PROJECT SUMMARY/ABSTRACT
This ONES award will elucidate the mechanisms by which phthalates, a class of endocrine-disrupting chemicals,
disrupt prostaglandin and angiogenic function during the critical period of ovulation. Further, rescue approaches
will be investigated to alleviate phthalate-induced inhibition of ovulation and fertility, which is crucial for
environmental and reproductive health as exposure to phthalates is unavoidable. Phthalates are incorporated in
several common consumer, medical, housing, and personal care products leading to daily human exposure.
However, little is known about the effects of environmentally relevant levels and mixtures of phthalates on
ovulation, especially in women. This is alarming because defects in ovulation are the leading cause of female
infertility. The abundant increase of prostaglandins in the ovary and the surge of new vasculature formation, via
angiogenesis, are vital for ovulation and fertility. Preliminary data for this proposal are the first to show that an
environmentally relevant phthalate mixture decreases the levels of prostaglandins and factors that drive
angiogenesis in human and mouse ovarian samples. Further, the phthalate mixture decreased ovulation rates
by 96% in mouse samples. These findings suggest that environmentally relevant phthalate exposure targets
ovulatory prostaglandin and angiogenic action, which may cause infertility. Our compelling preliminary data also
suggest that supplementation with cyclic adenosine monophosphate, a common cell signaling molecule, to
human ovarian cells may rescue the phthalate-induced decreases in ovulatory prostaglandin and angiogenic
factor levels. A major strength of this proposal is our ability to mimic human exposure to phthalates by the use
of environmentally relevant phthalate mixtures and human ovarian models. These models, as well as in vivo and
in vitro mouse models, will be used to test the hypothesis that phthalates inhibit ovulatory prostaglandin
production and function, leading to impaired angiogenesis and ovulatory failure/infertility. Specific Aim 1 will
elucidate the mechanism by which phthalates decrease ovulatory prostaglandin levels. Specific Aim 2 will
determine the deficiencies in angiogenesis, ovulation, and fertility caused by phthalates. Specific Aim 3 will define
approaches to alleviate phthalate toxicity. These findings will advance environmental health sciences by
providing mechanistic data establishing the impact of environmentally relevant phthalate mixture exposure on
prostaglandin and angiogenic function, which are essential mediators for fertility. Thus, these findings will reveal
novel actions of phthalates on infertility and reproductive dysfunction. Additionally, the use of human samples
and the establishment of rescue approaches provide a translational approach to understanding and mitigating
phthalate toxicities. Infertility in women seeking to conceive leads to a decreased quality of life, including
increased levels of stress, diminished social functioning, and mental and physical health issues. By delineating
the detrimental impacts of phthalate exposure on ovulation and fertility, the overarching goal of this proposal is
to provide a foundation to benefit women’s reproductive and general healthcare.
