@article{simmers_hudson_baptissart_cowley_2022, title={Epigenetic control of the imprinted growth regulator Cdkn1c in cadmium-induced placental dysfunction}, volume={7}, ISSN={["1559-2308"]}, url={https://doi.org/10.1080/15592294.2022.2088173}, DOI={10.1080/15592294.2022.2088173}, abstractNote={ABSTRACT Cadmium (Cd) is a toxic metal ubiquitous in the environment. In utero, 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 Cdkn1c/CDKN1C 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 in utero Cd exposure to determine if the increase in placental Cdkn1c 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 Cdkn1c expression at late gestation. Using polymorphisms to distinguish parental alleles, we demonstrate that increased Cdkn1c expression is not driven by changes to DNA methylation or LOI. We show that Cdkn1c 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 Cdkn1c 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 Cdkn1c/CDKN1C expression.}, journal={EPIGENETICS}, author={Simmers, Mark D. and Hudson, Kathleen M. and Baptissart, Marine and Cowley, Michael}, year={2022}, month={Jul} }
 @article{riegl_starnes_jima_baptissart_diehl_belcher_cowley_2022, title={The imprinted gene Zac1 regulates steatosis in developmental cadmium-induced nonalcoholic fatty liver disease}, volume={10}, ISSN={["1096-0929"]}, url={https://doi.org/10.1093/toxsci/kfac106}, DOI={10.1093/toxsci/kfac106}, abstractNote={Abstract
               Cadmium (Cd) exposure in adulthood is associated with nonalcoholic fatty liver disease (NAFLD), characterized by steatosis, inflammation, and fibrosis. The prevalence of NAFLD in children is increasing, suggesting a role for the developmental environment in programming susceptibility. However, the role of developmental Cd exposure in programming NAFLD and the underlying mechanisms remain unclear. We have proposed that imprinted genes are strong candidates for connecting the early life environment and later life disease. In support of this, we previously identified roles for the Imprinted Gene Network (IGN) and its regulator Zac1 in programming NAFLD in response to maternal metabolic dysfunction. Here, we test the hypothesis that developmental Cd exposure is sufficient to program NAFLD, and further, that this process is mediated by Zac1 and the IGN. Using mice, we show that developmental cadmium chloride (CdCl2) exposure leads to histological, biochemical, and molecular signatures of steatosis and fibrosis in juveniles. Transcriptomic analyses comparing livers of CdCl2-exposed and control mice show upregulation of Zac1 and the IGN coincident with disease presentation. Increased hepatic Zac1 expression is independent of promoter methylation and imprinting statuses. Finally, we show that over-expression of Zac1 in cultured hepatocytes is sufficient to induce lipid accumulation in a Pparγ-dependent manner and demonstrate direct binding of Zac1 to the Pparγ promoter. Our findings demonstrate that developmental Cd exposure is sufficient to program NAFLD in later life, and with our previous work, establish Zac1 and the IGN as key regulators of prosteatotic and profibrotic pathways, two of the major pathological hallmarks of NAFLD.}, journal={TOXICOLOGICAL SCIENCES}, author={Riegl, Sierra D. and Starnes, Cassie and Jima, Dereje D. and Baptissart, Marine and Diehl, Anna Mae and Belcher, Scott M. and Cowley, Michael}, year={2022}, month={Oct} }
 @article{baptissart_bradish_jones_walsh_tehrani_marrero-colon_mehta_jima_oh_diehl_et al._2022, title={Zac1 and the Imprinted Gene Network program juvenile NAFLD in response to maternal metabolic syndrome}, volume={2}, ISSN={["1527-3350"]}, url={https://doi.org/10.1002/hep.32363}, DOI={10.1002/hep.32363}, abstractNote={Abstract
          
            Background and Aims
            Within the next decade, NAFLD is predicted to become the most prevalent cause of childhood liver failure in developed countries. Predisposition to juvenile NAFLD can be programmed during early life in response to maternal metabolic syndrome (MetS), but the underlying mechanisms are poorly understood. We hypothesized that imprinted genes, defined by expression from a single parental allele, play a key role in maternal MetS‐induced NAFLD, due to their susceptibility to environmental stressors and their functions in liver homeostasis. We aimed to test this hypothesis and determine the critical periods of susceptibility to maternal MetS.
          
          
            Approach and Results
            We established a mouse model to compare the effects of MetS during prenatal and postnatal development on NAFLD. Postnatal but not prenatal MetS exposure is associated with histological, biochemical, and molecular signatures of hepatic steatosis and fibrosis in juvenile mice. Using RNA sequencing, we show that the Imprinted Gene Network (IGN), including its regulator Zac1, is up‐regulated and overrepresented among differentially expressed genes, consistent with a role in maternal MetS‐induced NAFLD. In support of this, activation of the IGN in cultured hepatoma cells by overexpressing Zac1 is sufficient to induce signatures of profibrogenic transformation. Using chromatin immunoprecipitation, we demonstrate that Zac1 binds the TGF‐β1 and COL6A2 promoters, forming a direct pathway between imprinted genes and well‐characterized pathophysiological mechanisms of NAFLD. Finally, we show that hepatocyte‐specific overexpression of Zac1 is sufficient to drive fibrosis in vivo.
          
          
            Conclusions
            Our findings identify a pathway linking maternal MetS exposure during postnatal development to the programming of juvenile NAFLD, and provide support for the hypothesis that imprinted genes play a central role in metabolic disease programming.
          }, journal={HEPATOLOGY}, author={Baptissart, Marine and Bradish, Christine M. and Jones, Brie S. and Walsh, Evan and Tehrani, Jesse and Marrero-Colon, Vicmarie and Mehta, Sanya and Jima, Dereje D. and Oh, Seh Hoon and Diehl, Anna Mae and et al.}, year={2022}, month={Feb} }
 @article{baptissart_lamb_to_bradish_tehrani_reif_cowley_2018, title={Neonatal mice exposed to a high-fat diet in utero influence the behaviour of their nursing dam}, volume={285}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85056612433&partnerID=MN8TOARS}, DOI={10.1098/rspb.2018.1237}, abstractNote={
            The behaviour of a nursing dam influences the development, physiology, and behaviour of her offspring. Maternal behaviours can be modulated both by environmental factors, including diet, and by physical or behavioural characteristics of the offspring. In most studies of the effects of the environment on maternal behaviour, F
            0
            dams nurse their own F
            1
            offspring. Because the F
            1
            are indirectly exposed to the environmental stressor
            in utero
            in these studies, it is not possible to differentiate between effects on maternal behaviour from direct exposure of the dam and those mediated by changes in the F
            1
            as a consequence of
            in utero
            exposure. In this study, we used a mouse model of high-fat (HF) diet feeding, which has been shown to influence maternal behaviours, combined with cross-fostering to discriminate between these effects. We tested whether the diet of the F
            0
            dam or the exposure experienced by the F
            1
            pups
            in utero
            is the most significant predictor of maternal behaviour. Neither factor significantly influenced pup retrieval behaviours. However, strikingly, F
            1
            in utero
            exposure was a significant predictor of maternal behaviour in the 15 min immediately following pup retrieval while F
            0
            diet had no discernable effect. Our findings suggest that
            in utero
            exposure to HF diet programmes physiological changes in the offspring which influence the maternal behaviours of their dam after birth.
          }, number={1891}, journal={Proceedings of the Royal Society B: Biological Sciences}, publisher={The Royal Society}, author={Baptissart, M. and Lamb, H.E. and To, K. and Bradish, C. and Tehrani, J. and Reif, David and Cowley, M.}, year={2018}, pages={20181237} }