Male germline transmits fetal alcohol epigenetic marks for multiple generations: a review

Sarkar, Dipak K.

doi:10.1111/adb.12186

Cited by 42 publications

(36 citation statements)

References 98 publications

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“…Interestingly, these epigenetic effects can be mitigated by choline supplementation during the fetal period (Bekdash et al, 2013). The brain-specific changes in Pomc expression and promoter modifications, as well as behavioral changes seen in animals exposed to fetal alcohol, are passed along through the male germline transgenerationally, indicating that epigenetic alterations may contribute to the inherited risk for stress-related alcohol addiction (Govorko et al, 2012; Sarkar, 2016). …”

Section: Developmental Alcohol Exposure Causes Long-lasting Alteramentioning

confidence: 99%

Epigenetic basis of the dark side of alcohol addiction

2017

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Alcoholism is a complex brain disease characterized by three distinct stages of the addiction cycle that manifest as neuroadaptive changes in the brain. One such stage of the addiction cycle is alcohol withdrawal and the negative affective states that promote drinking and maintain addiction. Repeated alcohol use, genetic predisposition to alcoholism and anxiety, and alcohol exposure during crucial developmental periods all contribute to the development of alcohol-induced withdrawal and negative affective symptoms. Epigenetic modifications within the amygdala have provided a molecular basis of these negative affective symptoms, also known as the dark side of addiction. Here, we propose that allostatic change within the epigenome in the amygdala is a prime mechanism of the biological basis of negative affective states resulting from, and contributing to, alcoholism. Acute alcohol exposure produces an anxiolytic response which is associated with the opening of chromatin due to increased histone acetylation, increased CREB binding protein (CBP) levels, and histone deacetylase (HDAC) inhibition. After chronic ethanol exposure, these changes return to baseline along with anxiety-like behaviors. However, during withdrawal, histone acetylation decreases due to increased HDAC activity and decreased CBP levels in the amygdala circuitry leading to the development of anxiety-like behaviors. Additionally, innately higher expression of the HDAC2 isoform leads to a deficit in global and gene-specific histone acetylation in the amygdala that is associated with a decrease in the expression of several synaptic plasticity-associated genes and maintaining heightened anxiety-like behavior and excessive alcohol intake. Adolescent alcohol exposure also leads to higher expression of HDAC2 and a deficit in histone acetylation leading to decreased expression of synaptic plasticity-associated genes and high anxiety and drinking behavior in adulthood. All these studies indicate that the epigenome can undergo allostatic reprogramming in the amygdaloid circuitry during various stages of alcohol exposure. Furthermore, opening the chromatin by inhibiting HDACs using pharmacological or genetic manipulations can lead to the attenuation of anxiety as well as alcohol intake. Chromatin remodeling provides a clear biological basis for the negative affective states seen during alcohol addiction and presents opportunities for novel drug development and treatment options.

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Section: Developmental Alcohol Exposure Causes Long-lasting Alteramentioning

confidence: 99%

Epigenetic basis of the dark side of alcohol addiction

2017

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“…“Germline-independent” epigenetic inheritance is another phenomenon, and occurs because of behavioral parental factors when the effects of environmental insults (i.e., alcohol exposure) affect the uterine environment or the maternal behavior of the exposed F0 female, and thus induce epimutations in the F1 generation due to changes in the prenatal environment and/or maternal care, independent of any effect on the germline (Grossniklaus, Kelly, Ferguson-Smith, Pembrey, & Lindquist, 2013; Sarkar, 2016; Weaver, 2007). These epimutations may then be transmitted again through altered parental behavior by the adult F1 animals to the F2 offspring, and so on.…”

Section: Epigenetic Inheritancementioning

confidence: 99%

“…Although human studies of generational transfer of alcohol-related health problems is lacking, there are many studies showing multigenerational and a small number of studies showing transgenerational effects of alcohol exposure in animal models (for excellent reviews, see also Finegersh et al, 2015; Sarkar, 2016; and Yohn et al, 2015). Many studies have shown that paternal preconception alcohol exposure has detrimental effects on the F1 offspring behavior and neurobiology in mouse and rat models.…”

