Zespół alkoholowy płodu – Patofizjologia i mechanizm

Zespół alkoholowy płodu
Patofizjologia i mechanizm

Zespół alkoholowy płodu (FAS) jest ciężkim zespołem wad wrodzonych wynikającym z prenatalnej ekspozycji na alkohol, który działa jako silny teratogen. Alkohol przenika swobodnie przez łożysko, osiągając u płodu stężenia równoważne z matczynymi, a jego metabolizm u płodu jest znacznie ograniczony (aktywność dehydrogenazy alkoholowej poniżej 10% w porównaniu do dorosłych). Ekspozycja na alkohol prowadzi do stresu oksydacyjnego, zwiększonej produkcji reaktywnych form tlenu (ROS), uszkodzenia DNA i apoptozy neuronów, szczególnie w okresie synaptogenezy, gdy poziom alkoholu we krwi przekracza 0,2% (200 mg/dl) przez co najmniej 4 godziny. Alkohol zaburza proliferację, migrację i różnicowanie komórek nerwowych, wpływa na rozwój oligodendrocytów, a także modyfikuje szlaki sygnalizacyjne (m.in. Sonic Hedgehog, kwasu retinowego) oraz epigenetyczne mechanizmy metylacji DNA, co prowadzi do trwałych deficytów neurobehawioralnych i strukturalnych uszkodzeń mózgu, takich jak mikroencefalia, zmniejszona objętość mózgu, nieprawidłowości ciała modzelowatego i móżdżku. Ponadto, alkohol powoduje zaburzenia hormonalne (HPA, hormony tarczycy, IGF-1), niedobory składników odżywczych i przewlekłe niedotlenienie płodu, co dodatkowo pogłębia patologię.

Wprowadzenie do Zespołu Alkoholowego Płodu

Zespół alkoholowy płodu (FAS – Fetal Alcohol Syndrome) stanowi jeden z pięciu zaburzeń wchodzących w skład spektrum alkoholowych zaburzeń płodu (FASD – Fetal Alcohol Spectrum Disorders). FAS jest ciężkim zespołem wad wrodzonych spowodowanym ekspozycją płodu na alkohol w życiu prenatalnym.¹ Alkohol jest silnym teratogenem, który powoduje nieodwracalne uszkodzenia o szerokim zakresie działania.¹² Szczególnie istotne jest to, że żadna ilość alkoholu spożyta w jakimkolwiek momencie ciąży nie jest bezpieczna i może spowodować nieodwracalne uszkodzenia prowadzące do rozwoju zaburzeń ze spektrum FASD.¹³

Patomechanizm transportu i metabolizmu alkoholu u płodu

Alkohol swobodnie przenika przez łożysko i szybko dociera do płodu. Liczne badania wykazały równoważne stężenia alkoholu u płodu i matki, co sugeruje niezakłócony dwukierunkowy przepływ alkoholu między tymi dwoma przedziałami.⁴ Płyn owodniowy działa jak rezerwuar dla alkoholu, przedłużając ekspozycję płodu.⁴⁵ Jest to szczególnie niebezpieczne, ponieważ płód nie posiada zdolności do efektywnego metabolizowania alkoholu:

Aktywność dehydrogenazy alkoholowej (ADH) w wątrobie płodu wynosi mniej niż 10% aktywności obserwowanej w wątrobie osoby dorosłej⁴
Płód jest zależny od detoksykacji wątrobowej matki⁴⁵
Alkohol jest usuwany z płynu owodniowego znacznie wolniej niż matka eliminuje go ze swojego organizmu, co prowadzi do jego akumulacji⁶

Po spożyciu alkoholu przez ciężarną kobietę, alkohol przedostaje się przez łożysko i pępowinę do rozwijającego się płodu. Alkohol metabolizuje się powoli u płodu i pozostaje przez długi czas w porównaniu z osobą dorosłą.³ Płód ludzki wydaje się być narażony na potrójne ryzyko wynikające z matczynego spożywania alkoholu: łożysko pozwala na swobodne wnikanie etanolu i toksycznych metabolitów jak aldehyd octowy do przedziału płodowego; rozwijający się płodowy układ nerwowy wydaje się szczególnie wrażliwy na toksyczność etanolu; ten ostatni zaburza proliferację, różnicowanie, migrację neuronalną, wzrost aksonalny, integrację i dostrajanie sieci synaptycznej.³

Główne mechanizmy uszkodzenia płodu przez alkohol

Stres oksydacyjny i produkcja wolnych rodników

Jednym z głównych mechanizmów patogenetycznych w FAS jest stres oksydacyjny wywołany przez alkohol.⁷⁸ Zarówno etanol, jak i jego metabolit aldehyd octowy są bezpośrednio toksyczne, jednak zgodnie z aktualną wiedzą, stres oksydacyjny stanowi główną ścieżkę uszkodzenia.⁸ Spożycie alkoholu prowadzi do:

Zwiększonej produkcji reaktywnych form tlenu (ROS)⁷
Zwiększonego stresu oksydacyjnego poprzez wzrost produkcji dinukleotydu nikotynamidoadeninowego (NADH)⁹
Uszkodzenia DNA, co aktywuje szlaki apoptozy prowadzące do neurodegeneracji⁸
Zmniejszenia aktywności naturalnych mechanizmów antyoksydacyjnych u płodu⁸⁹

Rozwijający się mózg jest szczególnie podatny na uszkodzenia z powodu podwyższonego poziomu ROS.¹⁰ Narażenie na etanol prowadzi do zwiększonej produkcji ROS w embrionie, co powoduje stres oksydacyjny, a w konsekwencji przyczynia się do rozwoju FASD.⁷ Uszkodzenie wywołane przez kaskadę stresu oksydacyjnego stanowi główną patogenezę procesu uszkodzenia oksydacyjnego indukowanego przez ROS, prowadzącego do FASD.¹¹

Neurozapalenie i apoptoza

Alkohol prowadzi do nadmiernej śmierci komórek i upośledzenia rozwoju prawidłowych sieci neuronalnych.¹¹ Główny mechanizm FASD jest ściśle związany z indukowanym przez alkohol neurozapaleniem i stresem oksydacyjnym, które potencjalnie prowadzą do apoptozy komórek nerwowych w rozwijającym się mózgu płodu, utrudniając tym samym rozwój mózgu zarodkowego.⁷ Proces ten obejmuje:

Aktywację kaskady kaspaz, która prowadzi do apoptozy komórek grzebienia nerwowego czaszki (CNCC)¹²
Hamowanie proliferacji komórek grzebienia nerwowego czaszki i zwiększenie ich apoptozy¹³
Nadmierną apoptozę w wyniku działania etanolu jako antagonisty receptorów NMDA glutaminianu¹⁴
Uwalnianie neurotoksycznych cytokin, w tym czynnika martwicy nowotworów alfa (TNF-α)¹⁵

Badania wykazały, że podwyższony poziom apoptozy był wyzwalany tylko wtedy, gdy poziom alkoholu we krwi był utrzymywany powyżej toksycznego progu około 0,2% (200 mg/dl) przez co najmniej 4 kolejne godziny.¹⁴ Wyzwalanie apoptozy przez etanol występowało podczas określonego przedziału czasowego odpowiadającego okresowi synaptogenezy.¹⁴ Przejściowa ekspozycja na etanol podczas synaptogenezy może usunąć miliony neuronów z rozwijającego się mózgu.¹⁴

Zaburzenia migracji i różnicowania komórek

Alkohol wpływa na wszystkie etapy rozwoju mózgu poprzez różnorodne mechanizmy, z których najistotniejsze prowadzą do dysfunkcji poznawczych, motorycznych i behawioralnych.¹³ Etanol zakłóca rozwój płodu poprzez:

Zaburzenia różnicowania i wzrostu komórkowego⁴
Zakłócenia syntezy DNA i białek⁴
Hamowanie migracji komórek⁴⁵
Wpływ na ekspresję lamininy, N-kadheryny i kadheryny 6B, przy jednoczesnej represji ekspresji kadheryny 7¹³
Zaburzenia formowania się grzebienia nerwowego, prawdopodobnie z powodu destabilizacji β-kateniny¹⁰

