A trend of declining sperm counts in humans has been documented for the past several decades.  Disruption of fetal testis development due to environmental toxicant exposure is one proposed cause of this disturbing trend.  In both humans and laboratory animals, in utero exposure to estrogenic compounds can result in testicular dysgenesis and impaired sperm production; however, the specific genetic pathways involved are unknown.  Using transgenic mouse models, we have recently identified activin A protein as a critical factor for normal testis morphogenesis.  Disruption of the activin A pathway results in fetal testis dysgenesis leading to low sperm counts in adult mice.  The similarities between the testes of mice with disrupted activin A signaling and those of mice with fetal exposure to estrogenic toxicants suggested the activin A pathway could be a target of estrogenic compounds.  Interestingly, links between the activin A pathway and estrogen have been demonstrated in the neonatal mouse ovary; however, it is unknown whether this relationship also exists in the fetal testis.  We hypothesize that one mechanism behind estrogen-induced fetal testis dysgenesis in mice is disruption of the activin A pathway.  To test our hypothesis, we are performing in vivo dosing studies of pregnant dams with the estrogenic compounds diethylstilbestrol (DES) and bisphenol A (BPA).  By evaluating changes in fetal testis histology and gene expression related to this pathway, we will analyze whether activin A signaling is influenced by estrogenic exposures. Since components of the activin A signaling pathway are also present in human fetal testes, this research may uncover potential mechanisms behind estrogen-induced changes in human testis development. 

I am currently a Neuroscience PhD student in the Schantz lab working on the effect of developmental polychlorinated biphenyl (PCB) exposure on the susceptibility to noise-induced hearing loss. PCBs have long been recognized as environmental neurotoxicants that were used in industry until they were banned in 1978.  Even though their production has halted, PCBs are still dispersed our environment. Humans are exposed to them primarily via consumption of contaminated fish, and a major concern is that PCBs can cross the mammalian placenta and enter breast milk.  This developmental exposure to the fetus can result in auditory deficits. Laboratory studies have identified the cochlea as the site of action for PCB toxicity due to a loss of outer hair cells, which can then increase susceptibility to noise-induced hearing loss. Because developmental exposure to PCBs is known to cause hearing deficits that are related to outer hair cell damage or loss, and outer hair cells are important for protecting against noise-induced damage, developmental PCB exposure may result in an increased susceptibility to noise-induced hearing loss.  We propose to examine this question by exposing female dam rats to the Fox River PCB mixture during gestation and through lactation.  At 100 days of age, those pups will be exposed to noise.  Their auditory function will be tested using distortion product otoacoustic emissions (DPOAEs) to measure cochlear function and auditory brain stem responses (ABRs) to measure the integrity of the auditory pathway, 1 and 4 weeks after noise exposure to determine if deficits are temporary or permanent.

I am currently a PhD student at Dr. Jodi Flaws’ lab in the department of veterinary biosciences. My current project focuses on the ‘Effects of Methoxychlor (MXC) on antral follicles and also the ovary’. MXC is known as reproductive toxicant and is used all over the world to control a wide range of pests that attack crops, trees, vegetables, fruits, gardens, stored grain, livestock, and domestic pets. MXC use became widespread after DDT use was banned in many parts of the world. The lipophilic nature of MXC as well as its slow chemical and biological degradation allows it to easily pass through membranes, accrue in tissues of organisms, and advance up food chains. MXC has diverse effects on reproductive tissues, which ultimately lead to decreased fertility in animal models. I propose to test the hypothesis that MXC works through estrogen receptor and/or aryl hydrocarbon receptor pathways to decrease ovarian estradiol levels and that the decreased estradiol levels alter Bcl-2/Bax levels, driving follicles towards atresia.   MXC may work through ERα, ERβ and/or AhR pathways to inhibit expression of enzymes required for estradiol (E2) synthesis and/or induce expression of the enzymes involved in metabolism of E2. Alternatively, MXC may affect E2 concentrations through non-ER and non-AhR pathways. The decreased synthesis of E2 and/or the increased metabolism of E2 then cause low levels of E2, which in turn alters Bcl-2/Bax ratios in antral follicles.  Altered Bcl-2/Bax ratios then lead to antral follicle atresia. Thus, the proposed studies will increase our understanding of the mechanisms by which endocrine disruption adversely affects ovarian function through multiple pathways. This improved understanding may lead to the development of novel ligands for the ERs and AhR, which may be used to treat infertility or may be used as contraceptive agents.