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1 종설 환경호르몬과신경계질환 양은영이동국 a 양재호 b 헤세드심리상담센터, 대구가톨릭대학교의과대학신경과학교실 a, 약리학교실 b Environmental Endocrine Disruptors and Neurological Disorders Eun Young Yang, MA, Dong Kuk Lee, MD a, Jae Ho Yang, PhD b Hesed Research Institute of Clinical Psychology, Seoul, Korea Departments of Neurology a and Pharmacology b, Catholic University of Daegu School of Medicine, Daegu, Korea We live in a world where daily exposure to environmental chemicals is inevitable. Many studies point to environmental chemicals a major cause of neurological diseases. Properly intervening in and managing the exposure requires up-to-date information about neurotoxic chemicals that may lead to neurological disorders. The recent literature on the neurotoxic effects of environmental chemicals was reviewed, including both animal and human studies. Parkinson s disease, Alzheimer s disease and autism are closely associated with environmental chemicals such as polychlorinated biphenys (PCBs), dioxins, polybrominated biphenyl ethers (PBDE), and perfluoroalkyls. There is strong evidence linking environmental chemical exposure to neurodevelopmental and neurodegenerative diseases. In particular, it is important to pay close attention to a high risk-age group where the window of exposure is critical to causing neurological disease. J Korean Neurol Assoc 36(3): , 2018 Key Words: Alzheimer disease, Parkinson disease, Neurotoxic chemicals, Endocrine disruptors 서 론 현대인은화학물질의홍수속에서생활한다해도지나친표현이아니다. 환경오염물질은남녀노소를가리지않고노출될수있기때문에특히취약인구집단에대한위해성은훨씬심각할수있다. 환경오염물질이암을비롯한여러가지급ㆍ만성질환을일으키고있음은이미잘알려진사실이다. 그러나최근들어환경오염물질과신경계질환의관련성이지속적으로입증되고있어이에대한관심이증가하고있다. 지난 30년간환경오염물질의생산량과신경계질환유병률은비례적으로증가하고있으며이러한추세는환경오염과관련성이높을것으로판단된다. 1,2 따라서신경계질환을일으키는물질의확인과정보의확산은노출억제를통한신경계질 Received February 12, 2018 Revised April 27, 2018 Accepted April 27, 2018 Address for correspondence: Jae Ho Yang, PhD Department of Pharmacology, Catholic University of Daegu School of Medicine, 33 Duryugongwon-ro 17-gil, Namgu, Daegu 42472, Korea Tel: Fax: yangjh@cu.ac.kr 환의예방및대책마련에매우중요하다. 알츠하이머병, 파킨슨병, 치매, 과다행동장애등과관련성이알려진화학물질은메칠수은, 유기인제제농약, 다이옥신 (dioxin)/polychlorinated biphenyl (PCB), 납, 자동차매연, 미세먼지등매우다양하다. 본연구에서는다이옥신 /PCB를포함하는기존환경호르몬과새롭게부상하는신종환경호르몬을중심으로신경계질환과의관련성을분석하고자한다 (Table). 