Alkohol zaburza prawidłowy rozwój oligodendrocytów (OL) w mózgu, co jest istotnym elementem patofizjologii FAS.¹⁶ Narażenie na etanol zakłóca ekspresję markerów specyficznych dla linii oligodendrocytów w ludzkich komórkach progenitorowych układu nerwowego przechodzących progresję linii OL, blokuje różnicowanie komórek macierzystych linii OL i powoduje zmniejszenie regulacji późnego markera prekursora OL – białka zasadowego mieliny (MBP).¹⁶

Zaburzenia układu neuroendokrynnego

Badania wykazały, że prenatalna ekspozycja na alkohol wpływa na oś podwzgórze-przysadka-nadnercza (HPA), a także zmienia podstawowe i postresowe poziomy kortyzolu.⁴ Inne zaburzenia hormonalne obejmują:

Zaburzenia równowagi hormonów tarczycy w mózgu, co jest krytycznie ważne w rozwoju mózgu płodu¹⁷
Zmniejszenie poziomu insulinopodobnego czynnika wzrostu 1 (IGF-1), który ma właściwości neuroprotekcyjne¹⁵
Wpływ na gen Dio3, który kontroluje ilość aktywnego hormonu tarczycy w mózgu¹⁷

Odkryto interesujący mechanizm różnic płciowych w podatności na FAS. Gdy płody męskie dziedziczą określoną odmianę genu Dio3 od matki, nie wytwarzają wystarczającej ilości enzymu w hipokampie, aby zapobiec nadmiarowi hormonów tarczycy. Wynikający z tego przedawkowanie hormonów sprawia, że hipokamp jest podatny na uszkodzenia nawet przez umiarkowaną ilość alkoholu.¹⁷ Alkohol powoduje problem, prawie całkowicie wyciszając kopię genu Dio3 ojca u zwierząt, których matka ma wariant genu. W rezultacie potomstwo nie wytwarza wystarczającej ilości tego enzymu, zakłócając delikatną równowagę poziomów hormonu tarczycy.¹⁸

Zaburzenia transportu składników odżywczych

Etanol i aldehyd octowy modyfikują metabolizm pośredni węglowodanów, białek i tłuszczów.⁴ Dodatkowo:

Zmniejszają transfer aminokwasów, glukozy, kwasu foliowego, cynku i innych składników odżywczych przez barierę łożyskową⁴
Pośrednio wpływają na wzrost płodu z powodu wewnątrzmacicznego niedoboru składników odżywczych⁴
Zaburzają transport cynku z matki do płodu z powodu defektu w transporcie łożyskowym¹⁹

Podwyższone poziomy erytropoetyny w krwi pępowinowej noworodków narażonych na działanie alkoholu sugerują stan przewlekłego niedotlenienia płodu.⁴ Alkohol powoduje zwężenie naczyń krwionośnych jednostki łożyskowo-pępowinowej i zmniejsza dostarczanie tlenu do płodu.²⁰

Mechanizmy molekularne i szlaki sygnałowe w FAS

Epigenetyczne modyfikacje i zmiany w ekspresji genów

Zarówno sam etanol, jak i wywołany przez niego stres oksydacyjny powodują zmiany w metylacji DNA, prowadząc do zmian w epigenetycznym imprintingu.¹⁰ Te epigenetyczne mechanizmy obejmują:

Zmiany w ekspresji DNA metyltransferazy 1, enzymu kluczowego dla rozwoju mózgu poprzez proces epigenetyczny zwany metylacją DNA²¹
Aktywację transferazy metylowej histonów G9a (HMT), która produkuje modyfikacje H3: 2me-H3K9 i 2me-H3K27²²
Wpływ na składniki szlaku metabolizmu jednowęglowego, w tym kwas foliowy, cholinę i SAM (donor metylowy)²²
Zmiany w poziomach czynników wzrostu, cytoszkieletu, cząsteczek adhezji komórkowej i w układzie neuroprzekaźników¹⁰

Badania wskazują, że te zmiany metylacji występują również w komórkach rozrodczych (i potomstwie) samców narażonych na działanie etanolu.¹⁰ Ekspresja genu jest modyfikowana przez status metylacji DNA i przez remodelowanie chromatyny po modyfikacji histonów, w tym metylacji, acetylacji i fosforylacji.²³

Zaburzenia szlaków sygnałowych

Ekspozycja prenatalna na etanol zakłóca liczne szlaki sygnalizacyjne, w tym:

Szlak Sonic Hedgehog (SHH) – odkryto, że jest zaburzony w prenatalnej ekspozycji na etanol²⁴
Warianty SHH i GLI2 znaleziono w modelach zwierzęcych podatnych na uszkodzenia szkieletowe wywołane przez etanol²⁴
Szlak sygnalizacyjny kwasu retinowego – etanol może zaburzać rozwój płodu przez zakłócanie sygnalizacji kwasu retinowego, gdyż aldehyd octowy może konkurować z aldehydem retinowym i zapobiegać jego utlenianiu do kwasu retinowego³²⁵
Ekspozycja na etanol aktywuje receptory sprzężone z białkiem G, aktywując fosfolipazę C, która rozkłada fosfatydyloinozytolo-bisfosforan do IP3 i DAG²²

Alkohol zaburza homeostazę cholesterolu, sygnalizację neuroprzekaźników i ma destrukcyjny wpływ na cytoszkielet.²⁶ Odkryto niedawno, że obniżone poziomy białka – apolipoproteiny E – są odpowiedzialne za trwające przez całe życie objawy poznawcze i neurologiczne w zaburzeniach ze spektrum alkoholowego płodu (FASD).²⁷

Zaburzenia morfogenezy i neurogenezy

Alkohol wywiera szczególny wpływ na rozwój twarzy i mózgu poprzez zaburzenie cząsteczek adhezji komórkowej.²⁸ Nawet przy niskich stężeniach ekspozycji na etanol, cząsteczki adhezji komórkowej są hamowane.²⁸ To ma następujące konsekwencje:

Wpływ na migrację neuronalną, fascykulację i synaptogenezę, które są niezbędne dla rozwijającego się mózgu²⁸
Zaburzenie tworzenia grzebienia nerwowego, który przyczynia się do formowania struktur czaszkowo-twarzowych²⁵
Wpływ na ekspresję koneksyny 43 (Cx43), która ułatwia komunikację międzykomórkową²⁹
Zaburzenie formowania oczu, przodomózgowia i śródmózgowia³⁰

W rombencefalonie (tyłomózgowie), komórki Cx43 gleju są strategicznie umiejscowione w centrach każdego rombomeru, z wypustkami sięgającymi do otaczającego neuropilu.²⁹ Ekspozycja na alkohol powoduje zaburzenia pozycjonowania komórek Cx43, co częściowo wyjaśnia redukcję zwojów nerwowych VII i VIII oraz anomalie czaszkowo-twarzowe.³¹

Wrażliwe struktury OUN w FAS

Ludzki ośrodkowy układ nerwowy (OUN) jest podatny na teratogenne działanie alkoholu od momentu formowania się płytki nerwowej w trzecim tygodniu przez całą resztę ciąży.³² Określone obszary rozwijającego się OUN są szczególnie podatne na wady wrodzone wywołane przez alkohol:

Układ wzrokowy³²
Ciało modzelowate³²³³
Jądra podstawy³²
Móżdżek³²
Rombencefalia (tyłomózgowie)³⁴

W FAS mikroencefalia odzwierciedla strukturalne uszkodzenie mózgu. Badania MRI wykazują zmniejszoną objętość mózgu i słabe pofałdowanie, nieprawidłowe lub nieobecne ciało modzelowate oraz mały móżdżek.³³ Ponadto, uszkodzenie czynnościowe mózgu może objawiać się napadami padaczkowymi lub nieprawidłowym EEG, oprócz obecności charakterystycznego fenotypu neurobehawioralnego.³³

