Embryonic inheritance of sperm methylome after adult exposure to phthalates

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Summary Phthalates, a class of endocrine disrupting compounds (EDCs) used in plastics and personal care products, are ubiquitous environmental contaminants resulting in widespread human exposure. Epidemiologic data implicate paternal phthalates with adverse reproductive health including poor sperm quality, and more recently, with longer time to pregnancy − the latter suggests a sperm-derived effect. A growing body of compelling data demonstrates that environmental exposures can be embodied within the developing male germ cell through epigenetic marks, which in turn, can impart information at fertilization to affect the trajectory of health and development of offspring. It is known that prenatal epigenetic reprogramming of male germ cells is a particularly susceptible window to environmental exposures such as phthalates. Research has now emerged demonstrating that other such susceptible windows exist during germ cell development. Our long- term goal is to provide an epigenetic understanding of how paternal EDC exposure affects reproductive and offspring health – in both embryonic and placental tissue. The objective here is to determine the effects of adult exposure to di(2-ethylhexyl) phthalate (DEHP) on sperm DNA methylation and the persistence of these sperm-derived changes on DNA methylation programming of the conceptus. Our central hypothesis is that adult DEHP exposure confers DNA methylation changes in sperm that persist in F1 conceptus. Adult reproductive age (7-8 wks old) male PWD mice will be treated with 0, 2.5 and 250 mg/kg body weight/day of DEHP for 60 days. Epididymal sperm will be collected and will be analyzed for whole genome bisulfite sequencing. Using parental strains that will allow for allele specific analysis across the genome, we will perform RNA-seq and whole genome bisulfite sequencing in embryonic and extraembryonic (placenta) tissues of E6.5 embryos. The research proposed in the above aims is expected to identify a DNA methylation signature in sperm as well as in the developing conceptus as a consequence of DEHP exposure in adult male mice. Such results are the first step to significantly advance our understanding of the mechanisms by which paternal environmental exposures in adulthood affect reproductive health, successful development and offspring health.