환경호르몬 은학술적으로환경에서검출되는내분비장애물질 (endocrine disruptor) 을의미하며잘분해되지않고지속적으로존재하는화학적특징때문에잔류성유기오염물질 (persistent organic pollutants, POPs) 에대부분포함된다. 환경호르몬 은관련학계에서통용되는전문용어는아니지만일반인및비전문가집단에게잘알려진용어임으로본연구에서는 내분비장애물질 이라는용어대신 환경호르몬 을사용하고자한다. 대표적인환경호르몬은다이옥신을비롯하여 PCB, bisphenol A, phthalate와같은기존환경호르몬과과불화화합물 (perfluorinated compounds), 브롬화난연제 (brominated flame retardants) 와같은신종환경호르몬으로크게나눌수있으며, 우리주변에서흔히노출될수있는화학물 J Korean Neurol Assoc Volume 36 No. 3,

2 양은영이동국양재호 질의대부분을차지하고있다. 신경계질환과관련되어있는환경호르몬의종류와특성등을파악하는것은이들물질의노출을최소화하여질병을관리할수있는출발점이될수있다. 이에본연구는신경정신질환과밀접한관계를가지고있는환경호르몬의최신정보를제공함으로써이에대한예방및대책확립에요구되는자료를제공하고자한다. 본론 1. 환경호르몬과신경전달물질 인체및동물실험연구에서환경호르몬의노출과신경계질환사이에유의한연관성이있다는증거들이많이보고되고있다. 3-5 하지만어떤신경조직의손상이이러한질병과관련이있는지는명확하지않다. 환경호르몬의화학구조적특성, 환자의나이, 성별등에따라반응이달라질수있기때문에이들오염물질의표적을확인하기는매우어렵다. 하지만지금까지연구결과가장설득력이있는생물표지자 (biomarker) 는수용체, 신경전달물질, 칼슘항상성, 산화성스트레스등을포함하는신경전달물질의신호전달작용과정이다. 6 PCB를비롯한환경호르몬은도파민, 세로토닌, 아세틸콜린등신경전달물질의변화를일으킨다. 이러한변화는그하단작용단계인세포내신호전달체계의변화와밀접한관계를가지고있는데, 세포내칼슘버퍼링, 아라키돈산 (arachidonic acid) 의유리, 시냅토솜 (synaptosome) 의칼슘흡수, protein kinase C (PKC) 의활성, ryanodine 및이노시톨트리인산 (inositol triphosphate, IP 3) 수용체결합, neural nitric oxide synthase (nnos), enos (endothelial nitric oxide synthase) 활성등을대표적으로들수있다. 7,8 다이옥신유사화합물에의한뇌도파민용량의변화는화합물의구조와밀접한 관계를가지고있다. 9 즉다이옥신수용체와결합하는다이옥신유사 (dioxin-like) 구조를가진화합물의경우도파민의용량및활성을억제하는반면비다이옥신유사 (non-dioxin-like) 구조를가진물질은변화를나타내지않는다. 따라서구조의특성에따라신경독성은크게달라질수있다. PCB에의한신경행동장애등은해마 (hippocampus) 의니코틴수용체감소및무수카린수용체의증가에의한것으로알려져있다. 10 또한글루탐산염 (glutamate) 및감마아미노부티르산 (gamma-aminobutyric acid, GABA) 의재흡수억제에도관여하여시냅스의신경전달물질상승에의한신경독성을일으키기도한다. 11 PCB 등은신경세포에서활성산소를생성하고후차적으로제2형신호전달물질인 PKC를활성화하는데 PKC는신경세포의사멸에중요한역할을한다. 12 그밖에도산화질소합성효소 (nitric oxide synthase, NOS) 의활성에의한장기강화작용 (long-term potentiation, LTP) 의생성변화, 칼슘항상성의변화, N-Methyl-D-Aspartate (NMDA) 수용체, 글루탐산염수용체의변화등일련의신경전달물질생성체계의변화에직간접적인영향을주고있다. 9 따라서신경세포의신경전달물질생성및작용단계는환경호르몬에의한신경계질환의생물표지자로활용가능성이있으며민감한생물표지자의개발은질병의조기발견및진행을조절하는데적용될수있다. 2. 환경호르몬의작용기전환경호르몬의작용기전은화학구조에따라매우다양하지만지용성이라는특성과신호전달체계의교란이라는공통된점이있다. 본연구에서는가장대표적인환경호르몬인다이옥신과 PCB를중심으로기술하고자한다. 다이옥신및 PCB의독성기전은방향족탄화수소수용체 (arylhydrocarbon receptor, AhR) 를매개체로하 Table. Neurological disorders associated with endocrine disruptors PCBs PBDEs Dioxins PFCs Motor deficits Established relationship Established relationship Established relationship Established relationship Sensory deficits Established relationship Established relationship Established relationship Peripheral NS effects Established