Dysregulation of TET enzymes contributes to transgenerational epigenetic inheritance in mice.

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Multi and transgenerational epigenetic effects of di-(2-ethylhexyl) phthalate (DEHP) in liver

Yi Wen  1 Saniya Rattan  2 Jodi A Flaws  2 Joseph Irudayaraj  3

Abstract

Di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous industrial pollutant, is a known endocrine disrupter implicated in metabolic diseases. Prenatal DEHP exposure promotes epigenetic multi- and transgenerational inheritance of adult onset disease in subsequent generations (F1-F3). However, the epigenetic toxicity is less understood in the liver. In this study, CD-1 mice were prenatally exposed to 20 μg/kg/day, 200 μg/kg/day, 500 mg/kg/day, or 750 mg/kg/day DEHP from gestational day (GD) 10.5 until birth of pups. Following prenatal exposure, the multigenerational and transgenerational effects of mRNA expression of epigenetic regulators were evaluated in F1, F2, and F3 generation mouse livers at postnatal days (PNDs) 8 and 60. Results showed that DEHP exposed mice livers exhibited significant changes in global DNA methylation levels in all three generations, with the effect being different in F2 after high dosage exposure. Histopathology indicated that DEHP exposure could induce mild damage in F1 livers. The expression levels of DNA methyltransferase 1 (Dnmt1) were significantly changed in both the F1 and F2 generations at PND 8, suggesting that maintenance Dnmt1 plays a major role in the multigenerational effect that occur in the early developmental stages. Additionally, DEHP exposure caused significant changes in ten-eleven translocation methylcytosine (Tet) dioxygenases encoding Tet1 expression in all three generations and Tet2 expression in F3 at PND 60, implicating their contributions in inducing both multi- and transgenerational effects after DEHP exposure in mouse liver. Overall, our results establish that prenatal and ancestral DEHP exposure are critical for epigenetic regulation of DNA methylation in female mouse livers.

Transgenerational epigenetic inheritance

Transgenerational epigenetic inheritance is the transmission of epigenetic marks from parent to child. Transgenerational epigenetic inheritance does not alter DNA of genes. To be at all useful in humans in terms of evolutionary fitness  epigenetic alterations on which transgenerational epigenetic inheritance is founded would have to be systematic    Both the wider organism and sperm cells and egg cells would have to be affected together by a class of epigenetic alterations.  Many illnesses that are classed as brain diseases such as autism, major depression and schizophrenia would have to have systematic effects which in fact these illnesses do have. Parents of children with autism, for example,  very frequently state that their children are systematically ill  and that all physical complaints of their children have to be addressed. Individuals with schizophrenia have much reduced life spans.   The heritability of  Alzheimer’s disease ranges from 49% to 79%. Alzheimer’s is classified as a brain disease but individuals with Alzheimer’s disease are ill in about every way imaginable.

Transgenerational epigenetic inheritance where stuff just happens to gametes and that stuff can be transgenerationally passed along would be totally useless in terms of human evolutionary fitness. Phenotypes are  selected by evolution. There are cultural traits which are very difficult to alter but which can be altered. If such cultural traits had a biological basis inheritance of such cultural traits would be feasible. Holding that there is a biological bases for cultural traits is usually viewed as racist, however, given the biological basis of cultural such traits depends on transgenerational epigenetic inheritances then though there are  biological bases for cultural traits such cultural traits are mutable over the course of generations rather than basically immutable due to such cultural traits being hardwired into DNA.

Any familiarity with history at all would disclose that women in the West are acting much differently than women acted three hundred years ago. Women in the elite classes three hundred years did not all  hold all was oppression and all secretly long to be scientists, head of businesses and heads governments but rather held there were various terrific advantages to being women of the elite classes in 1720.  The biology of women made being women of 1720, at least of the elite classes, very attractive to women in 1720, however, as is also clear cultural traits of women have not been immutable over the last 300 years. With transgenerational epigenetic inheritance various cultural traits of women can be both biologically based and mutable. Women as androgynous men will never work for women wholesale, DNA of women will always be different than the DNA of men, however, women as lawyers, women as doctors, women in business etc can and has worked for women.

A feature that distinguishes humans from  animal  could be that transgenerational epigenetic inheritances are very prevalent in humans.