Reconsidering "low-dose"-Impacts of oral estrogen exposure during preimplantation embryo development

Perturbations of estrogen signaling during developmental stages of high plasticity may lead to adverse effects later in life. Endocrine-disrupting chemicals (EDC) are compounds that interfere with the endocrine system by particularly mimicking the action of endogenous estrogens as functional agonists or antagonists. EDCs compose synthetic and naturally occurring compounds discharged into the environment, which may be taken up via skin contact, inhalation, orally due to contaminated food or water, or via the placenta during in utero development. Although estrogens are efficiently metabolized by the liver, the role of circulating glucuro- and/or sulpho-conjugated estrogen metabolites in the body has not been fully addressed to date. Particularly, the role of intracellular cleavage to free functional estrogens could explain the hitherto unknown mode of action of adverse effects of EDC at very low concentrations currently considered safe. We summarize and discuss findings on estrogenic EDC with a focus on early embryonic development to highlight the need for reconsidering low dose effects of EDC.