Development of a human liver microphysiological coculture system for higher throughput chemical safety assessment.

Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher-throughput 96-well format for the determination of toxicity on target tissues in the presence of physiologically relevant human liver metabolism. This 2-chamber system is a hydrogel formed within each well consisting of a central well (target tissue) and an outer ring-shaped trough (human liver tissue).

Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis.

Phthalic acid esters (phthalates) are a class of industrial chemicals that cause developmental and reproductive toxicity, but there are significant gaps in knowledge of phthalate toxicity mechanisms. There is evidence that phthalates disrupt retinoic acid signaling in the fetal testis, potentially disrupting control of spatial and temporal patterns of testis development. Our goal was to determine how a phthalate would interact with retinoic acid signaling during fetal mouse testis development.

Trichloroethylene exposure alters dimethylated histone three lysine four in protein kinase A signaling pathway chromatin of rat sperm†.

Histone three lysine four dimethylation (H3k4me2) in sperm is conserved across species and is linked to transgenerational epigenetic inheritance. To test whether H3K4me2 is a target for transgenerational inheritance of toxicity, a daily gavage bolus exposure of trichloroethylene (TCE) (1000 mg/kg/day) was given to rats for 14 weeks, then epididymal sperm were isolated and native chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) of H3K4me2 was performed. Differential region analysis determined there were 2608 significantly differential H3K4me2 regions after TCE exposure, 477 were significantly increased and 2131 were significantly decreased.

Spermatozoal large RNA content is associated with semen characteristics, sociodemographic and lifestyle factors.

Semen analysis is one of the standard diagnostic tools currently used to assess male infertility and reproductive toxicity. However, semen analysis has a limited ability to separate fertile from infertile populations. Additional methods to detect impaired fertility are needed.

Differential toxicity of water versus gavage exposure to trichloroethylene in rats.

Trichloroethylene (TCE) is a persistent environmental contaminant that causes male reproductive toxicity. We investigated whether transient increases in TCE exposure modulated male reproductive toxicity by exposing rats via daily oral to repeated gavage exposures (1000 mg/kg/day) and through drinking water (0.6% TCE) for 14 weeks.

Small RNAs in Rat Sperm Are a Predictive and Sensitive Biomarker of Exposure to the Testicular Toxicant Ethylene Glycol Monomethyl Ether.

Testicular histology and semen parameters are considered the gold standards when determining male reproductive toxicity. Ethylene glycol monomethyl ether (EGME) is a testicular toxicant with well-described effects on histopathology and sperm parameters. To compare the predictivity and sensitivity of molecular biomarkers of testicular toxicity to the traditional endpoints, small RNAs in the sperm were analyzed by next generation RNA-sequencing (RNA-seq).

All-trans Retinoic Acid Disrupts Development in Ex Vivo Cultured Fetal Rat Testes. II: Modulation of Mono-(2-ethylhexyl) Phthalate Toxicity.

Humans are universally exposed to low levels of phthalate esters (phthalates), which are used to plasticize polyvinyl chloride. Phthalates exert adverse effects on the development of seminiferous cords in the fetal testis through unknown toxicity pathways. To investigate the hypothesis that phthalates alter seminiferous cord development by disrupting retinoic acid (RA) signaling in the fetal testis, gestational day 15 fetal rat testes were exposed for 1-3 days to 10-6 M all-trans retinoic acid (ATRA) alone or in combination with 10-6-10-4 M mono-(2-ethylhexyl) phthalate (MEHP) in ex vivo culture.

All-Trans Retinoic Acid Disrupts Development in Ex Vivo Cultured Fetal Rat Testes. I: Altered Seminiferous Cord Maturation and Testicular Cell Fate.

Exposure to excess retinoic acid (RA) disrupts the development of the mammalian testicular seminiferous cord. However, the molecular events surrounding RA-driven loss of cord structure have not previously been examined. To investigate the mechanisms associated with this adverse developmental effect, fetal rat testes were isolated on gestational day 15, after testis determination and the initiation of cord development, and cultured in media containing all-trans RA (ATRA; 10-8 to 10-6 M) or vehicle for 3 days.

Effects of continuous bisphenol A exposure from early gestation on 90 day old rat testes function and sperm molecular profiles: A CLARITY-BPA consortium study.

