How do environmental factors produce transgenerational influences? Biol Psy.Feb.2013

27.02.2013

The  genetic factors responsible for psychiatric disorders and their heritability  still remains unclear. It is postulated that non genetic components,  epigenetic factors, may also contribute to disease heritability. These are mechanisms that modify the chromatin to modulate gene expression, without affecting the DNA sequence itself.  Major Epigenetic mechanisms  are 1. DNA methylation 2.Histone posttranslational modifications (HPTMs) 3. Small noncoding RNAs (sncRNAs).  The epigenetic alterations induced by environmental stimuli or events often persist a lifetime and, in certain conditions, can be transmitted to subsequent generations .Epigenetic factors  provide an evolutionary advantage ie adaptive responses to environmental challenges are rapidly acquired and passed across generations.

Johannes Bohacek, Katharina Gapp, Bechara J. Saab, and Isabelle M. Mansuy  review current evidence for transgenerational inheritance of cellular or behavioral traits induced by environmental conditions in mammals.

Epigenetic markers can propagate across generations via two routes: 1. Behavioural Transfer   2. Germline Transmission.

Behavioral Transfer  ( non germline transfer): Example: Good or poor maternal care in rats  alters DNA methylation throughout the genome. Good care decreases methylation at a transcription factor-binding site within the glucocorticoid receptor (GR) gene in the hippocampus, increasing GR expression.This  is associated with predisposition to stress resilience in adult animals. This effect can be passed to the following generation through altered maternal behaviors: it is not permanent and needs to be reinstated at each generation by maternal behaviors.

Germline Transmission : Germline transmission of behavioral and physiological traits induced by environmental conditions does not require reinstatement at each generation . This  is possibly by epigenetic process in sperm cells. But how do the epigenetic changes be establsihed in germ cells?  Most of DNA methylations  are erased by reprogramming during gametogenesis and most HPTMs are lost  during spermatogenesis.It is thought that certain molecular “loopholes”  would allow the transmission of some of the  DNAme and HPTMs. Some DNA methylations in germ cells  can be altered by environmental factors such as toxins , stress , or aging at specific genes and these remains altered across generations. Many sncRNAs have been detected in sperm and this may also contribute to transmission.

Evidence: Traumatic events in early post natal life (unpredictable maternal separation and maternal stress ) affects behaviour across several generations.  Pups subjected to these and their offsprings show specific behavioural and molecular changes at different stages of life. Maternally abused rats show DNA hypermethylation in the BDNF gene and have reduced BDNF mRNA expression in the prefrontal cortex.This effect is passed to the offspring by the mother and is only partially reversed by cross-fostering, suggesting that the germ line is contributing to the transmission. DNA methylation in germ cells is likely to play a role, but the precise mechanisms of transmission remain to be identified.

Toxins: Exposure to chemicals like Vinclozolin (fungicide),  and environmental estrogen bisphenol A (BPA) are shown to  exert transgenerational effects.

Enriched environements: Animal studies show that  enriched environmental conditions  have transgenerational effects. Juvenile mice (2–4 weeks old) raised in enriched conditions have enhanced memory performance and increased synaptic plasticity as adults, an effect that is also observed in their offspring.

Future: Research need to unravel how precisely  epigenetic factors are modified by environment and how they  get in to mature germ cells and translate later in to effects. Epigenetic processes can be manipulated and possibly corrected through pharmacological intervention.  Epigenetic drugs targeting DNA methylation and HPTMs can reverse these processes and provide  therapeutic benefits. Histone deacetylase inhibitors  mimic the effects of antidepressants and is shown to alleviate cognitive and neurological defects in animals . Drugs of this kind could relieve or cure symptoms of complex neuropsychiatric disorders in human patients.

Summary of the article:

Transgenerational epigenetic effects on brain functions. Bohacek J, Gapp K, Saab BJ, Mansuy IM. Biol Psychiatry. 2013 Feb 15;73(4):313-20.

 

 

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