use any one selected from the group consisting of ratting (Northern blotting) and a DNA chip.
  • the step of measuring the protein expression level is Western blot, ELISA (enzyme linked immunosorbent asay), radioimmunoassay (RIA), radioimmunodiffusion, Ouchterlony immune diffusion method, rocket (rocket) ) may be using any one selected from the group consisting of immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation assay, FACS and protein chip.
  • Prognosis of the present invention includes determining whether a subject, that is, a test subject will have a disease in the future for a specific disease or condition, or determining the responsiveness of a test subject to treatment.
  • Fluorescent polyethylene (PE) microspheres with a diameter of 10-20 ⁇ m were orally administered to BALB/c nude mice by 100 ppm/100 ⁇ L at a concentration of 100 ppm each for 4 weeks.
  • mice After 4 weeks, the mice were euthanized and the mice brains were harvested. After physically crushing the brain tissue, it was dried for one day using a freeze dryer, and the dried tissue was sufficiently dissolved in 70% nitric acid (HNO 3 ), and then neutralized using sodium hydroxide (NaOH). After filtering the liquid tissue with a 0.45 um Nitrocellulose membrane filter using a vacuum pump, the size and shape of the fluorescent plastic pieces adsorbed on the filter were observed using a confocal microscope and a scanning electron microscope. .
  • HNO 3 70% nitric acid
  • NaOH sodium hydroxide
  • the PE microspheres maintained an intact spherical shape before administration, but small pieces and irregular shapes were observed in the brain tissue filtration filter.
  • the size of the fluorescent PE microspheres before administration was observed to have an average diameter of 20.49 ⁇ m, whereas the microplastics adsorbed to the filter that filtered brain tissue had an average diameter of 3 ⁇ m.
  • microplastics including PE penetrate the brain, and it can be suggested that these microplastics have an effect on brain diseases including autism.
  • PE fluorescent polyethylene
  • 100 ppm / 100 ⁇ L of fluorescent polyethylene (PE) microspheres with a diameter of 10-20 ⁇ m in diameter were orally administered to C57BL6 mice at a concentration of 100 ppm at 100 ppm / 100 ⁇ L for 1 week, and autism was reduced by exposure to PE microspheres.
  • a 3-chamber experiment changes in sociality; Kaidanovich-Beilin, O., et al., Assessment of social interaction behaviors. J Vis Exp, 2011(48)
  • Y-maze cognitive and obsessive compulsive disorder; Roullet, F.I. and J.N. Crawley, Mouse models of autism: testing hypotheses about molecular mechanisms.
  • Egr1 Early growth response protein 1 in the brain region is known to be involved in methylation, and the increase in Egr1 in the brain region acts as an important factor in regulating oxidative stress.
  • the Arc Activity Regulated Cytoskeleton Associated Protein
  • the accumulation and increase of the Arc gene in neurons indicates an abnormality in the proteolytic process and is known to be related to autism.
  • high levels of IL-1 and IL-6 cytokines appear as high levels in actual autistic patients.
  • mice 100 ppm/100 ⁇ L were orally administered to BALB/c nude mice for 4 weeks, and after 4 weeks, the mice were euthanized, and the prefrontal cortex and hippocampus regions of the mouse brain were isolated and excised. After total RNA extraction from each region, microarray analysis was performed.
  • Prefrontal cortex Symbol full name Gene ID FC P-value Tceanc transcription elongation factor A N-terminal and central domain containing 245695 -1.5 0.002 Mx1 MX dynamin like GTPase 1 17857 -1.56 0.002 Ms4a6d membrane-spanning 4-domains, subfamily A, member 6D 68774 -1.75 0.003 Arc activity regulated cytoskeletal-associated protein 11838 1.98 0.006 Olfr912 olfactory receptor 912 258806 -1.87 0.007 Casc5 kinetochore scaffold 1 76464 1.57 0.008 Egr3 Early growth response 3 13655 1.53 0.009 GM11565 predicted gene 11565 670550 1.55 0.01 Gabra6 gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6 14399 1.52 0.01 cdkn1a cyclin-dependent kinase inhibitor 1A (P21) 12575 2.
  • PE fluorescent polyethylene
  • 100 ppm/100 ⁇ L of fluorescent polyethylene (PE) microspheres with a diameter of 10-20 ⁇ m in diameter were orally administered to C57BL6 mice at a concentration of 100 ppm at 100 ppm/100 ⁇ L for 1 week. After 1 week, the mouse was euthanized and the mouse brain was extracted. After total RNA was extracted from the extracted brain tissue, cDNA was synthesized and qPCR analysis was performed.
  • PE polyethylene
  • the oxidative stress marker Egr1 was 2.13 times (p ⁇ 0.05), the neuronal proteolysis process and autism-related gene Arc 1.97 times (p ⁇ 0.05), and the inflammatory response and autism-related gene IL -6 and IL-1 ⁇ were increased by 1.85-fold (p ⁇ 0.05) and 2.64-fold (p ⁇ 0.01), respectively.