Szczególna podatność układu nerwowego

Etanol wpływa na mózg płodu w sposób wieloczynnikowy. Główne konsekwencje wpływu alkoholu na rozwijające się neurony obejmują:

Zwiększenie programowanej śmierci komórkowej (apoptozy)³²
Stres oksydacyjny i uszkodzenie gleju promienistego, które są populacjami komórkowymi, które później w procesie rozwoju stają się neuronami³²
Zaburzenia w proliferacji i migracji komórek³²
Uszkodzenie puli komórek macierzystych/progenitorowych układu nerwowego, które dają początek neuronom i komórkom glejowym w OUN³⁵

Uszkodzenie tych populacji komórkowych może zmniejszyć ich objętość i powodować nieprawidłowości strukturalne, które mogą wpływać na OUN od jego początkowego rozwoju aż do rozwoju sieci neuronalnych.³⁵

Czynniki wpływające na ryzyko i nasilenie FAS

Czynniki związane z wzorem spożycia alkoholu

Nasilenie wad wrodzonych związanych z FAS może się różnić w zależności od intensywności, czasu trwania i częstotliwości ekspozycji na alkohol podczas ciąży.³⁶ Do kluczowych czynników wpływających na ryzyko należą:

Wzorzec spożywania alkoholu – zwiększone ryzyko przy ekspozycji na wysokie dawki, przy poziomie alkoholu we krwi 150 mg/dl⁵
Zwiększone ryzyko przy piciu typu „binge drinking” (upijanie się)⁵²⁰
Czas ekspozycji – alkohol wpływa na wszystkie etapy rozwoju mózgu, ale ekspozycja w różnych stadiach rozwojowych powoduje odmienne nieprawidłowości rozwojowe mózgu¹²

Wśród kobiet, które spożywają jakąkolwiek ilość alkoholu podczas ciąży, ryzyko urodzenia dziecka z FASD wynosi około 15%, a dziecka z FAS około 1,5%. Picie 2 standardowych drinków dziennie lub 6 standardowych drinków w krótkim czasie wiąże się z 4,3% ryzykiem urodzenia dziecka z FAS.³

Predyspozycje genetyczne

Podatność na rozwinięcie FAS po ekspozycji na alkohol może być modyfikowana przez czynniki genetyczne zarówno matki, jak i dziecka.³⁷ Różne grupy etniczne wykazują znaczny polimorfizm genetyczny dla enzymów wątrobowych odpowiedzialnych za detoksykację etanolu.³ Odkryto, że:

Warianty genów SHH i GLI2 znaleziono w modelach zwierzęcych podatnych na uszkodzenia szkieletowe wywołane przez etanol²⁴
Allel ADH2*2 genu dehydrogenazy alkoholowej (ADH2) wpływa na metabolizm alkoholu i jest częstszy wśród populacji normalnej niż wśród dzieci z FAS i ich matek³⁸
Allel ADH2*2 może zapewniać ochronę i/lub odporność na rozwój FAS³⁸

Metabolizm alkoholu u osób z grupy kontrolnej przebiegałby szybciej niż u matek i dzieci z FAS, co skutkowałoby niższym poziomem alkoholu we krwi niż u tych osób.³⁸ Prawdopodobnie wiele genów działa razem w każdej osobie, zapewniając albo podatność, albo ochronę przed skutkami działania alkoholu.³⁸

Wpływ okresu ciąży na rodzaj defektów

Wpływ alkoholu na rozwój płodu zależy od stadium rozwojowego w momencie ekspozycji:³⁹

W pierwszym trymestrze – głównie związany z anomaliami twarzowymi i poważnymi anomaliami strukturalnymi³⁹²
W drugim trymestrze – zwiększone ryzyko samoistnego poronienia³⁹
W trzecim trymestrze – zaburzony przyrost masy ciała, wzrost liniowy i wzrost mózgu³⁹

Podczas pierwszych trzech miesięcy ciąży zachodzą ważne etapy rozwoju twarzy i narządów, takich jak serce, kości, mózg i nerwy. Picie alkoholu w tym czasie może spowodować uszkodzenie rozwoju części ciała. A ponieważ dziecko nadal rozwija się w macicy, picie alkoholu w jakimkolwiek momencie ciąży jest szkodliwe.²

Perspektywy terapeutyczne w FAS

Biorąc pod uwagę, że uszkodzenie OUN spowodowane prenatalną ekspozycją na alkohol jest trwałe, nie ma lekarstwa na zaburzenia ze spektrum FASD.¹³ Jednak badania nad mechanizmami molekularnymi otwierają nowe możliwości terapeutyczne:

Odkryto, że dwa powszechnie stosowane leki usuwały deficyty uczenia się i pamięci spowodowane ekspozycją płodu na alkohol, gdy leki podawano po urodzeniu²¹
Badania wykazały, że podanie leku aktywującego receptor APOE uratowało deficyty uczenia się i stany lękowe w modelach przedklinicznych²⁷
Długołańcuchowy alkohol 1-oktanol z powodzeniem blokuje mechanizm prowadzący do zespołu alkoholowego płodu (FAS)⁴⁰

Badania na dorosłych zwierzętach wykazały, że zarówno metformina, jak i trichostatin A odwracały deficyty pamięci, a także niektóre zmiany molekularne spowodowane spożyciem alkoholu przez matkę.²¹ Dalsze badania wykazały, że leki normalizują geny, które kontrolują ekspresję metyltransferazy DNA 1, enzymu krytycznego dla rozwoju mózgu poprzez proces epigenetyczny zwany metylacją DNA.²¹

Obecna metodologia leczenia ma na celu dostosowanie określonych terapii w celu wzmocnienia i zajęcia się wszelkimi opóźnieniami lub deficytami poprzez dodatkową edukację, praktykę i przypomnienia.¹³

Podsumowanie mechanizmów patogenezy FAS

Patogeneza Zespołu Alkoholowego Płodu jest złożona i wieloczynnikowa. Obejmuje szereg nakładających się mechanizmów, które prowadzą do trwałych uszkodzeń strukturalnych i funkcjonalnych OUN. Główne mechanizmy to:

Bezpośrednia toksyczność etanolu i aldehydu octowego²⁶
Stres oksydacyjny i zwiększona produkcja wolnych rodników⁷⁸
Zaburzenia migracji, proliferacji i różnicowania komórek²⁰
Nadmierna apoptoza komórek nerwowych i glejowych¹¹
Modyfikacje epigenetyczne i zmiany w ekspresji genów¹⁰
Zaburzenia szlaków sygnalizacyjnych, w tym szlaku kwasu retinowego³
Niedobór składników odżywczych i niedotlenienie płodu⁴

Dokładny mechanizm teratogennego działania alkoholu pozostaje nie w pełni poznany, jednak rosnące dowody naukowe pozwalają na coraz lepsze zrozumienie złożonej patogenezy FAS oraz opracowanie potencjalnych strategii interwencyjnych.¹⁴¹