Bisphenol A (BPA) is a ubiquitous industrial chemical that has been identified as an endocrine disrupting compound (EDC). There is growing concern that early life exposures to EDCs, such as BPA, can adversely affect the male reproductive tract and function. This study was conducted as part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) to further delineate the toxicities associated with continuous exposure to BPA from early gestation, and to comprehensively examine the elicited effects on testes and sperm.

Spontaneous testicular atrophy occurs despite normal spermatogonial proliferation in a Tp53 knockout rat.

The tumor suppressor protein p53 (TP53) has many functions in cell cycle regulation, apoptosis, and DNA damage repair and is also involved in spermatogenesis in the mouse. To evaluate the role of p53 in spermatogenesis in the rat, we characterized testis biology in adult males of a novel p53 knockout rat (SD-Tp53 ). p53 knockout rats exhibited variable levels of testicular atrophy, including significantly decreased testis weights, atrophic seminiferous tubules, decreased seminiferous tubule diameter, and elevated spermatocyte TUNEL labeling rates, indicating a dysfunction in spermatogenesis.

The pregnant urologist.

Female urologists represent an ever-increasing percentage of the work force; more and more of our colleagues will be working through pregnancy. There is a lack of clear and concise advice for pregnant urologists about occupational risks during pregnancy. Urology exposes expectant mothers to potential risks from radiation, teratogenic and cytotoxic drugs, iodine hand scrub, infections, and long working hours.

Ghrelin modulates testicular damage in a cryptorchid mouse model.

Cryptorchidism or undescended testis (UDT) is a common congenital abnormality associated with increased risk for developing male infertility and testicular cancer. This study elucidated the effects of endogenous ghrelin or growth hormone secretagogue receptor (GHSR) deletion on mouse reproductive performance and evaluated the ability of ghrelin to prevent testicular damage in a surgical cryptorchid mouse model. Reciprocal matings with heterozygous/homozygous ghrelin and GHSR knockout mice were performed.

Identification of sperm mRNA biomarkers associated with testis injury during preclinical testing of pharmaceutical compounds.

The human testis is sensitive to toxicant-induced injury but current methods for detecting adverse effects are limited, insensitive and unreliable. Animal studies use sensitive histopathological endpoints to assess toxicity, but require testicular tissue that is not available during human clinical trials. More sensitive and reliable molecular biomarkers of testicular injury are needed to better monitor testicular toxicity in both clinical and preclinical.

Ghrelin Inhibits Post-Operative Adhesions via Blockage of the TGF-β Signaling Pathway.

Post-operative adhesions are a critical problem in pelvic and abdominal surgery despite a multitude of studies dedicated to finding modalities to prevent their occurrence. Ghrelin administration promotes an anti-fibrotic response in a surgical mouse model of adhesion-induction, but the mechanisms mediating this effect have not been established. In the current study, the molecular mechanisms that underlie the anti-adhesion effect of ghrelin were investigated.

Ghrelin ameliorates adhesions in a postsurgical mouse model.

Background: Peritoneal adhesion formation is a well-recognized consequence of abdominal and pelvic surgery, causing infertility, chronic pelvic pain, and intestinal obstruction. We hypothesized that ghrelin, a 28-amino acid peptide predominantly found in the stomach, plays an important role in preventing postoperative surgical adhesions. The purpose of this study was to develop a new surgical peritoneal adhesion model to define the role that ghrelin plays in wound healing and adhesion formation.

Retroperitoneal Gastrointestinal Type Schwannoma Presenting as a Renal Mass.

Retroperitoneal schwannomas are extremely rare, and unreported in Urology. Often thought to be malignant from imaging the diagnosis is often delayed until Histology. We report a case of retroperitoneal schwanoma thought to be a malignant renal mass.

Intussusceptive-like angiogenesis in human fetal lung xenografts: Link with bronchopulmonary dysplasia-associated microvascular dysangiogenesis?

Background: Human fetal lung xenografts display an unusual pattern of non-sprouting, plexus-forming angiogenesis that is reminiscent of the dysmorphic angioarchitecture described in bronchopulmonary dysplasia (BPD). The aim of this study was to determine the clinicopathological correlates, growth characteristics and molecular regulation of this aberrant form of graft angiogenesis.

