@article{hild_reel_dykstra_mann_marshall_2007, title={Acute adverse effects of the indenopyridine CDB-4022 on the ultrastructure of Sertoli cells, spermatocytes, and spermiatids in rat testes: Comparison to the known Sertoli cell toxicant di-n-pentylphthalate DPP}, volume={28}, ISSN={["0196-3635"]}, DOI={10.2164/jandrol.106.002295}, abstractNote={ABSTRACT:  Acute effects of CDB‐4022 on testicular ultrastructure were determined. Rats were treated orally with vehicle or a maximally effective single dose of CDB‐4022 or Di‐n‐pentylphthalate (DPP). Preserved testes were processed for transmission electron microscopy. Sertoli and germ cells of vehicle‐treated rats demonstrated normal morphological characteristics. Disruption of Sertoli cell ultrastructure was apparent in CDB‐4022‐treated rats by 3 hours. A decrease in the presence of nucleoli, an increase in the amount and diameter of swollen smooth endoplasmic reticulum, and decreases in cytoplasmic ground substance were observed. The severity of these degenerative effects increased at 6 and 12 hours: Vacuoles were apparent; increased cellular debris, swollen mitochondria, and phagocytic structures were observed; and membranes became more disorganized. Similar ultrastructural changes were observed in the Sertoli cells of DPP‐treated rats. By 3 hours, spermatocytes and spermatids were adversely affected by CDB‐4022 treatment with swelling of the nuclear envelope. The Step 8 spermatids were especially noteworthy; chromatin was more diffuse and rarefied, the nuclear envelopes were incomplete or broken, and the position of the spermatid nucleus within the cell and relative to Sertoli cell cytoplasm was unusual. Fusion of spermatids to form giant cells was observed by 12 hours. CDB‐4022 acts acutely on Sertoli cells to induce marked cellular rarefaction and degeneration, but not necrosis. A rapid and direct effect of CDB‐4022 on spermatocytes and spermatids was observed. The antispermatogenic activity of CDB‐4022 appears to be a consequence of direct effects on Sertoli and germ cells.}, number={4}, journal={JOURNAL OF ANDROLOGY}, author={Hild, Sheri Ann and Reel, Jerry R. and Dykstra, Michael J. and Mann, Peter C. and Marshall, Gary R.}, year={2007}, pages={621–629} }
 @article{dykstra_mann_elwell_ching_2002, title={Suggested Standard Operating Procedures (SOPs) for the preparation of electron microscopy samples for toxicology/pathology studies in a GLP environment}, volume={30}, ISSN={["0192-6233"]}, DOI={10.1080/01926230290166823}, abstractNote={ We provide a set of Standard Operating Procedures (SOPs) for preparing samples for electron microscopic evaluation that allow storage of samples in the primary fixative for at least 17 years without noticeable degradation, do not compromise the ability to prepare the same samples for standard light microscopic evaluation, and provide tips for orientation of samples that may be necessary for evaluation. Guidelines for proper sample size, buffer composition, and fluid concentration s during processing are given. The impact of these procedures on specimen quality, ability to produce truly comparable samples for drug development studies, and ways to minimize time spent by technicians preparing these samples during necropsies is evaluated. Although many laboratories routinely employ most of these techniques, this compilation will facilitate the simultaneou s light and electron microscopic preparation by the pathologist of comparable specimens that can be stored long-term at 4°C in McDowell's and Trump's 4F:1G fixative (4F:1G). }, number={6}, journal={TOXICOLOGIC PATHOLOGY}, author={Dykstra, MJ and Mann, PC and Elwell, MR and Ching, SV}, year={2002}, pages={735–743} }
 @article{lambright_ostby_bobseine_wilson_hotchkiss_mann_gray_2000, title={Cellular and molecular mechanisms of action of linuron: An antiandrogenic herbicide that produces reproductive malformations in male rats}, volume={56}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/56.2.389}, abstractNote={Antiandrogenic chemicals alter sex differentiation by several different mechanisms. Some, like flutamide, procymidone, or vinclozolin compete with androgens for the androgen receptor (AR), inhibit AR-DNA binding, and alter androgen-dependent gene expression in vivo and in vitro. Finasteride and some phthalate esters demasculinize male rats by inhibiting fetal androgen synthesis. Linuron, which is a weak competitive inhibitor of AR binding (reported Ki of 100 microM), alters sexual differentiation in an antiandrogenic manner. However, the pattern of malformations more closely resembles that produced by the phthalate esters than by vinclozolin treatment. The present study was designed to determine if linuron acted as an AR antagonist in vitro and in vivo. In vitro, we (1) confirmed the affinity of linuron for the rat AR, and found (2) that linuron binds human AR (hAR), and (3) acts as an hAR antagonist. Linuron competed with an androgen for rat prostatic AR (EC(50) = 100-300 microM) and human AR (hAR) in a COS cell-binding assay (EC(50) = 20 microM). Linuron inhibited dihydrotestosterone (DHT)-hAR induced gene expression in CV-1 and MDA-MB-453-KB2 cells (EC(50) = 10 microM) at concentrations that were not cytotoxic. In short-term in vivo studies, linuron treatment reduced testosterone- and DHT-dependent tissue weights in the Hershberger assay (oral 100 mg/kg/d for 7 days, using castrate-immature-testosterone propionate-treated male rats; an assay used for decades to screen for AR agonists and antagonists) and altered the expression of androgen-regulated ventral prostate genes (oral 100 mg/kg/d for 4 days). Histological effects of in utero exposure to linuron (100 mg/kg/d, day 14-18) or DBP (500 mg/kg/d, day 14 to postnatal day 3) on the testes and epididymides also are shown here. Taken together, these results support the hypothesis that linuron is an AR antagonist both in vivo and in vitro, but it remains to be determined if linuron alters sexual differentiation by additional mechanisms of action.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Lambright, C and Ostby, J and Bobseine, K and Wilson, V and Hotchkiss, AK and Mann, PC and Gray, LE}, year={2000}, month={Aug}, pages={389–399} }
 @article{mahler_flagler_malarkey_mann_haseman_eastin_1998, title={Spontaneous and chemically induced proliferative lesions in Tg.AC transgenic and p53-heterozygous mice}, volume={26}, ISSN={["0192-6233"]}, DOI={10.1177/019262339802600406}, abstractNote={ Recently, the use of selected genetically altered mouse models in the detection of carcinogens after short-term chemical exposures has been evaluated. Studies of several chemicals conducted by the National Toxicology Program in Tg.AC transgenic and heterozygous p53-deficient mice have been completed recently and represent a major contribution to this effort, as well as the largest accumulation to date of toxicologic pathology data in these 2 lines of mice. The purpose of this report is to describe the proliferative target organ effects observed in this set of studies, as well as to present the tumor profile in the control groups of this data set. These findings provide a comprehensive toxicologic assessment of these 2 genetically altered mouse strains, which are of emerging importance in toxicologic pathology. }, number={4}, journal={TOXICOLOGIC PATHOLOGY}, author={Mahler, JF and Flagler, ND and Malarkey, DE and Mann, PC and Haseman, JK and Eastin, W}, year={1998}, pages={501–511} }