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#1 Fetal Alcohol Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448178/
Fetal alcohol syndrome is one of the five disorders that comprise fetal alcohol spectrum disorders (FASD). […] This activity describes the pathophysiology, evaluation, and management of fetal alcohol syndrome and highlights the role of the interprofessional team in preventing this pathology. […] All of the conditions that comprise fetal alcohol spectrum disorders stem from one common cause, which is prenatal exposure to alcohol. Alcohol is extremely teratogenic to a fetus. Its effects are wide-ranging and irreversible. […] In summary, any amount of alcohol consumed at any point during pregnancy has the potential cause of irreversible damage that can lead to a fetal alcohol spectrum disorder. […] The exact mechanism by which alcohol causes its teratogenic effects is not known. […] We do know that alcohol is a teratogen that causes irreversible damage to the central nervous system (CNS).
#2 Fetal alcohol syndrome – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/fetal-alcohol-syndrome/symptoms-causes/syc-20352901
Fetal alcohol syndrome is a condition in a child that results from alcohol exposure during the mother’s pregnancy. […] Alcohol is toxic to the baby’s cells. Exposure to alcohol before birth can harm how the body develops and cause permanent brain damage in the developing baby. […] The more you drink while pregnant, the greater the risk to your unborn baby. But any amount of alcohol puts your baby at risk. Your baby’s brain, heart and blood vessels begin to develop in the early weeks of pregnancy, before you may know you’re pregnant. […] During the first three months of pregnancy, important stages of development happen with the face and organs such as the heart, bones, brain and nerves. Drinking alcohol during this time can cause damage to how body parts develop. And as the baby continues to develop in the womb, it’s damaging to drink at any time during pregnancy.
#3 Fetal alcohol spectrum disorder – Wikipedia
https://en.wikipedia.org/wiki/Fetal_alcohol_spectrum_disorder
Fetal alcohol spectrum disorders are caused by alcohol exposure during gestational development. If an individual was not exposed to alcohol before birth, they will not have FASD. However, not all infants exposed to alcohol in utero will have detectable FAS, FASD, or pregnancy complications. […] No safe level of fetal alcohol exposure has been established. Because alcohol is a known teratogen, it is considered unethical to do randomized controlled trials on pregnant women to determine the precise toxicity effects of alcohol. Among women who consume any quantity of alcohol during pregnancy, the risk of giving birth to a child with FASD is about 15%, and to a child with FAS about 1.5%. Drinking 2 standard drinks a day, or 6 standard drinks in a short time, carries a 4.3% risk of a FAS birth.
#3 Fetal alcohol spectrum disorder – Wikipedia
https://en.wikipedia.org/wiki/Fetal_alcohol_spectrum_disorder
After a pregnant woman consumes alcohol, the alcohol crosses through the placenta and umbilical cord to the developing fetus. Alcohol metabolizes slowly in the fetus and remains for a long time when compared to an adult. A human fetus appears to be at triple risk from maternal alcohol consumption: The placenta allows free entry of ethanol and toxic metabolites like acetaldehyde into the fetal compartment. The developing fetal nervous system appears particularly sensitive to ethanol toxicity. The latter interferes with proliferation, differentiation, neuronal migration, axonal outgrowth, integration, and fine-tuning of the synaptic network. In short, all major processes in the developing central nervous system appear compromised. […] Although alcohol is known to be a teratogen (causing birth defects), the exact biological mechanisms for the development of FAS or FASD are unknown. However, clinical and animal studies have identified a broad spectrum of pathways through which maternal alcohol can negatively affect the outcome of a pregnancy. Clear conclusions with universal validity are difficult to draw, since different ethnic groups show considerable genetic polymorphism for the hepatic enzymes responsible for ethanol detoxification. Genetic examinations have revealed a continuum of long-lasting molecular effects that are not only timing specific but are also dosage specific; with even moderate amounts being able to cause alterations. Additionally, ethanol may alter fetal development by interfering with retinoic acid signaling as acetaldehyde can compete with retinaldehyde and prevents its oxidation to retinoic acid.
#4 Fetal Alcohol Syndrome: Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/974016-overview
Alcohol crosses the placenta and rapidly reaches the fetus. Extensive studies have demonstrated equivalent fetal and maternal alcohol concentrations, suggesting an unimpeded bidirectional movement of alcohol between the two compartments. The fetus appears to depend on maternal hepatic detoxification because the activity of alcohol dehydrogenase (ADH) in the fetal liver is less than 10% of that observed in the adult liver. Furthermore, the amniotic fluid acts as a reservoir for alcohol, prolonging fetal exposure. […] The mechanism for the spectrum of adverse effects on virtually all organ systems of the developing fetus is unknown. Ethanol and its metabolite acetaldehyde can alter fetal development by disrupting cellular differentiation and growth, disrupting DNA and protein synthesis and inhibiting cell migration. Both ethanol and acetaldehyde modify the intermediary metabolism of carbohydrates, proteins, and fats. Both also decrease the transfer of amino acids, glucose, folic acid, zinc, and other nutrients across the placental barrier, indirectly affecting fetal growth due to intrauterine nutrient deprivation. Elevated levels of erythropoietin in the cord blood of newborns exposed to alcohol are reported and suggest a state of chronic fetal hypoxia. […] Studies have shown that prenatal alcohol exposure affects the hypothalamic-pituitary-adrenal (HPA) axis as well as alters basal and poststress cortisol levels.
#5 Fetal Alcohol Spectrum Disorder | Concise Medical Knowledge
https://www.lecturio.com/concepts/fetal-alcohol-spectrum-disorder/
Alcohol is a teratogen that has irreversible effects: […] Exact mechanism unknown […] Factors that contribute to pathogenesis: […] Ethanol and its metabolites transfer across placenta. […] Fetus cannot metabolize alcohol: depends on maternal alcohol dehydrogenase. […] Amniotic fluid acts as reservoir for alcohol (prolongs fetal exposure). […] Ethanol affects the fetus’s developing CNS by altering cell proliferation, differentiation, and migration. […] Variation in susceptibility of fetus affected by: […] Pattern of alcohol ingestion: Increased risk with high-dose exposure of BAC 150 mg/dL […] Increased risk with binge drinking.
#6
https://www.gov.uk/government/publications/fetal-alcohol-spectrum-disorder-health-needs-assessment/fetal-alcohol-spectrum-disorder-health-needs-assessment
FASD is a lifelong condition caused by alcohol exposure to the developing fetus. It can have a significant impact on early-years development and life chances. […] What we do know is that alcohol can pass through the placenta and spread rapidly to the amniotic fluid surrounding the fetus. The alcohol is removed from the fluid far more slowly than the mother eliminates it from her own system, meaning that it accumulates. This creates a reservoir of alcohol around the fetus, which will be swallowed and circulated in the fetus system. The fetus only has a limited ability to process, or metabolise, the alcohol compared to the mother, and so the effect is prolonged. […] While some of the mechanisms of alcohol teratogenesis have been discovered, many also remain uncertain. However, we do know alcohol can have characteristic impacts on development that persist after birth and throughout life. These may include pervasive and long-standing central nervous system dysfunction in the following areas: motor skills, neuroanatomy or neurophysiology, cognition, language, academic achievement, memory, attention, executive function, including impulse control and hyperactivity, affect regulation, adaptive behaviours, social skills or social communication.
#7 An overview of current advances in perinatal alcohol exposure and pathogenesis of fetal alcohol spectrum disorders | Journal of Neurodevelopmental Disorders | Full Text
https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-024-09537-w
The main mechanism of FASD is closely related with alcohol-induced neuroinflammation and oxidative stress, by which potentially result in neural cell apoptosis in the developing embryonic brain, thus impeding the development of the embryonic brain. Ethanol neurotoxicity is another major mechanism by which ethanol causes FASD by direct damage to various signaling pathways. […] The pathogenesis of FASD is mainly attributed to the autophagy of growing neurons following the inflammatory response caused by ethanol in the fetal body through oxidative stress, which is directly linked to the raise in reactive oxygen species (ROS) in the embryo after ethanol ingestion. […] The damage to DNA and the damage triggered by associated inflammatory factors serve as the primary pathogenesis of the process of ROS-induced oxidative stress leading to FASD.