Methods: Fetal lung xenografts, derived from 12 previable fetuses (15 to 22 weeks' gestation) and engrafted in the renal subcapsular space of SCID-beige mice, were analyzed 4 weeks posttransplantation for morphology, vascularization, proliferative activity and gene expression.

Di-n-Butyl Phthalate Induces Multinucleated Germ Cells in the Rat Fetal Testis Through a Nonproliferative Mechanism.

In utero exposure to some phthalate esters adversely affects the development of the rat seminiferous cord, causing germ cell loss and increasing the number of multinucleated germ cells (MNGs). To understand the timing of MNG formation and determine whether it requires nuclear division, timed pregnant Sprague Dawley rats were exposed to 500 mg/kg di-n-butyl phthalate (DBP) or corn oil vehicle by oral gavage on Gestational Day (GD) 17 or 18 (0 h) and euthanized after 2, 4, 6, or 24 h or given a second dose at 24 h and euthanized 48 h after the initial dose. Dams were simultaneously exposed to 0.

Differential response to abiraterone acetate and di-n-butyl phthalate in an androgen-sensitive human fetal testis xenograft bioassay.

In utero exposure to antiandrogenic xenobiotics such as di-n-butyl phthalate (DBP) has been linked to congenital defects of the male reproductive tract, including cryptorchidism and hypospadias, as well as later life effects such as testicular cancer and decreased sperm counts. Experimental evidence indicates that DBP has in utero antiandrogenic effects in the rat. However, it is unclear whether DBP has similar effects on androgen biosynthesis in human fetal testis.

Predictors of anxiety and depression in people with colorectal cancer.

Background: People living with colorectal cancer are at risk of anxiety and depression. We investigated what factors were most highly associated with these.

Methods: Four hundred and ninety-six people with colorectal cancer completed the Hospital Anxiety and Depression Scale (HADS).

Maturation of the developing human fetal prostate in a rodent xenograft model.

Background: Prostate cancer is the most commonly diagnosed nonskin cancer in men. The etiology of prostate cancer is unknown, although both animal and epidemiologic data suggest that early life exposures to various toxicants, may impact DNA methylation status during development, playing an important role.

Methods: We have developed a xenograft model to characterize the growth and differentiation of human fetal prostate implants (gestational age 12-24 weeks) that can provide new data on the potential role of early life stressors on prostate cancer.

Rodent thyroid, liver, and fetal testis toxicity of the monoester metabolite of bis-(2-ethylhexyl) tetrabromophthalate (tbph), a novel brominated flame retardant present in indoor dust.

Background: Bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a replacement for polybrominated diphenyl ethers (PBDEs) in commercial flame retardant mixtures such as Firemaster 550. It is also used in a commercial mixture called DP 45. Mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) is a potentially toxic metabolite.

Sperm mRNA transcripts are indicators of sub-chronic low dose testicular injury in the Fischer 344 rat.

Current human reproductive risk assessment methods rely on semen and serum hormone analyses, which are not easily comparable to the histopathological endpoints and mating studies used in animal testing. Because of these limitations, there is a need to develop universal evaluations that reliably reflect male reproductive function. We hypothesized that toxicant-induced testicular injury can be detected in sperm using mRNA transcripts as indicators of insult.

Human fetal testis xenografts are resistant to phthalate-induced endocrine disruption.

Background: In utero exposure to endocrine-disrupting chemicals may contribute to testicular dysgenesis syndrome (TDS), a proposed constellation of increasingly common male reproductive tract abnormalities (including hypospadias, cryptorchidism, hypospermatogenesis, and testicular cancer). Male rats exposed in utero to certain phthalate plasticizers exhibit multinucleated germ cell (MNG) induction and suppressed steroidogenic gene expression and testosterone production in the fetal testis, causing TDS-consistent effects of hypospadias and cryptorchidism. Mice exposed to phthalates in utero exhibit MNG induction only.

The effects of instruction and hand dominance on grip-to-load force coordination in manipulation tasks.

The force applied upon a vertically oriented hand-held object could be decomposed into two orthogonal and highly coordinated components: the grip force (GF; the component perpendicular to the hand-object contact area that provides friction) and the load force (LF; the parallel component that can move the object or support the body). The aim of this study was to investigate the underexplored effects of task instruction and hand dominance on GF-LF coordination. Sixteen right-handed subjects performed bimanual manipulation against a horizontally oriented instrumented device under different sets of instructions.