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3 Introduction to the Study of Generational Effects
Pages 41-62

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From page 41...
... This chapter describes how environmental exposures can affect the genome and epigenome, explains how those changes can be transmitted to children and subsequent generations, and provides a brief background on the evolving field of generational health effects. The committee cautions, however, that not all adverse effects on reproduction or fetal development are the result of genetic or epigenetic mechanisms: during gestation, on the developing embryo and fetus.
From page 42...
... The sperm and the egg (the mature male and female germ cells, also called gametes) have only one set of 23 chromosomes each.
From page 43...
... Thus, in addition to DNA mutations and small variations in DNA sequence within populations (polymorphisms) , environmental exposures and life experiences may also affect an individual's susceptibility to disease.
From page 44...
... Thus, the epigenome of developing germ cells in the embryo and fetus is quite susceptible to environmental exposures (Fraser and Lin, 2016; Xu and Xie, 2018)
From page 45...
... , generational effects caused by that exposure could be mediated by a different type of epigenetic factor, such as DNA methylation. The epigenetic machinery -- the enzymes that "read, write, and erase" epigenetic marks -- controls DNA methylation, histone marks, ncRNAs, and chromatin-remodeling proteins and is essential for the proper installation and maintenance of epigenetic functions.
From page 46...
... This is termed meiotic inheritance and can lead to generational effects. Depending on the timing of the exposure during development, DNA methylation changes can profoundly affect germ cells (Ly et al., 2015; Wu et al., 2015)
From page 47...
... . Given their important functions in human germ cells, miRNAs are particularly relevant to the study of generational inheritance.
From page 48...
... In Figure 3-3, effects of the maternal exposure observed in the children and grandchildren (F1 and F2 generations) constitute intergenerational effects, while effects observed in the greatgrandchildren -- that is, the F3 generation, the first generation to not have been exposed directly or via germ cells -- are considered to be transgenerational effects.
From page 49...
... Consequently, the effects of gestational exposures on children and grandchildren (F1 and F2) are considered to be intergenerational effects, while effects observed in the great-grandchildren -- that is, the F3 generation, the first generation to not have been exposed directly or via germ cells -- are considered to be transgenerational effects.
From page 50...
... germ cells that may be affected by toxicant exposures are shown in the top and bottom panels, respectively. Epigenetic remodeling of DNA methylation and histone marks take place during both male and female germ cell development.
From page 51...
... Toxic Insult to Sperm or Eggs Prior to Conception Animal models and epidemiological studies have demonstrated a significant role of sex in the response of parental germ cells to toxicants. Because the timing of germ cell production and maturation is vastly different for men and for women (refer to Figure 3-4 for details)
From page 52...
... After the stem cell phase, epigenetic changes can be incorporated into sperm in two main ways: at the time of the repackaging of DNA and through RNAs included with the sperm in semen. Key epigenetic modifications normally occur in male germ cells during the repackaging of chromatin.
From page 53...
... . To emphasize the complexity of the challenge of understanding intergenerational effects, it should be noted that for epigenetic marks to have an effect on future generations they need to be malleable enough to be affected by a subtle environmental effect but, at the same time, stable enough to survive the reprogramming that occurs during the formation of the early embryo and the germ line and during development.
From page 54...
... . That is, epigenetic marks are gained in male germ cells in the fetal period, whereas epigenetic marks are gained in female germ cells as adults.
From page 55...
... (top) An exposure during pregnancy can affect the fetus and the germ cells developing in the fetus' ovaries or testes.
From page 56...
... However, some epidemiological studies examining men exposed to the Swedish famines or to the Dutch "Hunger Winter" have attempted to identify periods of development where germ cells may be more susceptible to environmental stresses (Vansant et al., 2016)
From page 57...
... . Studies in male mice exposed to chronic stress prior to mating also showed a significant epigenetic reprogramming of their germ cells.
From page 58...
... 2017. The interplay of epigenetic marks during stem cell differentiation and development.
From page 59...
... 2010. Distinguishing epigenetic marks of developmental and imprinting regulation.
From page 60...
... 2016. MicroRNAs: From female fertility, germ cells, and stem cells to cancer in humans.
From page 61...
... 2015. Multigenerational and transgenerational effects of endocrine disrupting chemicals: A role for altered epigenetic regulation?


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