#8 Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders | Molecular Psychiatry
https://www.nature.com/articles/s41380-018-0095-4
Alcohol exposure during pregnancy affects the development of the fetus in various ways and may lead to Fetal Alcohol Spectrum Disorders (FASD). […] In addition to single outcome experiments, omics data should be generated to overcome this problem. Therefore, for future studies we recommend holistic data driven analysis, which allows integrative analyses over multiple levels of genetic variation, transcriptomics and metabolomics data to investigate the whole image of FASD development and to provide insight in potential drug targets for intervention. […] EtOH and its catabolite acetaldehyde are toxic themselves, but according to the current knowledge oxidative stress is the major damage pathway. […] Increased DNA damage triggers apoptosis pathways leading to neurodegeneration. […] The cellular pathways to clear ROS (which also occur during mitochondrial respiration and several other normal parts of metabolism) involves a battery of enzymatic and non-enzymatic pathways including SOD, CAT, GPx, (reduced) glutathione, and several antioxidant metabolites (e.g., tocopherol, melatonin).
#9 Neurocognitive and behavioral profile of fetal alcohol spectrum disorder | Anales de PediatrÃa
https://analesdepediatria.org/en-neurocognitive-behavioral-profile-fetal-alcohol-articulo-S2341287921001344
Prenatal alcohol exposure is the leading preventable cause of cognitive deficit in developed countries and can lead to fetal alcohol spectrum disorder (FASD). This term encompasses a wide range of physical, mental, behavioral, and cognitive effects that result from damage caused by exposure to alcohol during intrauterine life. […] Alcohol toxicity depends directly on ethanol and its metabolites (acetaldehyde and reactive oxygen species [ROS]). The oxidative stress caused by alcohol and ROS is caused by an increased production of nicotinamide adenine dinucleotide (NADH), which results in an increased NAD/NADH ratio that is balanced by the formation of lactate dehydrogenase. Ethanol crosses the placenta, and while its concentration in amniotic fluid is 40% the concentration in maternal blood, its slow clearance results in prolonged foetal exposure. The foetal brain is the main target on account of its greater metabolic requirements and production of ROS combined with the lower concentration of enzymes and antioxidants.
#10 Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders | Molecular Psychiatry
https://www.nature.com/articles/s41380-018-0095-4
In particular, the developing brain is susceptible to damage due to elevated ROS levels. […] Therefore, the downstream effects of EtOH, oxidative stress towards permanent, and long-term influence in the developing brain needs to be elucidated to understand the etiology thoroughly. […] Long-term effects include changes in the levels of growth factors, cytoskeleton, cell adhesion molecules, and in the neurotransmitter system. […] Especially neuronal crest formation is affected probably due to destabilization of -catenin. […] Furthermore, EtOH itself and oxidative stress-induced downstream pathways cause changes in DNA methylation, leading to changes in epigenetic imprinting. […] Initial studies indicate that these methylation changes are also found in the germ cells (and offspring) of EtOH-exposed males.
#11 An overview of current advances in perinatal alcohol exposure and pathogenesis of fetal alcohol spectrum disorders | Journal of Neurodevelopmental Disorders | Full Text
https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-024-09537-w
The damage caused by oxidative stress cascade serves as the primary pathogenesis of the process of ROS-induced oxidative insult leading to FASD. […] In addition to direct damage to DNA, ROS production by alcohol triggers an oxidative stress response which suppresses the growth of neural cells through mediation of inflammatory-related cytokines and several pathways, leading to cell apoptosis and FASD. […] Neuroinflammation arising from ROS by ethanol metabolism has far more influence on the nervous system. […] The ultimate outcome of alcohol damage to trophoblast cells almost is cell destruction or apoptosis, and the damaging neurotoxic effects of alcohol are immediate and long-lasting. […] In summary, prenatal alcohol exposure to varying degree could cause excessive neuronal death and distinct impairments of the development of normal neural networks, leading to the pathogenesis of FASD.
#12 Fetal Alcohol Spectrum Disorder (FASD) Associated Neural Defects: Complex Mechanisms and Potential Therapeutic Targets
https://www.mdpi.com/2076-3425/3/2/964
Studies on animal models showed that ethanol interferes in all stages of brain development, but exposure at various developmental stages caused distinct brain developmental abnormalities. […] Early work on alcohol-induced CNS defects focused on mechanisms underlying learning disabilities examined hyperactivation of GABA receptors that triggers a neurodegenerative response, which is particularly sensitive during the period of synaptogenesis. […] Animal models and tissue-culture studies identified numerous potential mechanisms of alcohol induced craniofacial and brain defects. […] Ethanol exposure can induce the caspase cascade, which leads to apoptosis of the cranial neural crest cells (CNCCs) via two known mechanisms. […] Ethanol-induced neurotoxicity was primarily attributed to ROS-induced cellular damage.
#13 Fetal Alcohol Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448178/
From animal models, we know that prenatal alcohol exposure affects all stages of brain development through a variety of mechanisms, the most significant of which result in cognitive, motor, and behavioral dysfunction. […] The cranial neural crest cells (NCCs) contribute to the formation of the craniofacial bones. Exposure to 2% ethanol (alcohol) induced craniofacial defects in the developing chick fetus. […] The use of double-immunofluorescent stainings for Ap-2/pHIS3 and Ap-2/c-caspase 3 showed that alcohol treatment inhibited cranial NCC proliferation and increased NCC apoptosis. […] Alcohol exposure of the dorsal neuroepithelium increased laminin, N-cadherin, and cadherin 6B expressions while Cadherin 7 expression was repressed. […] The history that is associated with undiagnosed fetal alcohol spectrum disorders is fairly wide. […] Given that the CNS damage from prenatal alcohol exposure is permanent, there is no cure for fetal alcohol spectrum disorders. […] This treatment methodology seeks to tailor specific therapies to reinforce and address any delays or deficiencies with additional education, practice, and reminders.
#14 Fetal Alcohol Syndrome and Apoptosis: R&D Systems
https://www.rndsystems.com/resources/articles/fetal-alcohol-syndrome-and-apoptosis
Fetal alcohol syndrome is a neurotoxic syndrome resulting from exposure of a fetus to high levels of alcohol during pregnancy. […] The mechanisms through which ethanol exerts its deleterious effects are unknown, however. […] Ethanol is a known antagonist of NMDA glutamate receptors. […] A recent study demonstrated that blockade of these receptors results in widespread apoptotic neurodegeneration in infant rat brain. […] Elevated levels of apoptosis were triggered only if the level of blood alcohol was maintained above a toxic threshold range of approximately 0.2% (200 mg/dL) for a minimum of 4 consecutive hours. […] Triggering of apoptosis by ethanol occurred during a distinct time window corresponding to the period of synaptogenesis. […] Transient ethanol exposure during synaptogenesis can delete millions of neurons from the developing brain.
#15
https://journals.lww.com/nrronline/fulltext/2022/03000/oligodendrocyte_pathology_in_fetal_alcohol.5.aspx
Acute EtOH exposure reduced levels of the neuroprotective cytokine insulin-like growth factor 1 (IGF-1) in fetal and maternal sheep. […] Thus, part of the neurotoxic effect of EtOH may be mediated by release of TNF- from EtOH-activated microglia. […] Recent data on the effect of EtOH on OL development demonstrated that expression of the neuroprotective IGF-1 was reduced, while the neurotoxic TNF- was increased. […] Thus, the significant correlations that were observed between alcohol measures and DTI values indicated that the white matter damage found in several regions was dose-dependent.
#16
https://journals.lww.com/nrronline/fulltext/2022/03000/oligodendrocyte_pathology_in_fetal_alcohol.5.aspx
The pathophysiology of fetal alcohol syndrome (FAS) includes prominent dysmyelination in the brain due to abnormal development of oligodendrocytes (OLs). […] We summarize the effects of alcohol exposure on markers of oligodendrocyte precursor cell (OPC) and OL mRNA and protein expression, and on the expression of specific cytokines and chemokines in the developing brain that may affect human fetal OL differentiation. […] It was suggested that EtOH exposure interferes with the expression of OL lineage-specific markers in human neural progenitor cells undergoing OL lineage progression, blocks the differentiation of OL lineage stem cells, and causes a downregulation of the late OPC marker, MBP. […] Thus, two mechanisms were proposed to account for the effects of EtOH exposure in causing dysmyelination – a delay in maturation of OPC to OL, as well as a loss of mature OL, and apoptotic signaling may contribute to both of these.