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Abstract

본 발명은 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 바이오마커 조성물 및 이의 용도에 관한 것으로, 보다 상세하게는 폴리에틸렌 미세구체(PS)가 경구 투여된 마우스 동물모델에서 PS가 뇌 조직에 침투하여 뇌 조직 내 유전자 발현 수준을 변화시켜 뇌질환을 유도하는 것을 확인함에 따라, PS 노출이 의심되는 개체에서 발현 수준 변화가 확인된 유전자를 미세플라스틱에 의해 유도되는 뇌질환의 예후 예측을 위한 바이오마커 조성물 및 이를 이용한 뇌질환 예후 예측 방법을 제공하고자 한다.

Description

미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 바이오마커 조성물 및 이를 이용한 예후 예측방법
본 발명은 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 바이오마커 조성물 및 이의 용도에 관한 것이다.
자폐증이란, 의사소통과 사회적 상호작용 이해 능력에 저하를 일으키는 신경 발달 장애를 뜻한다. 이 증상의 원인은 아직 명확하게 밝혀지지 않았지만 몇몇 연구자들은 정서적인 원인이 아닌 유전적 발달 장애로 추측하고 있다. 발생확률은 1000명에 한 명꼴이며 남녀의 비율은 미국 기준으로 4:1정도이다. 2011년의 조사에 의하면 국내에서의 자폐증 유병률은 2% 이상으로 나타나서 주목을 받고 있다. 자폐증은 전반적으로 '자폐 스펙트럼 장애' 혹은 '자폐 범주성 장애'(Autism Spectrum Disorder)라고 부르며, 이 장애는 학계에서 3가지 정도로 나뉘어 논의된다.
첫째로는 레오 카너가 정의한 아동을 부르는 자폐증(Autism; Kanner's Syndrome), 둘째로는 한스 아스퍼거가 논의한 아스퍼거 증후군(Asperger's Syndrome), 그리고 마지막으로는 서번트 증후군(Savant Syndrome)을 포함한 고기능성 자폐증(High Functional Autism)이다.
성장하는 아기들은 일반적으로 사람들을 응시하거나 목소리를 주목하거나 손가락을 움켜쥐거나 웃음을 보이는 등의 사회적 활동을 보인다. 하지만 자폐 증상이 있는 아기는 얼굴을 마주 보는 것을 싫어하고, 인간 사회의 상호 작용을 이해하는 것에 굉장한 어려움을 겪는다. 의사소통과 관련해선, 일반적인 아기들이 첫 생일 즈음에 단어들을 말하고, 자신의 이름을 부르면 반응하고 장난감을 원하면 손가락으로 가리키는 등의 행동을 하는 반면, 자폐 증상이 있는 아기는 의사소통 발달에서 다른 길을 선택한다. 몇몇은 읽고 쓸 수 있는 능력이 충분함에도 불구하고 평생동안 침묵을 지키고, 대신에 이들은 다른 방법, 즉 그림이나 수화 등의 방법을 선호한다.
자폐증의 원인과 관련해서 초기에는 후천적으로 발생한다고 보는 학설도 있었으나, 현재는 선천적 원인으로 발병한다고 보는 것이 지배적이다. 대개 뇌 구조의 이상, 유전적 결함, 그리고 신경전달물질 이상이 원인으로 지목되고 있다. 또한 아이가 음주를 좋아하는 임신 상태의 산모로부터 악영향을 받는 태아 알코올 증후군 역시 원인으로 지목되기도 했다. 그러나 아직까지 정확한 원인인자에 대해선 논란이 있다.
플라스틱은 기능이 우수하고 가격이 저렴하여 현대인의 풍요로운 일상생활과 산업발달에 크에 이바지해왔지만, 버려지는 플라스틱이 시간 경과에 따라, 시각적으로 확인하기 어려운 미세한 크기로 분해되어 최근에는 환경을 오염시키고 인체 건강을 위협하는 원인으로 보고되어졌으나, 미세플라스틱이 뇌 질환에 미치는 영향에 대해서는 연구되어 있지 않다.
본 발명은 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 바이오마커 조성물 및 이를 이용한 뇌 질환 예후 예측방법을 제공하고자 한다.
본 발명은 Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin), Dusp1 (dual specificity phosphatase 1), Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)으로 이루어진 군에서 선택되는 하나 이상의 유전자 또는 상기 유전자가 코딩하는 단백질을 포함하며, 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 바이오마커 조성물을 제공한다.
본 발명은 Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin), Dusp1 (dual specificity phosphatase 1), Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)으로 이루어진 군에서 선택되는 하나 이상의 유전자에 특이적으로 결합하는 프로브, 상기 유전자를 증폭하기 위한 프라이머, 상기 유전자가 코딩하는 단백질에 특이적으로 결합하는 항체 또는 상기 단백질에 특이적인 결합 도메인을 갖는 펩티드를 포함하는 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 키트를 제공한다.
또한, 본 발명은 개체로부터 분리된 생물학적 시료로부터 Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin), Dusp1 (dual specificity phosphatase 1), Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)으로 이루어진 군에서 선택되는 하나 이상의 유전자의 mRNA 발현 수준 또는 상기 유전자가 코딩하는 단백질의 발현 수준을 측정하는 단계; 및
상기 유전자의 mRNA 발현 수준 또는 상기 유전자가 코딩하는 단백질의 발현 수준을 대조군과 비교하는 단계를 포함하는 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측 방법을 제공한다.