relationship Established relationship Autism Established relationship Established relationship Suspected relationship ADHD Established relationship Established relationship Established relationship Established relationship Alzheimer s disease Suspected relationship Established relationship Parkinson s disease Established relationship Suspected relationship Established relationship Suspected relationship ALS Suspected relationship PCBs; polychlorinated biphenyls, PBDEs; polybrominated biphenyl ethers, PFCs; perfluoroalkyl compounds, NS; neurological symptom, ADHD; attention deficit hyperactive disorder, ALS; amyotrophic lateral sclerosis. 140 대한신경과학회지제 36 권제 3 호, 2018

3 환경호르몬과신경계질환 여독성을나타내는공통점이있다. 지용성인다이옥신이세포막으로들어가면세포기질 (cytosol) 내에있는 AhR과결합한후 AhR nuclear translocator (ARNT) 에의해핵내로이동한다. 이후핵의다이옥신반응요소 (dioxin responsive element, DRE) 와결합하여시토크롬 P450와같은효소의전사를가져오며이러한효소의활성이다이옥신의독성을일으키는시발점을제공한다. 13 하지만최근들어 AhR경로를거치지않는물질들이새롭게밝혀지면서다이옥신계열의물질은 AhR-의존적물질과 AhR-비의존적물질로분류하고있다. 특히최근알려진신경독성의경우 AhR 비의존적인통로로독성작용이일어나고있는것으로파악된다. PCB 의경우 209가지이성질체가있는데이들중신경독성을나타내는구조는다이옥신과유사한구조가아닌비공면 (non-coplanar) 구조로서 AhR과결합하지않는것으로알려져있다. 14 비공면구조를가진 PCB는세포표면에있는수용체와결합하여세포막의인지질분해효소 (phospholipase C, phospholipase A 2, phospholipase D) 를활성화시켜 arachidonic acid, IP 3 등의유리를촉진하고후차적으로칼슘의세포내농도를증가시켜 PKC 등의인산화효소를활성화시킨다. 세포내벽으로이동하여활성화된 PKC는연속적인인산화과정을통하여핵의전사를일으키고궁극적으로단백질체의활성변화를가져온다. 15 PKC는뉴런세포의발달및사멸에중요한신호전달물질로서 PCB가신경독성을일으키는표적물질중하나이다. 12 그밖에도많은환경호르몬이활성산소를증가시키는작용을가지고있는데뇌미토콘드리아의활성산소증가는신경퇴행질환과밀접한관계가있다. 16 특히뉴런처럼생의주기가길고분화하지않는세포의경우활성산소의증가나항산화효소의감소등에따른산화-환원체계의불균형은뉴런세포의사멸에영향을주어알츠하이머병, 파킨슨병, 헌팅톤병을일으키는것으로보고되고있다 다이옥신과 PCB 다이옥신과 PCB는우리주변에널리퍼져있고먹이사슬을통해체내에축적되어인체의위해성이우려되는대표적인환경호르몬이다. 17 다이옥신은 75가지이성질체 (isomer) 를가지고있으며이와유사한벤조퓨란은 135가지, PCB는 209가지의이성질체를가지고있다. 이물질들의작용기전은구조에따라서성장기초기에신경전달물질의변화와같은신경내분비계장애를유발하여신경계독성을일으키는특성을가지고있다. 다이옥신및이와유사한구조를가진화합물들은인체의모유에서다량발견되며젖먹이아기의경우성인의 50배정도더노출될수있어서신생아가 다이옥신노출의특수위해성집단임을 WHO가보고한바있다. 18 역학조사결과임신중노출된태아의경우성장과정에서청각장애, 기억및학습의장애, 운동신경장애등을일으키는것으로보고된바있으며특히신경세포의성장및발달이활발한시기의노출은더욱심각한영향을줄수있다. 19 최근국내 4개대도시의산모를대상으로한조사에서 PCB의농도가높은산모일수록아이들의행동장애가높다고보고된바있다. 20 PCB의경우화학구조특성에따라 AhR 수용체와반응하는공면 (coplanar) PCB와 AhR 수용체와친화성이없는비공면 (non-coplanar) PCB로분류하는데, 공면 PCB는다이옥신과구조가유사하여다이옥신과유사한독작용을가진것으로분류되는반면비공면 PCB의경우에는뚜렷한작용기전이나심각한독성이발견되지않아위해성평가에누락되는경우가많다. 17 그러나신경독성의경우비공면 PCB가신경세포및신경조직의발달에미치는영향이공면 PCB보다훨씬더높은것으로알려져있다. 