#17 Sex Differences in Fetal Alcohol Syndrome | Women’s Health Research Institute
https://womenshealth.obgyn.msu.edu/blog/sex-differences-fetal-alcohol-syndrome
Male fetuses most vulnerable to alcohol. […] One answer is a gene variation passed on by the mother to her son, according to new Northwestern Medicine research. This gene variation contributes to a fetus vulnerability to even moderate alcohol exposure by upsetting the balance of thyroid hormones in the brain. […] The gene involved, Dio3, makes the enzyme that controls how much active thyroid hormone is in the brain. A delicate balance of the thyroid hormone is critically important in the development of the fetal brain and in the maintenance of adult brain function. […] When males inherit this variation of the Dio3 gene from their mother, they dont make enough of this enzyme in their hippocampus to prevent an excess of thyroid hormones. The resulting overdose of the hormones makes the hippocampus vulnerable to damage by even a moderate amount of alcohol.
#18 Sex Differences in Fetal Alcohol Syndrome | Women’s Health Research Institute
https://womenshealth.obgyn.msu.edu/blog/sex-differences-fetal-alcohol-syndrome
The alcohol causes the problem by almost completely silencing the fathers copy of the Dio3 gene in animals whose mother has the gene variation. As a result, the offspring dont make enough of this enzyme, disrupting the delicate balance of the thyroid hormone levels. […] The identification of this novel mechanism will stimulate more research on other genes that also influence alcohol-related disorders, especially in females. […] These results show they had social and memory deficits, Redei said. This indicates the damage to the hippocampus from the alcohol exposure.
#19 554 FETAL ALCOHOL SYNDROME: A MECHANISM FOR GROWTH RETARDATION | Pediatric Research
https://www.nature.com/articles/pr1981879
Growth retardation (GR) is a principle feature of Fetal Alcohol Syndrome (FAS). […] Since Zinc (Zn) is an essential element for protein synthesis and growth during the critical prenatal and postnatal periods, we postulated that ethanol (E) may interfere with placental Zn transport. […] Our results indicate that maternal to fetal Zn transport is depressed by E because of a defect in placental transport of zinc. These results may explain partly the GR seen in FAS.
#20 fetal-alcohol-spectrum-disorder-pathogenesis-and-clinical-findings | Calgary Guide
https://calgaryguide.ucalgary.ca/fetal-alcohol-spectrum-disorder-pathogenesis-and-clinical-findings/fasd_4_er/
Fetal Alcohol Spectrum Disorder: Pathogenesis and clinical findings […] Maternal alcohol consumption during pregnancy (greatest risk with binge drinking and daily/chronic intake) […] Prenatal alcohol exposure to fetus via placenta-umbilical transport […] There is no known safe amount of prenatal alcohol exposure (PAE). […] Alcohol acts directly as a teratogen […] Vasoconstriction of placental-umbilical unit blood flow and oxygen delivery to fetus […] Neuronal cell death disruption of migration proliferation […] Altered signaling, neurotransmitter imbalance, neural connectivity.
#21 Reducing Fetal Alcohol Syndrome After Birth | Northwestern Medicine
https://www.nm.org/healthbeat/medical-advances/reducing-fetal-alcohol-syndrome-after-birth
Two commonly used drugs erased the learning and memory deficits caused by fetal alcohol exposure when the drugs were given after birth, thus potentially identifying a treatment for the disorder, according to new Northwestern Medicine study published in Molecular Psychology. […] The scientists also identified a key molecular mechanism by which alcohol neurologically and developmentally harms the developing fetus. […] We showed in the adult animals that both these treatments reversed the memory deficits as well as some of the molecular changes caused by maternal alcohol consumption, Redei said. […] These changes are dangerous to the brain development of the fetus and are at least part of the reason for learning and memory deficits of the offspring, Redei said. […] Further investigations showed the drugs normalize genes that control the expression of DNA methyl transferase1, an enzyme critical for brain development via an epigenetic process called DNA methylation. […] To further validate the role of DNA methyl transferase1 in fetal alcohol syndrome, the scientists took normal rat pups and gave them a drug to inhibit the gene. The result was alcoholic look-alike pups. When researchers then gave the pups metformin, the pups memory returned to normal.
#22 Fetal Alcohol Spectrum Disorder (FASD) Associated Neural Defects: Complex Mechanisms and Potential Therapeutic Targets
https://www.mdpi.com/2076-3425/3/2/964
Ethanol exposure can activate G-protein coupled receptors, activating phospholipase C, which breaks down phosphatidylinositol-bisphosphate to IP3 and DAG. […] Ethanol exposure enhanced transcriptional activation of G9a, a histone methyltransferase (HMT), which produces the H3 modifications 2me-H3K9 and 2me-H3K27. […] Ethanol interferes with components of the one carbon metabolism pathway, including folate, choline (a derivative of homocysteine) and SAM (methyl donor).
#23 Genetic and epigenetic insights into fetal alcohol spectrum disorders | Genome Medicine | Full Text
https://genomemedicine.biomedcentral.com/articles/10.1186/gm148
The question is, therefore, what is the nature and magnitude of the genetic effect and how does genetic variation interact with environmental factors (for example, nutrition and environmentally induced epigenetic remodeling) to cause teratogenic effects. […] Gene expression is known to be altered by DNA methylation status and by chromatin remodeling following histone modification, including methylation, acetylation and phosphorylation. […] Given that abnormal neuronal development and neurodegeneration are characteristics of FASD and alcoholism, it is important to understand how these molecular processes are altered in affected tissues. […] The previous section provided some evidence supporting the involvement of epigenetic remodeling in alcohol teratogenesis, and this hypothesis is further summarized in a recent review supporting an epigenetic dimension as one of the key molecular mechanisms in FASD.
#24 Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders | Molecular Psychiatry
https://www.nature.com/articles/s41380-018-0095-4
There are several omics data driven approaches to investigate the downstream effects of EtOH-induced damage, which lead to the distinct phenotype of FASD. […] Starting with a known phenotype and investigation of the known underlying genetic causes, the Hedgehog pathway was discovered to be disrupted in prenatal EtOH exposure. […] Certain variants of SHH and GLI2 were found in animal models susceptible to EtOH-induced skeletal damage, indicating that the degree of damage is dependent on the genetic background as well. […] The aim of this paper is to provide a current status and a gap analysis of FASD knowledge with a focus on molecular pathways. […] The main deficits in knowledge about FASD are the lack of pathophysiological understanding and doseresponse relationships, together with the lack of reliable biomarkers for either FASD detection or estimation of susceptibility. […] The authors would like to thank all contributors to the Knowledge Synthesis.
#25 Abnormal Development – Fetal Alcohol Syndrome – Embryology
https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Fetal_Alcohol_Syndrome
Fetal alcohol syndrome is a malformation syndrome caused by maternal consumption of alcohol during pregnancy. It is characterized by prenatal and/or postnatal growth deficiency (weight and/or height 10th percentile); a unique cluster of minor facial anomalies (short palpebral fissures, flat and smooth philtrum, and thin upper lip) that presents across all ethnic groups, is identifiable at birth, and does not diminish with age. Affected children present severe central nervous system abnormalities including: microcephaly, cognitive and behavioral impairment (intellectual disability, deficit in general cognition, learning and language, executive function, visual-spatial processing, memory, and attention). […] Alcohol exposure affects cranial neural crest cell migration and survival, that impacts upon frontonasal prominence and pharyngeal arch development. A second effect may be through alcohol exposure inducing retinoic acid deficiency in the embryo, affecting downstream pathways that are transcriptionally controlled retinoic acid target genes.
#26 Society for Birth Defects Research and Prevention
https://www.birthdefectsresearch.org/primer/fas.asp
Besides direct cell toxicity of ethanol and its metabolite acetaldehyde, alcohol increases oxidative stress and leads to alterations in epigenetic imprinting, gene expression, and the generation of abnormal cell metabolites. Alcohol affects several genetic pathways, cholesterol homeostasis, neurotransmitter signaling, and has destructive effects on the cytoskeleton. No single or simple mechanism is responsible for the damage, and research evidence of how PAE causes brain damage suggests potential therapeutic targets to modify or reverse some of the deleterious effects of alcohol in brain cells.