본 발명에 따르면, 폴리에틸렌 미세구체(PS)가 경구 투여된 마우스 동물모델에서 PS가 뇌 조직에 침투하여 뇌 조직 내 유전자 발현 수준을 변화시켜 뇌질환을 유도하는 것을 확인함에 따라, PS 노출이 의심되는 개체에서 발현 수준 변화가 확인된 유전자를 미세플라스틱에 의해 유도되는 뇌질환의 예후 예측을 위한 바이오마커 조성물 및 이를 이용한 뇌질환 예후 예측 방법을 제공하고자 한다.
도 1은 경구로 투여된 폴리에틸렌 미세구체의 뇌 조직 침투과정을 나타낸 모식도와 폴리에틸렌 미세구체를 경구 투여한 마우스 동물모델의 뇌 조직에서 폴리에틸렌 미세구체 침투 여부를 확인한 결과이다.
도 2는 폴리에틸렌 미세구체에 노출된 마우스 동물 모델의 자폐증 발병 여부를 확인하기 위해 3-chamber 실험 (사회성의 변화), Y-maze (인지 및 강박), marble-burying behavior study (강박장애) 및 nestlet shredding test (강박장애)을 수행한 결과이다.
이하, 본 발명을 보다 상세하게 설명한다.
본 발명자들은 직경 5 mm 미만인 미세플라스틱이 새로운 환경 및 인체 건강 위험 인자로 인식됨에 따라, 미세플라스틱의 한 종류인 폴리스티렌 미세소구 (Polystyrene microspheres, PS)가 생체 내로 섭취되었을 때 나타날 수 있는 위험성을 연구하던 중 생체 내로 흡수된 PS가 뇌 조직에 침투하여 뇌 조직 내 유전자 발현 수준을 변화시키는 것을 확인함에 따라 상기 발현 수준 변화가 확인된 유전자를 미세플라스틱에 의해 유도되는 뇌질환의 예후 예측을 위한 바이오마커 조성물로 제공하고자 본 발명을 완성하였다.
본 발명은 Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin), Dusp1 (dual specificity phosphatase 1), Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)으로 이루어진 군에서 선택되는 하나 이상의 유전자 또는 상기 유전자가 코딩하는 단백질을 포함하는 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 바이오마커 조성물을 제공할 수 있다.
보다 상세하게는 상기 Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin) 및 Dusp1 (dual specificity phosphatase 1)으로 이루어진 군에서 선택되는 하나 이상의 유전자 또는 상기 유전자가 코딩하는 단백질은 미세플라스틱 노출에 의해 전전두엽 (Prefrontal cortex)에서 발현 수준 변화가 확인되는 것일 수 있다.
또한, 상기 Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)로 이루어진 군에서 선택되는 하나 이상의 유전자 또는 상기 유전자가 코딩하는 단백질은 미세플라스틱 노출에 의해 해마 (Hippocampus)에서 발현 수준 변화가 확인되는 것일 수 있다.
상기 미세플라스틱 노출은 경구 노출, 흡입 노출 및 경피 노출로 이루어진 군에서 선택되는 것일 수 있다.
상기 미세플라스틱은 폴리스티렌, 폴리프로필렌, 폴리에틸렌, 폴리아미드(Polyamide, PA), 아크릴로니트릴 부타디엔 스티렌 (Acrylonitrile-butadiene-styrene, ABS), 폴리테트라플루오르에틸렌(Polytetrafluoroethylene, PTFE), 셀룰로오스아세테이트(Cellulose Acetate, CA), 폴리카보네이트(Polycarbonate, PC), 폴리메틸메타크릴레이트(Polymethyl methacrylate, PMMA), 폴리비닐 클로라이드 (Polyvinyl chloride, PVC), 폴리에틸렌 테레프타레이트 (Polyethylene terephthalate, PET), 아크릴 (Acrylic), 멜라민수지 및 폴리우레탄 (polyurethane, PU)로 이루어진 군에서 선택되는 것일 수 있다.
상기 미세플라스틱은 플라스틱에서 용출 및 탈착되는 유해물질을 포함하는 것일 수 있다.
상기 플라스틱에서 용출되는 유해물질은 미네랄오일, 스티렌 다이머, 트리머 과불화화합물, 살균보존제, 폴리올류, 아크릴레이트류, 페놀류, 멜라민 및 니트로사민류로 이루어진 군에서 선택되는 것일 수 있다.
상기 플라스틱에서 탈착되는 유해물질은 중금속류, 살균보존제, 프탈레이트, 비스페놀 A, 과불화화합물, PCBs (Polychlorinated biphenyls), DDTs(, HCH (Hexachlorocyclohexane), 다환방향족탄화수소류 (PAHs), 지방족탄화수소, 노닐페놀, 윤활유, 의약, CBZ(Carbamazepine), 4MBC(4-MethylBenzylidene Camphor), TCS(TriCloSan), EE2(17α-Ethinyl Estradiol), (SDZ(Sulfadiazine), AMX(Amoxicillin), TC(Tetracycline), CIP(Ciprofloxacin) 및 TMP(Trimethoprim)으로 이루어진 군에서 선택되는 것일 수 있다.