공면과비공면구조를모두가진 Aroclor1254 라는 PCB 혼합물을투여할경우뇌에축적되는대부분의형태는비공면형태의 PCB인것으로알려져있다. 21 PCB와벤조퓨란등다이옥신유사물질에오염된식용유를많은사람들이섭취하는사고가일본과대만에서일어났다. 오염된기름을섭취한사람은신경전도속도 (nerve conduction velocity) 저하, 무감각증, 사지근육위축등이나타났으며, 특히아이의경우운동신경발달저하, 기억및학습력저하, IQ 저하등이보고된바있다 미국미시간주와노스캐롤라이나주의연구에서는 PCB 에오염된생선을섭취한산모의경우그자녀들의행동장애가높은것으로나타났다. 25 PCB노출과주의력결핍과다활동장애 (attention deficit hyperactive disorder, ADHD) 유병률과의상관성은이미많은연구에서보고되고있으며, 동물실험을통해서도유의성이검증되고있다. 26 자폐증 (autism spectrum disorder, ASD) 과환경호르몬의상관성은많은연구가있으나연구방법등의한계등으로연구에따라서로상반된결과를가지는경우도많다. 27 하지만최근실시된역학조사에따르면임신기간높은농도의 PCB에노출된산모의경우자녀들의 ASD 발병률이유의하게높게나타났다. 이연구는직접산모의혈청을측정하고샘플사이즈도가장커서지금까지의어떤연구결과보다신뢰성이높은결과이다. 근위축측삭경화증 (amyotrophic lateral sclerosis, ALS) 은신경퇴행질환으로원인이정확히밝혀지지않은희귀질환이다. 일명 루게릭병 으로알려진이질병은 TAR DNA-binding protein (TDP)-43이라는단백질체의축적과이에따른운동신경세포의손실이병리적인원인으로지목되고있다. 산발 ALS의 95% 는이 J Korean Neurol Assoc Volume 36 No. 3,

4 양은영이동국양재호 단백질체의축적과직접적인관계가있다. 다이옥신과 PCB 등은인체세포모델에서 AhR 수용체를매개로 TDP-43을 3배이상증가시키는것이최근확인되어다이옥신과같은환경호르몬이 ALS의발병에중요한역할을할것으로보고된바있다. 28,29 또한뇌의 PCB 총량이높을수록파킨슨병관련증상이증가하는것으로알려져있다. 수녀집단의시료를분석한결과파킨슨병의시작을의미하는흑질탈색 (nigral depigmentation) 뇌조직에서매우높은수준의 PCB가검출되었으며이러한환경오염물질유발신경계질환에는여성이더욱취약한것으로보고되었다 브롬화난연제 (brominated flame retardants, BFR) 다이옥신이나 PCB와는달리브롬화난연제의독성은잘알려져있지않으나최근이에대한연구가활발하게일어나고있다. 브롬화난연제의주성분인 polybrominated diphenyl ether (PBDE) 는전자제품, 플라스틱제품, 건축자재등우리생활과밀접한분야에서난연제 (flame retardant) 로널리쓰이고있는환경호르몬이다. PBDE는제품의외부에도포되어가연성을줄여주는역할을하기때문에시간이지날수록표면에서분리되어환경중에노출된다. TV와같은가전제품이나카펫과같은실내용품은 PBDE의실내공기오염을증가시키는주요오염원이다. PBDE 는전세계적으로연간 4만톤이생산되고있으며지용성인동시에환경중잔류성이높아먹이사슬을통한인체내축적이일어남으로인체의혈액, 모유, 지질층에서지난 20-30년간꾸준히증가하고있다. PBDE는수년이내에 DDT나 PCB를추월하는주요환경오염물질이될것으로예상된다. 19 PBDE는잠복고환, 성호르몬의감소, 정자활동감소, 갑상선호르몬변화등내분비계장애를일으키는것으로만알려져왔으나, 최근들어신경독성에대한보고가증가하고있다. 동물실험등을통하여 PBDE는신경전달물질합성의변화, 행동발달장애뿐만아니라인식장애, 기억장애등지적발달에도영향을주며이러한독성은태아나영유아기의노출과관련성이높은것으로알려져있다. 31 최근조사에의하면미국의경우어린이 6명중 1명이신경발달장애를앓고있으며장애를앓고있는아이모두에서 PBDE가검출되었다. 특히임신중또는영유아기에노출시운동신경세포의손상, 신경발달장애, IQ수치저하등이나타나며 PBDE의이성질체인 hexabromocyclododecane (HBCDD) 는도파민항상성유지에핵심인 dopamine transporter 및 vesicular monoamine transporter 2의작용을억제하는것으로알려져있다. 32,33 임신중 PBDE의노출은출생자녀의자폐증증가의원인으로도지목되고있으며 PBDE에의한미토콘드리아산화-환원체계 의손상이자폐증을일으키는기전으로추정되고있다. 16,34 PBDE 는비공면 PCB와구조적인유사성을가지고있으며 AhR 수용체와친화력이없거나매우낮아작용기전의유사성도가지고있다. 6 PBDE의연구자료는 PCB보다상대적으로적지만구조의유사성등으로비공면 PCB와비슷한독성을가진것으로추정된다. 