Epigenetic control of the imprinted growth regulator <i>Cdkn1c</i> in cadmium-induced placental dysfunction

Cadmium (Cd) is a toxic metal ubiquitous in the environment. <i>In utero</i>, Cd is inefficiently transported to the foetus but causes foetal growth restriction (FGR), likely through impairment of the placenta where Cd accumulates. However, the underlying molecular mechanisms are poorly understood. Cd can modulate the expression of imprinted genes, defined by their transcription from one parental allele, which play critical roles in placental and foetal growth. The expression of imprinted genes is governed by DNA methylation at Imprinting Control Regions (ICRs), which are susceptible to environmental perturbation. The imprinted gene <i>Cdkn1c/CDKN1C</i> is a major regulator of placental development, is implicated in FGR, and shows increased expression in response to Cd exposure in mice. Here, we use a hybrid mouse model of <i>in utero</i> Cd exposure to determine if the increase in placental <i>Cdkn1c</i> expression is caused by changes to ICR DNA methylation and loss of imprinting (LOI). Consistent with prior studies, Cd causes FGR and impacts placental structure and <i>Cdkn1c</i> expression at late gestation. Using polymorphisms to distinguish parental alleles, we demonstrate that increased <i>Cdkn1c</i> expression is not driven by changes to DNA methylation or LOI. We show that <i>Cdkn1c</i> is expressed primarily in the placental labyrinth which is proportionally increased in size in response to Cd. We conclude that the Cd-associated increase in <i>Cdkn1c</i> expression can be fully explained by alterations to placental structure. These results have implications for understanding mechanisms of Cd-induced placental dysfunction and, more broadly, for the study of FGR associated with increased <i>Cdkn1c/CDKN1C</i> expression.