상기 미세플라스틱은 플라스틱에 첨가되는 가소제, 난연제, 안정제·산화방지제·UV안정제, 열안정제, 슬립제, 윤활유, 정전기 방지제, 경화제, 발포제, 살생물제, 수용성 착색제, 유기 안료, 무기 안료, 특수 효과 착색제, 충전제 및 증강제로 이루어진 첨가물군에서 하나 또는 둘 이상을 포함하는 것일 수 있다.
상기 뇌질환은 조현병 (schizophrenia), 전두엽 간질(Forntal lobe epilepsy), 자폐증(autism) 및 주의력결핍 과잉행동장애 (ADHD, attention deficit hyperactivity disorder)로 이루어진 군에서 선택되는 것일 수 있다.
본 발명은 Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin), Dusp1 (dual specificity phosphatase 1), Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)으로 이루어진 군에서 선택되는 하나 이상의 유전자에 특이적으로 결합하는 프로브, 상기 유전자를 증폭하기 위한 프라이머, 상기 유전자가 코딩하는 단백질에 특이적으로 결합하는 항체 또는 상기 단백질에 특이적인 결합 도메인을 갖는 펩티드를 포함하는 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 키트를 제공할 수 있다.
상기 키트는 RT-PCR 키트, DNA 칩 키트 또는 단백질 칩 키트일 수 있으나, 이에 제한되지 않는다.
본 발명은 개체로부터 분리된 생물학적 시료로부터 Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin), Dusp1 (dual specificity phosphatase 1), Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)으로 이루어진 군에서 선택되는 하나 이상의 유전자의 mRNA 발현 수준 또는 상기 유전자가 코딩하는 단백질의 발현 수준을 측정하는 단계; 및
상기 유전자의 mRNA 발현 수준 또는 상기 유전자가 코딩하는 단백질의 발현 수준을 대조군과 비교하는 단계를 포함하는 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측 방법을 제공할 수 있다.
상기 mRNA 발현 수준을 측정하는 방법은 RT-PCR, 경쟁적 RT-PCR(Competitive RT-PCR), 실시간 RT-PCR (Real-time RT-PCR), RNase 보호 분석법 (RPA; RNase protection assay), 노던 블랏팅 (Northern blotting) 및 DNA 칩으로 이루어진 군에서 선택된 어느 하나를 이용하는 것일 수 있다.
상기 단백질 발현 수준을 측정하는 단계는 웨스턴 블랏, ELISA(enzyme linked immunosorbent asay), 방사선면역분석(Radioimmunoassay; RIA), 방사면역확산법(radioimmunodiffusion), 오우크테로니(Ouchterlony) 면역 확산법, 로케이트(rocket) 면역전기영동, 조직면역염색, 면역침전 분석법 (Immunoprecipitation assay), 보체고정분석법 (Complement Fixation Assay), FACS 및 단백질 칩으로 이루어진 군에서 선택된 어느 하나를 이용하는 것일 수 있다.
본 발명의 "예후"는 특정 질병 또는 질환에 대한 한 객체 즉 검사 대상자가질환을 차후에 가지게 될지의 여부를 판단하거나 치료에 대한 검사 대상자의 반응성을 판단하는 것을 포함한다.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.
<실시예 1> 경구 노출에 따른 폴리에틸렌 미세구체의 뇌조직 침투 확인
BALB/c 누드마우스에 직경 10-20 μm 크기의 형광 폴리에틸렌(Polyethylene, PE) 미세구체를 100ppm 농도로 100 μL씩 4주간 100 ppm/100 μL를 경구 투여하였다.
4주 후, 마우스를 안락사시키고 마우스의 뇌를 적출하였다. 뇌 조직을 물리적으로 파쇄해준 후 동결건조기를 이용하여 하루 동안 건조하고, 건조 조직을 70% 질산(HNO3)에 충분히 녹인 후, 수산화나트륨(NaOH)을 이용하여 중화하였다. 진공 펌프를 이용하여 액상 조직을 0.45 um Nitrocellulose membrane 필터로 여과한 후 필터에 흡착된 형광 플라스틱조각을 공초점현미경(Confocal microscope)과 주사전자현미경(Scanning Electron Microscope)을 이용하여 크기와 형태를 관찰하였다.
그 결과, 도 1과 같이 투약 전 PE 미세구체는 온전한 구형태를 유지하였으나, 뇌 조직 여과 필터에서는 작은 조각 및 불규칙한 형태로 관찰되었다. 또한, 투약 전 형광 PE 미세구체의 크기는 평균직경 20.49 μm로 관찰된 반면, 뇌 조직을 여과한 필터에 흡착된 미세플라스틱은 평균 직경 3 μm 로 관찰되었다. 이러한 결과는 위에서 소화과정을 거친 후 파편화된 미세플라스틱이 뇌에 침투하였음을 입증하는 증거이다.