따라서 PBDE에대한구체적인연구자료가미흡한부분에서는비공면 PCB의신경독성에준하여독성을추정하고관리대책을마련할필요가있다. PBDE는기존에알려진환경호르몬인다이옥신이나 PCB에비해이들의위해성이최근발견되어환경독성물질의사용을규제하는국제기구인스톡홀름회의 (stockholm convention) 에서는 PBDE를신종환경호르몬 (emerging endocrine disruptors) 으로분류하고새롭게규제목록에추가하였다 과불화화합물 (perfluoroalkyl compounds, PFC) 과불화화합물 (PFC) 은자연환경에서는발생하지않는합성수지이다. PFC는불소수지고분자화합물을생산하는데필수적인물질로서거의모든산업현장에서활용된다고해도과언은아니다. PFC에의해생성된불소고분자화합물은우리생활주변에서사용용도가너무다양하여이것이사용되지않는물질을가려내기가쉽지않을정도이다. 특히 PFC의한이성질체인 perfluooctanoic acid (PFOA) 는달라붙지않는프라이팬의원료인테플론 (teflon) 을만드는과정에필수재료로사용되며, 카펫, 의류등의방수효과를나타내는데도활용된다. 냉장고의냉매, 표면마감재, 화장품, 샴푸, 주방재료등이관련제품이다. PFOA를사용하거나방출할수있는산업도매우다양해서자동차, 기계, 화학, 전자, 반도체, 의약, 건설자재등은그일부에속한다. 36 PFOA는발암성이외에면역계장기인흉선및비장의정상적인작용을억제해면역계기능의교란을가져온다. 또한지용성이높아태반을쉽게통과함으로기형을유발할수있고, 혈액뇌장벽 (blood brain barrier) 을통과하여뇌에쉽게축적되어갑상선호르몬과같은신경계호르몬의변화를일으킨다. 뇌의발달이왕성한시기인태아나영유아기의갑상선호르몬변화는정상적인두뇌발달에심각한영향을미쳐기억력감퇴, 학습장애등과같은신경독성을나타낼수있다. 1 특히두뇌의발달에필수적인갑상선호르몬의장애등은 PFC가신경독성물질임을증명하는좋은근거이다. 37 PCB만큼자료가축적되어있지않지만 PFC도신경계에서는 PCB와유사한패턴의독성작용을일으키는것이동물실험으로확인되어있다. PFC는갑상선호르몬뿐만아니라세포내칼슘의항상성, PKC와같은신호전달체계및시냅스유연성등에영향을 142 대한신경과학회지제 36 권제 3 호, 2018

5 환경호르몬과신경계질환 주어신경독성을나타내는것으로알려져있다. 최근국내연구진에서도우리몸에서검출되는대표적인 PFC 이성질체인 perfluorooctane sulfonic acid (PFOS), PFOA, perfluorohexane sulfonate (PFHxS) 등이뉴런세포의사멸을촉진하고 PKC와같은중요신호전달체계를저해함을확인하여 PFC가중요한신경독성을가진환경오염물질임을입증한바있다. 38,39 실험동물의신경독성결과와함께 PFC의인체신경계질환관련성연구사례또한크게증가하고있다. 최근증가하고있는어린이의행동장애질환의높은유병률은 PFC의노출과관련성이높은것으로평가되고있다. 태아상태에서 PFC에노출될경우아이가 18개월이되는시점에서행동이상반응을나타낸다는보고가있으며, PFC의혈중농도가높을수록주의력결핍과다활동장애 (ADHD) 또는외현화행동문제 (externalizing behavior problem) 를일으키는것으로보고된바있다. 40 그밖에 PFHxS 또는 perfluorononanoic acid (PFNA) 가행동장애와관련성이있다는보고도있다. 그러나이러한보고는연구대상이나방식에따라서로상반된결과를나타내는경우도있어더많은연구가필요하다. PBDE와마찬가지로 PFC도새롭게부상하는환경호르몬으로분류되어스톡홀름회의에서신종환경호르몬으로규제목록에포함되었다. 41 결론 산업의발달과함께환경오염은점점심각해지고있으며현대인은주변에서쉽게환경오염물질에노출되고있다. 세계보건기구 (WHO, 2016) 에따르면전세계질환의 24% 는환경오염노출에의해일어나며특히 5세미만의어린이질환의 33% 는환경오염에기인하기때문에위해요소의노출을줄이는것만으로도연간 4백만명의생명을구할수있다고보고한바있다. 42 전세계적으로증가추세에있는신경계질환의원인으로최근환경오염물질을지목하고있다. 대부분의경우환경독성물질의노출에가장민감하게반응하는장기 (organ) 는신경계이다. 특히신경독성의경우뇌가폭발적으로발달하는시기인 brain growth spurt 기간동안에노출될시그영향은노출시점뿐만아니라성체가된이후에도각종신경계질환을나타내는것으로알려져있다. 앞서언급한대표적인환경호르몬들역시노출시기 (window of exposure) 가매우중요한신경독성물질이다. 2 따라서신경독성물질노출의고위험군에대한보다연령특이적인노출한계를정하는등적극적인노출회피노력이필요하다. 인체를대상으로한역학조사는유전적요인, 식생활습관등많은혼란변수 (confounding variables) 때문에연구결과에대한한계가있고결과또한연구대상과연구자 에따라서로상반된경우가있는것도사실이다. 그러나최근연구결과의경향은역학조사가가지고있는이러한한계점을고려하더라도환경호르몬과신경계질환의인과관계가지속적으로명확해지고있는추세이다. 신경계질환은유전적인요소를포함한다양한내재적인원인이발병원인일수있다. 이러한내재적인요소의발견과치료는매우힘든반면, 외부적인발병요소인환경오염물질의노출에의한발병은노출원을확인하고제거함으로써질병을예방하고관리할수있다. 