Section: Evidence For Epigenetic Inheritance Of Alcohol-related Pamentioning

confidence: 99%

“…The reason why methylation patterns on this gene along the male germline can be preserved and escape reprogramming during development is unknown. A possible explanation for this would be, since the phenotype is only passed down along the male germline and Pomc expression is regulated by the non-pairing region of the Y chromosome (Botbol et al, 2011), alcohol exposure leads to epigenetic modifications on the Y chromosome that are spared from reprogramming during development and are then passed down to subsequent generations (Sarkar, 2016). Future studies are needed to address this possibility.…”

Section: Possible Mechanisms For Germline-dependent Epigenetic Inhmentioning

confidence: 99%

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Alcohol effects on the epigenome in the germline: Role in the inheritance of alcohol-related pathology

Chastain

Sarkar

2017

Alcohol

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Excessive alcohol exposure has severe health consequences, and clinical and animal studies have demonstrated that disruptions in the epigenome of somatic cells, such as those in brain, are an important factor in the development of alcohol-related pathologies, such as alcohol-use disorders (AUDs) and fetal alcohol spectrum disorders (FASDs). It is also well known that alcohol-related health problems are passed down across generations in human populations, but the complete mechanisms for this phenomenon are currently unknown. Recent studies in animal models have suggested that epigenetic factors are also responsible for the transmission of alcohol-related pathologies across generations. Alcohol exposure has been shown to induce changes in the epigenome of sperm of exposed male animals, and these epimutations are inherited in the offspring. This paper reviews evidence for multigenerational and transgenerational epigenetic inheritance of alcohol-related pathology through the germline. We also review the literature on the epigenetic effects of alcohol exposure on somatic cells in brain, and its contribution to AUDs and FASDs. We note gaps in knowledge in this field, such as the lack of clinical studies in human populations and the lack of data on epigenetic inheritance via the female germline, and we suggest future research directions.

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“…The fact that epigenetic remodelling also takes place in the primordial germ cells of the developing foetus has raised concerns that suboptimal in-utero conditions not only programme the phenotype of the F1 generation but also of the subsequent generations F2 (intergenerational epigenetic effect), F3 (nonexposed generation; transgenerational effect) and beyond [40][41][42][43]. Thus, for example, consumption of a high-fat diet by mice during pregnancy and lactation has been reported to epigenetically alter metabolism-related genes such as leptin and peroxisome proliferator-activated receptor-a (PPAR-a), but not imprinted ones, in the hepatic tissue of the female offspring as well as in their oocytes [44 & ].…”

Section: Transgenerational Epigenetic Metabolic Programming Effects: mentioning

confidence: 99%

Developmental programming of type 2 diabetes

Ong

Ozanne

2015

Current Opinion in Clinical Nutrition and Metabolic Care

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Epigenetic processes may represent a central underlying mechanism of developmental programming of type 2 diabetes. During embryonic and foetal development, extensive epigenetic remodelling takes place not only in somatic but also in primordial germ cells. Therefore, concerns have been raised that epigenetic dysregulation induced by a suboptimal early environment could programme altered phenotypes not only in the first generation but also in the subsequent ones. Characterizing these altered epigenetic marks has great implications for identifying individuals at an increased disease risk as well as potentially leading to novel preventive and treatment strategies.

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Male germline transmits fetal alcohol epigenetic marks for multiple generations: a review

Cited by 42 publications

References 98 publications

Epigenetic basis of the dark side of alcohol addiction

Epigenetic basis of the dark side of alcohol addiction

Alcohol effects on the epigenome in the germline: Role in the inheritance of alcohol-related pathology

Developmental programming of type 2 diabetes

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