상기 결과로부터 PE를 포함한 미세플라스틱은 뇌에 침투하는 것이 확인되었으며, 이러한 미세플라스틱의 뇌 침투는 자폐를 포함한 뇌질환에 영향을 나타내는 것으로 제안될 수 있다.
<실시예 2> 폴리에틸렌 미세구체 노출에 의한 자폐증 증상 확인
자폐증 마우스 모델에서 Social Novelty 및 Interaction이 감소하는 것으로 보고되었으며, 자폐 환자의 미생물을 이식하여 자폐증을 유발한 마우스 모델에서 social interaction 감소한 것으로 확인되었으며, 이외 다양한 자폐증 관련 마우스모델에서 사회성 감소되는 것으로 확인되었다.
이에 따라, C57BL6 마우스에 직경 10-20 μm 크기의 형광 폴리에틸렌(Polyethylene, PE) 미세구체를 100 ppm 농도로 100 μL씩 1주일간 100 ppm / 100 μL를 경구 투여하고, PE 미세구체 노출에 의해 자폐증이 유발될 수 있는지를 확인하기 위해, 3-chamber 실험 (사회성의 변화; Kaidanovich-Beilin, O., et al., Assessment of social interaction behaviors. J Vis Exp, 2011(48)), Y-maze (인지 및 강박; Roullet, F.I. and J.N. Crawley, Mouse models of autism: testing hypotheses about molecular mechanisms. Curr Top Behav Neurosci, 2011. 7: p. 187-212.) 및 marble-burying behavior study & nestlet shredding test (강박장애; Angoa-Perez, M., et al., Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice. J Vis Exp, 2013(82): p. 50978.)를 수행하였다.
그 결과, 도 2와 같이 3-chamber 실험 결과, PE 미세구체 노출 마우스는 Social interaction 및 Social novelty 모두 대조군 대비 감소하였다. 또한, Y-maze 실험 결과에서는 PE 미세구체 노출 마우스의 Alternation triplet 및 SAP Score가 감소하였다.
또한, nest building test 결과, PE 미세구체 노출 마우스에서 더 높은 % Nestlet shredding 관찰되었으며, marble-burying behavior 실험에서는 PE 미세구체 노출 마우스의 marble-buried 더 높게 나타났다.
상기 결과로부터 미세플라스틱 노출은 인지기능을 저하시키고, 강박증상을 증가시키는 것이 확인되었다.
<실시예 3> 미세구체 노출에 의한 뇌 영역 유전자 발현 변화 확인
뇌 영역에서 Egr1 (Early growth response protein 1)은 메틸화(Methylation)에 관여하는 것으로 알려져 있으며, 뇌 영역에서 Egr1 증가는 산화스트레스를 조절하는 중요 인자로서 작용한다. 또한, Arc (Activity Regulated Cytoskeleton Associated Protein) 유전자의 경우 다발성 신경정신계 장애 (multiple neuropsychiatric disorders)에 관련있다. 특히, 신경세포에 Arc 유전자의 축적 및 증가는 단백분해과정의 이상을 나타내며, 자폐증과 관련된 것으로 알려져있다. 또한, 실제 자폐증 환자에서 높은 수치의 IL-1 및 IL-6 사이토카인이 높은 수치로 나타난다.
이에 따라, 미세구체 노출에 따른 뇌 영역 내 유전자 발현 변화를 확인하였다. BALB/c 누드마우스에 PE 미세구체를 4주간 100 ppm/100 μL 경구 투여하고, 4주 후, 마우스를 안락사시키고 마우스의 뇌의 전전두엽 (Prefrontal cortex)과 해마(Hippocampus) 영역을 분리 적출하였다. 각각의 영역에서 전체 RNA 추출 후, Microarray 분석을 수행하였다.
그 결과, 표 1과 같이 PE 미세구체에 노출된 마우스 뇌조직에서 다양한 유전자 발현에 변화가 확인되었다. 표 1을 참고하면, 전전두엽 영역에서 15개의 유전자가 감소하였고, 18개의 유전자가 증가하였으며, 해마 영역에서는 18개의 유전자가 감소하였고, 14개의 유전자 증가가 확인되었다.
