Environmental influence on gametes and embryos

National Institute Of Environmental Health Sciences

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Linked publications, trials & patents

Abstract

A universal feature of fertilization in mammals is that the fertilizing sperm evokes a series of repetitive calcium oscillations in the egg that persist for several hours and terminate with pronucleus formation. This pattern of calcium oscillations in mice is essential for both early events of egg activation in response to fertilization and for full term intrauterine development to occur. The factor within sperm responsible for inducing these calcium oscillations is a testis-specific phospholipase C, PLC zeta, which is released from the sperm head after sperm-egg plasma membrane fusion and is found in all mammalian sperm studied to date, including human. Calcium oscillations are also controlled by factors within the egg. Studies are being performed using the mouse model to examine molecules within the egg that are responsible for controlling calcium oscillation behavior and calcium reuptake, processes that are essential for the continuation of calcium oscillations at fertilization. We found that plasma membrane calcium ATPases are critical mediators of calcium signaling at fertilization, and that TRPM7 is required in the preimplantation embryo for successful development. Our results support the importance of egg-intrinsic properties in determining calcium oscillation patterns and have important implications for the interpretation and comparison of studies on calcium dynamics at fertilization. Because TRPM7 activity is modulated by the concentration of divalent cations in embryo culture medium, this finding has important implications for the environmental conditions under with human embryos are cultured during assisted reproduction procedures. In our ongoing studies, we are determining additional mechanisms by which calcium fluxes are regulated following fertilization and the impact of alterations in these fluxes on offspring development and health. We anticipate that by achieving a better understanding of the molecular and cellular modes of regulation of calcium oscillatory behavior during egg activation, we can learn how early embryo development is altered by environmental factors and by disease states. A number of essential molecules are encoded by maternal mRNAs that are dormant until oocyte maturation but critically important for fertilization and the early steps of embryonic development. One of these steps, embryonic genome activation (EGA), is orchestrated by an intrinsic developmental program initiated during oocyte maturation, but we have an incomplete understanding of how the transcriptional machinery and/or sequence-specific transcription factors dictate the timing of EGA in mammals and contribute to developmental potential. We found that endogenous DNA damage in the early embryo activates the tumor suppressor protein, p53, which in turn activates transcription of DUX, a key driver of EGA. A similar DNA damage-induced signaling pathway activates DUX4 (the human homolog of mouse DUX) in cells from patients with facioscapulohumeral muscular dystrophy, a human disease characterized by a progressive degeneration of affected muscle groups. A paper describing these results was published. These studies shed light on basic genetic processes that can be disrupted by exposure to environmental chemicals and could impact human fertility and other human disease states.