NIH grant: Mechanisms of Phthalate Toxicity in Testis Development and Later-Life Function (1R01ES038190-01A1)

retained text

NIH grant 1R01ES038190-01A1: Mechanisms of Phthalate Toxicity in Testis Development and Later-Life Function
Institute: {'code': 'ES', 'abbreviation': 'NIEHS', 'name': 'National Institute of Environmental Health Sciences', 'admin_org_id': '12500022', 'admin_funding_url': ''}. PI: Daniel James Spade. Award: $582295.
Start: 2026-08-21T00:00:00.
PROJECT SUMMARY/ABSTRACT
The objectives of this project, Mechanisms of phthalate toxicity in testis development and later-life
function, are to define the mechanisms of phthalate toxicity to fetal testicular germ cell development and testis
morphogenesis, as well as the role of sperm RNAs in the persistent effects of phthalate toxicity in F1 adult males
and embryonic development of F2 embryos following paternal exposure. Phthalic acid esters (phthalates) are
chemicals used to make some plastics flexible and also used in some consumer products such as personal care
products. Humans are broadly exposed to low levels of phthalates, and some situations, such as medical
treatment requiring blood transfusions, can lead to higher levels of exposure. Because there is evidence of
increasing rates of adverse male reproductive health conditions in humans, such as decreased sperm count,
and because in utero phthalate exposure causes similar effects in rats, phthalates are considered a model for a
syndrome of adverse male reproductive health effects, known as Testicular Dysgenesis Syndrome. Phthalate
exposure during fetal development in the rat is known to disrupt the development of seminiferous cords, to cause
germ cell toxicity in the short term, and to decrease fertility and cause persistent testicular lesions in adults after
cessation of exposure. Further, there is evidence that paternal exposure to germ cell toxicants can result in
adverse effects on embryonic development in their offspring. However, it is largely unknown how paternal early-
life or preconception exposures can lead to adverse effects on offspring development or what biological
molecules in sperm mediate these effects. In this project, we will test how in utero exposure to a mixture of
phthalates disrupts the development of the testis and impairs germ cell health, the later-life effects on sperm
RNAs, and the consequences for embryo development. Our preliminary data show that exposure to dipentyl
phthalate causes adverse germ cell effects (multinucleated germ cells) at a lower dose than other effects of
phthalates; and that exposure to a mixture of phthalates can induce multinucleated germ cells, even when the
chemical doses would be individually non-toxic. To build on these preliminary findings, this project will test the
working hypothesis that in utero phthalate exposure persistently diminishes germline health, leading to impaired
offspring development. This hypothesis will be tested by fulfilling the following Specific Aims. Aim 1: Define the
mechanisms by which a low-dose phthalate mixture disrupts testis morphogenesis and germ cell development.
Aim 2: Identify sperm RNAs that mediate phthalate effects on fertility in later life and embryo development
outcomes in the next generation. The proposed research is innovative because it will test how a low-dose male
reproductive toxicant mixture can alter reproductive development and function in multiple life stages and between
generations. The proposed research is significant because it will address the lack of a mechanistic explanation
for disrupted seminiferous cord development. Completion of this work will improve our understanding of phthalate
toxicity mechanisms and dose-response, enabling science-based risk assessment to protect human health.

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