전전두엽 (Prefrontal cortex)
Symbol Full name Gene ID FC P-value
Tceanc transcription elongation factor A N-terminal and central domain containing 245695 -1.5 0.002
Mx1 MX dynamin like GTPase 1 17857 -1.56 0.002
Ms4a6d membrane-spanning 4-domains, subfamily A, member 6D 68774 -1.75 0.003
Arc activity regulated cytoskeletal-associated protein 11838 1.98 0.006
Olfr912 olfactory receptor 912 258806 -1.87 0.007
Casc5 kinetochore scaffold 1 76464 1.57 0.008
Egr3 Early growth response 3 13655 1.53 0.009
Gm11565 predicted gene 11565 670550 1.55 0.01
Gabra6 gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6 14399 1.52 0.01
Cdkn1a cyclin-dependent kinase inhibitor 1A (P21) 12575 2.19 0.011
Egr1 early growth response 1 13653 1.84 0.011
Zfp184 zinc finger protein 184 (Kruppel-like) 193452 1.62 0.013
Ms4a14 membrane-spanning 4-domains, subfamily A, member 14 383435 1.53 0.015
Tas2r121 taste receptor, type 2, member 121 387349 1.63 0.016
AB124611 cDNA sequence AB124611 382062 -1.99 0.017
Irs4 insulin receptor substrate 4 16370 1.5 0.019
Fut2 fucosyltransferase 2 14344 1.56 0.021
Gm10754 predicted gene 10754 100038699 -1.79 0.023
Rgs21 regulator of G-protein signalling 21 624910 1.56 0.024
Srsx serine-rich, secreted, X-linked 100151772 1.71 0.025
Rad51b RAD51 paralog B 19363 -1.66 0.026
Nr4a1 nuclear receptor subfamily 4, group A, member 1 15370 1.61 0.029
Olfr1442 olfactory receptor 1442 258692 -1.65 0.031
1700074P13Rik RIKEN cDNA 1700074P13 gene 73481 1.52 0.033
Ctla2a cytotoxic T lymphocyte-associated protein 2 alpha 13024 -1.6 0.034
Ifit3b interferon-induced protein with tetratricopeptide repeats 3B 667370 -2.08 0.039
Gm4924 predicted gene 4924 237412 -1.52 0.039
Vmn2r95 vomeronasal 2, receptor 95 328759 -1.52 0.04
Trpc7 transient receptor potential cation channel, subfamily C, member 7 26946 -1.59 0.041
Smc4 structural maintenance of chromosomes 4 70099 -1.51 0.042
Sult1c1 sulfotransferase family, cytosolic, 1C, member 1 20888 1.53 0.043
Tg thyroglobulin 21819 -1.63 0.046
Dusp1 dual specificity phosphatase 1 19252 1.65 0.048
해마 (Hippocampus)
Symbol Full name Gene ID　 FC P-value
Ptpn20 protein tyrosine phosphatase, non-receptor type 20 19256 1.51 4E-04
Tex14 testis expressed gene 14 83560 -1.56 0.002
Bhlhe23 basic helix-loop-helix family, member e23 140489 -1.58 0.002
Loxl2 lysyl oxidase like 2 94352 -1.51 0.006
Rora RAR-related orphan receptor alpha 19883 1.51 0.007
Nrap nebulin-related anchoring protein 18175 -1.64 0.008
Olfr435 olfactory receptor 435 258647 1.54 0.008
Htr2a 5-hydroxytryptamine (serotonin) receptor 2A 15558 1.53 0.008
Fcer1g Fc receptor, IgE, high affinity I, gamma polypeptide 14127 -1.55 0.014
Ecscr endothelial cell surface expressed chemotaxis and apoptosis regulator 68545 -1.51 0.015
Lrrk2 leucine-rich repeat kinase 2 66725 1.54 0.016
Ddx51 DEAD box helicase 51 69663 1.51 0.017
Olfr1284 olfactory receptor 1284 258379 -1.54 0.019
Stfa2l1 stefin A2 like 1 268885 -1.6 0.022
Parpbp PARP1 binding protein 75317 -1.53 0.022
Drd5 dopamine receptor D5 13492 1.52 0.022
Olfr1352 olfactory receptor 1352 259074 1.71 0.024
Olfr1303 olfactory receptor 1303 258397 1.53 0.024
Eif2ak2 eukaryotic translation initiation factor 2-alpha kinase 2 19106 -1.57 0.024
Eme1 essential meiotic structure-specific endonuclease 1 268465 1.51 0.026
Pcbd1 pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1 13180 -1.51 0.033
Clic1 chloride intracellular channel 1 114584 -1.53 0.038
Itgb1bp1 integrin beta 1 binding protein 1 16413 1.54 0.041
Serpinb3c serine (or cysteine) peptidase inhibitor, clade B, member 3C 381286 -1.66 0.043
BC048671 cDNA sequence BC048671 243535 -1.51 0.044
Zfy2 zinc finger protein 2, Y-linked 22768 1.61 0.047
Gm20865 predicted gene, 20865 100041223 -1.63 0.048
또한, C57BL6 마우스에 직경 10-20 μm 크기의 형광 폴리에틸렌(Polyethylene, PE) 미세구체를 100ppm 농도로 100 μL씩 1주일간 100 ppm/100 μL를 경구 투여하고 1주 후, 마우스를 안락사시켜 마우스의 뇌를 적출하였다. 적출된 뇌 조직에서 전체 RNA를 추출한 후, cDNA를 합성하여 qPCR 분석을 수행하였다.
그 결과, PE 미세구체 노출 이후 대조군 대비 산화스트레스 마커 Egr1은 2.13배(p<0.05), 뉴런의 단백분해과정 및 자폐증관련 유전자인 Arc 1.97배(p<0.05), 염증반응 및 자폐증 관련 유전자인 IL-6 및 IL-1β는 각각 1.85배(p<0.05) 및 2.64배(p<0.01) 증가하였다.
상기 결과로부터 PE 미세구체 노출에 의해 자폐증을 포함한 뇌질환이 유발될 수 있음이 확인되었다.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.