#27 Adjusting key protein could improve brain function in children with fetal alcohol syndrome – Children’s NationalSearchLink to: Pioneering gene therapy as a treatment for sickle cell diseaseLink to: Mission critical: Pentagon awards grant to combine two no
https://innovationdistrict.childrensnational.org/adjusting-key-protein-could-improve-brain-function-in-children-with-fetal-alcohol-syndrome/
Reduced levels of a protein â called apolipoprotein E â are responsible for the lifelong cognitive and neurological symptoms in fetal alcohol spectrum disorders (FASD), according to a new study published in the journal Molecular Psychiatry. […] „The new data shows that we understand the mechanism by which prenatal alcohol exposure causes a decrease of the APOE level in the brain.” […] „We found that providing a drug that activates the APOE receptor rescued learning deficits and anxiety in pre-clinical models.”
#28 Fetal Alcohol Spectrum Disorder | Intellectual Disability and Health
https://www.intellectualdisability.info/conditions-associated-with-intellectual-disability/articles/fetal-alcohol-spectrum-disorder
Reports have shown increasingly that there are vulnerable periods of neonatal development that can be affected by teratogenic ingestion. In terms of neural development, which occurs throughout pregnancy, it is often the inter-neuron connections that are damaged. This is especially the case at lower levels of consumption. Charness et al (12) report that even at low concentrations of ethanol exposure, cell adhesion molecules are inhibited. These have subsequent effects on neuronal migration, fasciculation and synaptogenesis, which are all vital to the developing brain. These risk factors, as well as protective factors, need further clarification. […] More recently work by Hepper et al(13) using ultrasound monitoring of fetal behaviour where mothers consumed alcohol at levels within current UK government guidance showed effects on fetal startle which did not habituate to a level achieved by those that consumed no alcohol. They suggest that this is a sign that even at low levels of alcohol consumption (an average of 4.3 units per week +/- 1.9) permanent damage to the developing fetal brains is occurring.
#29 Fetal Alcohol Syndrome: Effects on the Auditory System – Article 845
https://www.audiologyonline.com/articles/fetal-alcohol-syndrome-effects-on-845
In the hindbrain, in contrast, there is no information on which signaling systems are targeted by alcohol exposure, in spite of abundant evidence of the precise and balanced interplay of multiple signaling systems. In our laboratory, we examined how alcohol exposure may change gene expression in the hindbrain of the frog, Xenopus laevis, especially the rostral hindbrain, which is critical for auditory function (Barsheff et al., 2010). In an earlier work, we showed that one of the connexin genes, connexin 43 (Cx43), turns on precisely when the auditory system and its neural connections are emerging from the hindbrain (Katbamna et al., 2004). Connexin genes facilitate cell-cell communication; therefore, mutation, loss, or downregulation of connexin genes could produce dysfunctional cells. This is demonstrated by the connexin 26 (Cx26) mutation which produces congenital cochlear hearing loss, because Cx26 is found in the cochlea. Cx43 is found in astrocytes (star shaped support or glial cells of the nervous system), and within the frog hindbrain Cx43 is strategically positioned within the centers of each rhombomere with processes reaching out into the outlying neuropil. Moreover, Cx43 glial cells alternate with other non-Cx43 expressing glial cells, which occupy the border regions of each rhombomere. This suggests that Cx43 glial cells may serve as guide post cells guiding neural development, whereas glial cells of rhombomeric boundaries may be involved in maintaining hindbrain segments (Katbamna et al., 2004).
#30 Fetal Alcohol Syndrome: Effects on the Auditory System – Article 845
https://www.audiologyonline.com/articles/fetal-alcohol-syndrome-effects-on-845
Alcohol may also interfere with pattern formation and gene cascades important for craniofacial development. There is growing evidence that prenatal exposure to alcohol disrupts pattern formation during early development in both humans and animal models. Pattern formation refers to the time- and location-specific order in which genes are turned on and off during development. When key regulatory genes do not turn on and off in a predictable manner, organization and positioning of specific cell types are disrupted, which leads to malformations of the craniofacial structures and other problems with normal growth. There is extensive literature on the effects of prenatal alcohol exposure on the eyes, forebrain, and midbrain, and the possible regulatory genes producing these effects. Examples include alcohol induced loss or downregulation (reduction) of sonic hedgehog (shh) in the forebrain, Fgf-8 in various organizing centers of the brain, and Pax6 in the forebrain and eyes; in addition, a number of genes regulating bone morphogenetic proteins involved in cell death cascades have been linked to craniofacial anomalies (reviewed in Sulik, 2005).
#31 Fetal Alcohol Syndrome: Effects on the Auditory System – Article 845
https://www.audiologyonline.com/articles/fetal-alcohol-syndrome-effects-on-845
In our alcohol exposure experiment, we predicted that if alcohol targeted the Cx43 gene, it would not only produce craniofacial anomalies in the frog, but it would also disrupt the spatiotemporal organization of Cx43 within the hindbrain (Barsheff et al., 2010). In fact, our results, showed alcohol induced neural and craniofacial anomalies in the frog that were associated with reduced facial and auditory-vestibular ganglia but not the ear and hindbrain structures. Furthermore, these changes occurred in concert with aberrant positioning of Cx43 cells, so that Cx43 clusters in the rostral hindbrain were displaced or absent, which in part explained the reduction of VII and VIII cranial ganglia and craniofacial anomalies. These findings clearly indicate that alcohol exposure interferes with timed gene expression, thereby targeting gene cascades that may be critical for the development of the hindbrain and its derivative ear and VII and VIII cranial nerves.
#32 Fetal Alcohol Syndrome (FAS) | Embryo Project Encyclopedia
https://embryo.asu.edu/pages/fetal-alcohol-syndrome-fas
The human CNS is vulnerable to the teratogenic effects of alcohol from when the neural plate begins to form in the third week through the rest of gestation. […] Certain areas of the developing CNS are particularly susceptible to alcohol-induced birth defects, including the ocular system, corpus callosum, basal ganglia, and cerebellum. […] Alcohol’s impact on developing neurons include an increase in programmed cell death (apoptosis), as well as oxidative stress and damage to radial glia which are the cellular populations that later in the process of development become neurons. […] All of those mechanisms impair the proliferation and migration of cells, and damage to cell populations has been proposed as a process for how alcohol causes birth defects and CNS damage. […] Scientists have debated whether or not the alcohol-induced apoptosis prematurely eliminates specific cell populations during development, such as cranial neural crest cells, retinal cells, cerebellum cells and other vulnerable populations.
#33 Society for Birth Defects Research and Prevention
https://www.birthdefectsresearch.org/primer/fas.asp
In FAS, microcephaly reflects structural damage to the brain. MRI findings show decreased brain volume and poor gyration, abnormal or absent corpus callosum, and small cerebellum. In addition, functional brain damage can become evident as seizures or abnormal EEG in addition to the presence of a characteristic neurobehavioral phenotype. […] Decades of research have determined that brain damage in FASD is complex and multidimensional. Early animal studies revealed that development of the face and brain are intimately interrelated, as the brain provides structural, cellular, and molecular input that guides the development of the face. Studies in the mouse that began soon after the identification of FAS in humans provided the first experimental evidence that both brain and craniofacial abnormalities result from prenatal alcohol exposure and that the defects in the mouse are similar to those seen in humans.
#34 Fetal Alcohol Syndrome: Effects on the Auditory System – Article 845
https://www.audiologyonline.com/articles/fetal-alcohol-syndrome-effects-on-845
