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


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


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.

Friedreich’s ataxia and tight iron utilization


Friedreich’s ataxia is a genetic disease, where there are expansions of GAA trinucleotide repeats in intron 1 of both frataxin alleles. Gait and limb ataxia, dysarthria and loss of lower limb reflexes are clinical features Friedrich’s ataxia.

Mice models of Friedreich’s ataxia have been developed in which the gene for frataxin in is mutated, where the mice exhibit a progressive Friedreich’s ataxia-like pathology. Frataxin binds iron which assists in iron-sulfur cluster biogenesis.

Giving mice, with ataxia due to mutations in genes for frataxin, iron from iron carbonyl by gavage three times a day could be a treatment for such an ataxia as iron carbonyl given by gavage three times a day could tightly regulate iron utilization, making iron constantly available thereby making the frataxin protein less required or even redundant. As the iron chelator, desferal decreases expressiot of frataxin, carbonyl iron given by gavage three times a day to mice could also increase expression of the gene for frataxin.

As deferiprone, an iron chelator, can worsen ataxia in patients with Friedreich’s ataxia iron carbonyl given three times a day to humans could be part of a treatment for Friedreich’s ataxia. Prior to any clinical trials in humans, carbonyl iron, given by gavage three times a day from birth to mice with mutated frataxin genes, would have to stop a Friedreich’s ataxia-like pathology from developing and/or treat in mice, a Friedreich’s ataxia-like pathology after mice with mutated frataxin genes develope a Friedreich’s ataxia-like pathology.