Claims (15)

  1. Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin), Dusp1 (dual specificity phosphatase 1), Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)으로 이루어진 군에서 선택되는 하나 이상의 유전자 또는 상기 유전자가 코딩하는 단백질을 포함하는 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 바이오마커 조성물.
  2. 청구항 1에 있어서, 상기 Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin) 및 Dusp1 (dual specificity phosphatase 1)으로 이루어진 군에서 선택되는 하나 이상의 유전자 또는 상기 유전자가 코딩하는 단백질은 미세플라스틱 노출에 의해 전전두엽 (Prefrontal cortex)에서 발현 수준 변화가 확인되는 것을 특징으로 하는 뇌질환 예후 예측용 바이오마커 조성물.
  3. 청구항 1에 있어서, 상기 Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)로 이루어진 군에서 선택되는 하나 이상의 유전자 또는 상기 유전자가 코딩하는 단백질은 미세플라스틱 노출에 의해 해마 (Hippocampus)에서 발현 수준 변화가 확인되는 것을 특징으로 하는 뇌질환 예후 예측용 바이오마커 조성물.
  4. 청구항 1에 있어서, 상기 미세플라스틱 노출은 경구 노출, 흡입 노출 및 경피 노출로 이루어진 군에서 선택되는 것을 특징으로 하는 뇌질환 예후 예측용 바이오마커 조성물.
  5. 청구항 1에 있어서, 상기 미세플라스틱은 폴리스티렌, 폴리프로필렌, 폴리에틸렌, 폴리아미드(Polyamide, PA), 아크릴로니트릴 부타디엔 스티렌 (Acrylonitrile-butadiene-styrene, ABS), 폴리테트라플루오르에틸렌(Polytetrafluoroethylene, PTFE), 셀룰로오스아세테이트(Cellulose Acetate, CA), 폴리카보네이트(Polycarbonate, PC), 폴리메틸메타크릴레이트(Polymethyl methacrylate, PMMA), 폴리비닐 클로라이드 (Polyvinyl chloride, PVC), 폴리에틸렌 테레프타레이트 (Polyethylene terephthalate, PET), 아크릴 (Acrylic), 멜라민수지 및 폴리우레탄 (polyurethane, PU)로 이루어진 군에서 선택되는 것을 특징으로 하는 뇌질환 예후 예측용 바이오마커 조성물.
  6. 청구항 1에 있어서, 상기 미세플라스틱은 플라스틱에서 용출 및 탈착되는 유해물질을 포함하는 것을 특징으로 하는 뇌질환 예후 예측용 바이오마커 조성물.
  7. 청구항 6에 있어서, 상기 플라스틱에서 용출되는 유해물질은 미네랄오일, 스티렌 다이머, 트리머 과불화화합물, 살균보존제, 폴리올류, 아크릴레이트류, 페놀류, 멜라민 및 니트로사민류로 이루어진 군에서 선택되는 것을 특징으로 하는 뇌질환 예후 예측용 바이오마커 조성물.
  8. 청구항 6에 있어서, 상기 플라스틱에서 탈착되는 유해물질은 중금속류, 살균보존제, 프탈레이트, 비스페놀 A, 과불화화합물, PCBs (Polychlorinated biphenyls), DDTs(, HCH (Hexachlorocyclohexane), 다환방향족탄화수소류 (PAHs), 지방족탄화수소, 노닐페놀, 윤활유, 의약, CBZ(Carbamazepine), 4MBC(4-MethylBenzylidene Camphor), TCS(TriCloSan), EE2(17α-Ethinyl Estradiol), (SDZ(Sulfadiazine), AMX(Amoxicillin), TC(Tetracycline), CIP(Ciprofloxacin) 및 TMP(Trimethoprim)으로 이루어진 군에서 선택되는 것을 특징으로 하는 뇌질환 예후 예측용 바이오마커 조성물.
  9. 청구항 1에 있어서, 상기 미세플라스틱은 플라스틱에 첨가되는 가소제, 난연제, 안정제·산화방지제·UV안정제, 열안정제, 슬립제, 윤활유, 정전기 방지제, 경화제, 발포제, 살생물제, 수용성 착색제, 유기 안료, 무기 안료, 특수 효과 착색제, 충전제 및 증강제로 이루어진 첨가물군에서 하나 또는 둘 이상을 포함하는 것을 특징으로 하는 뇌질환 예후 예측용 바이오마커 조성물.
  10. 청구항 1에 있어서, 상기 뇌질환은 조현병 (schizophrenia), 전두엽 간질(Forntal lobe epilepsy), 자폐증(autism) 및 주의력결핍 과잉행동장애 (ADHD, attention deficit hyperactivity disorder)로 이루어진 군에서 선택되는 것을 특징으로 하는 뇌질환 예후 예측용 바이오마커 조성물.
  11. Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin), Dusp1 (dual specificity phosphatase 1), Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)으로 이루어진 군에서 선택되는 하나 이상의 유전자에 특이적으로 결합하는 프로브, 상기 유전자를 증폭하기 위한 프라이머, 상기 유전자가 코딩하는 단백질에 특이적으로 결합하는 항체 또는 상기 단백질에 특이적인 결합 도메인을 갖는 펩티드를 포함하는 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측용 키트.