FAS pathogenesis and mechanisms of damage […] Although multiple aspects of the CNS have been shown to be altered by in utero exposure to alcohol in both humans and animal models, the typical facial features and CNS abnormalities associated with FAS have been attributed to excessive cell death in the embryonic face and brain regions (reviewed in Sulik, 2005). This loss of cell populations may not only explain the concomitant craniofacial anomalies, but also the accompanying middle ear problems observed in FAS cases. […] Other vulnerable cell populations identified in animal models include those that are responsible for the formation of the ear and its nerve projections to the brain. In vertebrates, immediately after neural tube closure, the hindbrain or rhombencephalon is organized into seven segments called rhombomeres, and the ear emerges from a placode that forms at the junction of the third and fourth rhombomere (e.g., Lumsden, 1990; Guthrie, 1996). Studies that exposed mouse and chick embryos to alcohol have shown that the rhombomeres, neural crest cells, and placodes are highly sensitive to the effects of alcohol (Kotch Sulik, 1992; Du Hamre, 2001; Dunty et al., 2001; 2002; Sulik et al., 1988; Cartwright Smith, 1995; Church et al., 1987). Neural crest cells are cells that delaminate from dorsal neural tube and overlying ectoderm regions and migrate into and contribute to the formation of the craniofacial structures, the cranial ganglia, the heart, and the thymus. Thus, widespread cell death within the hindbrain neuroepithelium, cranial neural crest cells, and placodes, leads to disruption of hindbrain segmentation and abnormalities of several cranial nerves including, V, VII-VIII, IX, and X. The abnormalities range from fusion or absence of the cranial ganglia to improper positioning or disorganization of nerve fibers (Dunty et al., 2001; 2002; Cartwright Smith, 1995). Alcohol induced reduction in neuronal numbers within the auditory brainstem nuclei have also been documented (Pettigrew Hutchinson, 1984; Mooney Miller, 2001). Thus, teratogenic actions of alcohol on the embryonic precursor cells that contribute to the cochlea, auditory nerve, and brainstem may explain the auditory and audiologic manifestations observed in FAS.
#35 Fetal Alcohol Syndrome (FAS) | Embryo Project Encyclopedia
https://embryo.asu.edu/pages/fetal-alcohol-syndrome-fas
Numerous studies confirm that the biomechanical mechanism occurring during this cell death as being a capsase-3 enzyme activation cascade, which is a component of programmed cell death by apoptosis. […] Scientists have also hypothesized that this programmed cell death may be triggered by the metabolic breakdown of alcohol into acetaldehyde, which can inhibit the formation of retinoic acid. […] In addition to those proposed apoptotic mechanisms, alcohol damages the neural stem cell progenitor pools, like radial glia, that give rise to neurons and the supporting glial cells in the CNS. […] Damage to these cell populations can decrease their volumes and it can cause structural abnormalities, which can impact the CNS from its initial development through to the development of neural networks.
#36 Fetal Alcohol Syndrome (FAS) | Embryo Project Encyclopedia
https://embryo.asu.edu/pages/fetal-alcohol-syndrome-fas
The alcohol-induced defects include pre- and post-natal growth deficiencies, minor facial abnormalities, and damage to the developing central nervous system (CNS). […] The severity of birth defects associated with FAS can vary depending on the intensity, duration, and frequency of exposure to alcohol during gestation. […] As birth defects and anomalies can arise when pregnant women consume alcohol, alcohol is a teratogen, an environmental agent that negatively impacts the course of normal embryonic or fetal development. […] Many FAS-related defects occur in the developing central nervous system (CNS), and scientists have correlated them with gross morphological abnormalities of the brain and compared to normal children, an overall decrease in white matter, particularly in the cerebrum, or forebrain.
#37 Genetic and epigenetic insights into fetal alcohol spectrum disorders | Genome Medicine | Full Text
https://genomemedicine.biomedcentral.com/articles/10.1186/gm148
The magnitude of the detrimental effects following in utero alcohol exposure, including fetal alcohol syndrome and other fetal alcohol spectrum disorders (FASD), is globally underestimated. […] Genetic attributes (susceptibility and protective alleles) of the mother and the fetus contribute to the risk of developing FASD and specific additional environmental conditions, including malnutrition, have an important role. […] Several developmental pathways are affected in FASD, including nervous system development, growth and remodeling of tissues, as well as metabolic pathways that regulate glucocorticoid signaling and balanced levels of retinol, insulin and nitric oxide. […] A body of knowledge has accumulated to support the role of environmentally induced epigenetic remodeling during gametogenesis and after conception as a key mechanism for the teratogenic effects of FASD that persist into adulthood.
#38 Genetic Protection Against Fetal Alcohol Syndrome? – Addiction Technology Transfer Center (ATTC) Network
https://attcnetwork.org/asme_articles/genetic-protection-against-fetal-alcohol-syndrome/
Fetal Alcohol Syndrome (FAS) may be influenced by genetic factors in both the mother and child. […] Allelic variations of the alcohol dehydrogenase (ADH2) gene influences alcohol metabolism. […] Researchers have found that the ADH2*2 allele is more common among the normal population than among FAS children and their mothers. […] The ADH2*2 allele may confer protection against and/or resistance to developing FAS. […] There is some good scientific evidence to suggest that FAS, like virtually all diseases, has some genetic and some environmental influences. […] The inference is that the metabolism of alcohol by individuals from the control group would proceed more rapidly than in the mothers and FAS children, and result in lower blood alcohol levels than the latter subjects. […] This is the first study to find any connection between a gene and FAS. […] Presumably, many genes are working in concert within each person to provide either susceptibility to or protection from the effects of alcohol. […] Also, the pathogenesis of FAS could become clearer.
#39 Neurocognitive and behavioral profile of fetal alcohol spectrum disorder | Anales de PediatrÃa
https://analesdepediatria.org/en-neurocognitive-behavioral-profile-fetal-alcohol-articulo-S2341287921001344
Although prenatal exposure is a necessary condition, the genetic aetiology and pathogenesis of the neurodevelopmental disorders observed in cases of FASD is unknown. The discovery of genetic and epigenetic markers of FASD would contribute greatly to its diagnosis. […] No amount of alcohol is safe to consume during pregnancy, although its negative effects depend mainly on the dose, duration and pattern of consumption and individual genetic susceptibility. […] Significant exposure to alcohol in the first trimester is mainly associated with facial anomalies and major structural anomalies, in the second trimester, with increased risk of spontaneous miscarriage, and in the third trimester, with impaired weight gain, linear growth and brain growth. […] Although the clinical picture based on the timing of exposure is well defined, neurocognitive and behavioural sequelae may result from exposure at any time during gestation.
#40 Long-Chain Alcohol Found To Block Mechanism Of Fetal Alcohol Syndrome | ScienceDaily
https://www.sciencedaily.com/releases/2001/05/010518083627.htm
An article in todays Federation of American Societies for Experimental Biology (FASEB) Journal reports that the long-chain alcohol 1-octanol successfully blocks a mechanism leading to fetal alcohol syndrome (FAS). […] Todays study advances the work to mouse whole embryo cultures and demonstrates that 1-octanol can block alcohol teratogenesis (abnormal physical development) and associated excessive apoptosis (programmed cell death). […] „Our findings suggest that ethanol disruption of L1-mediated cell adhesion contributes to its teratogenic actions through the induction of cell death. This suggests an avenue for the development of safe compounds for the prevention of FAS,” said Dr. Charness, Associate Professor in the Department of Neurology, Harvard Medical School, and Chief of Neurology, VA Boston Healthcare System.
#41 Fetal alcohol spectrum disorder: pathogenesis and mechanisms – PubMed
https://pubmed.ncbi.nlm.nih.gov/25307590/
This chapter provides an overview of animal model-based studies that have generated information critical to our understanding of the pathogenesis and mechanisms underlying alcohol-induced birth defects, in particular those involving the brain. […] Components of the cascades of alcohol-induced damage that are considered herein are excessive cell death, changes in the cell cycle and proliferation, cell migration, cell morphogenesis, and gene expression as well as free radical damage and interference with cell signaling. […] The roles played by one or more of these various factors in the genesis of structural and functional birth defects are dependent upon alcohol exposure patterns and dosage, the involved tissue, and the prenatal stage(s) at the time of exposure. […] Technologic advances and rapidly increasing knowledge in the fields of genetics, cell, developmental, and neurobiology are critical to accurately piecing together experimental evidence in refining our understanding of the genesis of alcohol-induced birth defects, to the planning and execution of future studies, and to applying the knowledge gained to diminish the severity or occurrence of fetal alcohol spectrum disorder.