Dissertation
Effects of phthalates on the reproductive tissues in rodents
Washington State University
Doctor of Philosophy (PhD), Washington State University
12/2009
DOI:
https://doi.org/10.7273/000006015
Abstract
Di-2-ethylhexyl phthalate (DEHP) and other phthalate esters are potent peroxisome proliferator plasticizers, pervasive in the environment. Phthalates readily leach into the environment, leading to multi-factorial exposure, subsequently, linked to adverse hormonal, reproductive, developmental effects in developing and adult animals. We treated gestating rodents with DEHP during the time of primordial germ cell migration, epigenetic reprogramming and urogenital development, but prior to steroidogenesis in the gonads or adrenal gland. Sprague Dawley rats were treated with 1 g/kg/day DEHP on embryonic day 8 (E8)-E15, while CD1 females were treated with 500 mg/kg/day on E7-15. CD1 offspring were mated for four consecutive generations to determine maternal (WT male x F1 female), paternal (F1 male x WT female) or double-cross (F1 male x F1 female) inheritance. In F1 generation, phthalates induced altered developmental, endocrine-related hallmarks in both rats and mice, suggestive of phthalates working by anti-androgenic mechanisms, where the balance of testosterone to estradiol is disturbed. These endocrine-related changes were not observed in F2 or F3 generations, indicating that effects were directly on embryos. In F1 to F4 generations, phthalates caused decreased testis weight, increased abnormal seminiferous tubule morphology, increased germ cell apoptosis and stacking of the late stages of the spermatogenic cycle, and decreased sperm count and forward progressive motility. Systemically, DEHP increased adult body weight, decreased cell population of pancreatic Islets of Langerhans, as well as increased vacuolization of glomulerus and renal tubules. The F1 to F4 effects were observed in offspring produced by the maternal and paternal lines and, was amplified in the double-cross lines. We concluded that embryonic exposure to DEHP, during the treatment time window, not only disrupted normal endocrine functions in the embryo, the consequent of which was observed in the F1 generation, but also negatively impacted gonadal, pancreatic and renal tissue physiology, which may be through a non-endocrine related, transgenerational mechanism. The molecular mechanism of transmission remains undetermined. Phthalates can act as anti-androgen and/or they can bind peroxisome proliferator-activated receptors and can inhibit retinoic acid receptor transcription. Notwithstanding, future investigation is required to determine the molecular mode of transgenerational effects.
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Details
- Title
- Effects of phthalates on the reproductive tissues in rodents
- Creators
- Jennifer Lee Bowman
- Contributors
- Kwanhee Kim (Chair)Heiko Jansen (Committee Member) - Washington State University, Department of Integrative Physiology and NeuroscienceDEREK J MCLEAN (Committee Member)Michael K. Skinner (Committee Member) - Washington State University, School of Biological SciencesJohn Jason Wyrick (Committee Member) - Washington State University, School of Molecular Biosciences
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 170
- Identifiers
- 99901055120401842
- Language
- English
- Resource Type
- Dissertation