  12. 청구항 11에 있어서, 상기 키트는 RT-PCR 키트, DNA 칩 키트 또는 단백질 칩 키트인 것을 특징으로 하는 뇌질환 예후 예측용 키트.
  13. 개체로부터 분리된 생물학적 시료로부터 Tceanc (transcription elongation factor A N-terminal and central domain containing), Mx1 (MX dynamin like GTPase 1), Ms4a6d (membrane-spanning 4-domains, subfamily A, member 6D), Arc (activity regulated cytoskeletal-associated protein), Olfr912 (olfactory receptor 912), Casc5 (kinetochore scaffold 1), Egr3 (Early growth response 3), Gm11565 (predicted gene 11565), Gabra6 (gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6), Cdkn1a (cyclin-dependent kinase inhibitor 1A (P21)), Egr1 (early growth response 1), Zfp184 (zinc finger protein 184 (Kruppel-like)), Ms4a14 (membrane-spanning 4-domains, subfamily A, member 14), Tas2r121 (taste receptor, type 2, member 121), AB124611 (cDNA sequence AB124611), Irs4 (insulin receptor substrate 4), Fut2 (fucosyltransferase 2), Gm10754 (predicted gene 10754), Rgs21 (regulator of G-protein signalling 21), Srsx (serine-rich, secreted, X-linked), Rad51b (RAD51 paralog B), Nr4a1 (nuclear receptor subfamily 4, group A, member 1), Olfr1442 (olfactory receptor 1442), 1700074P13Rik (RIKEN cDNA 1700074P13 gene), Ctla2a (cytotoxic T lymphocyte-associated protein 2 alpha), Ifit3b (interferon-induced protein with tetratricopeptide repeats 3B), Gm4924 (predicted gene 4924), Vmn2r95 (vomeronasal 2, receptor 95), Trpc7 (transient receptor potential cation channel, subfamily C, member 7), Smc4 (structural maintenance of chromosomes 4), Sult1c1 (sulfotransferase family, cytosolic, 1C, member 1), Tg (thyroglobulin), Dusp1 (dual specificity phosphatase 1), Ptpn20 (protein tyrosine phosphatase, non-receptor type 20), Tex14 (testis expressed gene 14), Bhlhe23 (basic helix-loop-helix family, member e23), Loxl2 (lysyl oxidase like 2), Rora (RAR-related orphan receptor alpha), Nrap (nebulin-related anchoring protein), Olfr435 (olfactory receptor 435), Htr2a (5-hydroxytryptamine (serotonin) receptor 2A), Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide), Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator), Lrrk2 (leucine-rich repeat kinase 2), Ddx51 (DEAD box helicase 51), Olfr1284 (olfactory receptor 1284), Stfa2l1 (stefin A2 like 1), Parpbp (PARP1 binding protein), Drd5 (dopamine receptor D5), Olfr1352 (olfactory receptor 1352), Olfr1303 (olfactory receptor 1303), Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2), Eme1 (essential meiotic structure-specific endonuclease 1), Pcbd1 (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 1), Clic1 (chloride intracellular channel 1), Itgb1bp1 (integrin beta 1 binding protein 1), Serpinb3c (serine (or cysteine) peptidase inhibitor, clade B, member 3C), BC048671 (cDNA sequence BC048671), Zfy2 (zinc finger protein 2, Y-linked) 및 Gm20865 (predicted gene, 20865)으로 이루어진 군에서 선택되는 하나 이상의 유전자의 mRNA 발현 수준 또는 상기 유전자가 코딩하는 단백질의 발현 수준을 측정하는 단계; 및
    상기 유전자의 mRNA 발현 수준 또는 상기 유전자가 코딩하는 단백질의 발현 수준을 대조군과 비교하는 단계를 포함하는 미세플라스틱 노출에 의해 유도되는 뇌질환 예후 예측 방법.
  14. 청구항 13에 있어서, 상기 mRNA 발현 수준을 측정하는 방법은 RT-PCR, 경쟁적 RT-PCR(Competitive RT-PCR), 실시간 RT-PCR (Real-time RT-PCR), RNase 보호 분석법 (RPA; RNase protection assay), 노던 블랏팅 (Northern blotting) 및 DNA 칩으로 이루어진 군에서 선택된 어느 하나를 이용하는 것을 특징으로 하는 뇌질환 예후 예측 방법.
  15. 청구항 13에 있어서, 상기 단백질 발현 수준을 측정하는 단계는 웨스턴 블랏, ELISA(enzyme linked immunosorbent asay), 방사선면역분석(Radioimmunoassay; RIA), 방사면역확산법(radioimmunodiffusion), 오우크테로니(Ouchterlony) 면역 확산법, 로케이트(rocket) 면역전기영동, 조직면역염색, 면역침전 분석법 (Immunoprecipitation assay), 보체고정분석법 (Complement Fixation Assay), FACS및 단백질 칩으로 이루어진 군에서 선택된 어느 하나를 이용하는 것을 특징으로 하는 뇌질환 예후 예측 방법.
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