그러므로본연구는신경계질환의원인분석에환경호르몬의중요성을각인시키고환경오염물질에의한신경계질환의예방및관리에요구되는기본정보를제공하고자하였다. REFERENCES 1. Berghuis SA, Bos AF, Sauer PJ, Roze E. Developmental neurotoxicity of persistent organic pollutants: an update on childhood outcome. Arch Toxicol 2015;89: Heyer DB, Meredith RM. Environmental toxicology: sensitive periods of development and neurodevelopmental disorders. Neurotoxicology 2017;58: Jurewicz J, Polanska K, Hanke W. Exposure to widespread environmental toxicants and children s cognitive development and behavioral problems. Int J Occup Med Environ Health 2013;26: Caudle WM, Guillot TS, Laxo C, Miller GW. Parkinson s disease and the environment: beyond pesticides. Neurotoxicology 2012;33: Polanska K, Jurewicz J, Hanke W. Review of current evidence on the impact of pesticides, polychlorinated biphenyls and selected metals on attention deficit / hyperactivity disorder in children. Int J Occupat Med Environ Health 2013;26: Kodavanti PRS. Neurotoxicity of persistent organic pollutants: possible mode(s) of action and further considerations. Dose-Response 2006;3: Fonnum F, Mariussen E. Mechanisms involved in the neurotoxic effects of environmental toxicants such as polychlorinated biphenyls and brominated flame retardants. J Neurochem 2009;111: Inglefield JR, Mundy WR, Shafer TJ. Inositol 2,4,5-triphosphate receptor-sensitive Ca 2+ release, store-operated Ca 2+ entry, and camp responsive element binding protein phosphorylation in developing cortical cells following exposure to polychlorinated biphenyls. J Pharmacol Exp Ther 2001;297: Kodavanti PR, Tilson HA. Structure-activity relationships of potentially neurotoxic PCB congeners in the rat. Neurotoxicology 1997;18: Provost TL, Juarez de Ku LM, Zender C, Meserve LA. Dose- and age-dependent alterations in choline acetyltransferase (ChAT) activity, learning and memory, and thyroid hormones in 15- and 30-day old rats exposed to 1.25 or 12.5 ppm polychlorinated biphenyl (PCB) beginning at conception. Prog Neuropsychopharmacol Biol Psychiatry 1999;23: Mariussen E, Fonnum F. The effect of polychlorinated biphenyls on the high affinity uptake of the neurotransmitters, dopamine, serotonin, glutamate and GABA, into rat brain synaptosomes. Toxicology J Korean Neurol Assoc Volume 36 No. 3,

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