Sertoli cells are the primary cellular target for a number of pharmaceutical and environmental testicular toxicants, including 2,5-hexanedione, carbendazim, and mono-(2-ethylhexyl) phthalate. Exposure to these individual compounds can result in impaired Sertoli cell function and subsequent germ cell loss. The loss of testicular function is marked by histopathological changes in seminiferous tubule diameter, seminiferous epithelial sloughing, vacuolization, spermatid head retention, germ cell apoptosis, and altered microtubule assembly. The present study investigates dose-response relationships for these classic Sertoli cell toxicants using histopathology endpoints. Understanding the relationship between the Sertoli cell toxicant dose and its histopathologic manifestations will help establish the sensitivity of these endpoints as markers of testicular injury. The results indicate that no single histopathology endpoint was sensitive on its own in identifying altered testicular morphology resulting from toxicant exposure. However, when multiple endpoints were combined dose-response relationships could be associated with incremental alterations in histopathology. The data generated from these experiments will be useful in further investigating the effects of Sertoli cell toxicant exposure in animal toxicity studies. In addition, this work is fundamental to a planned investigation of the histopathologic and gene expression changes associated with testicular toxicant co-exposures, which may occur both occupationally and environmentally.

The Raf kinase inhibitory protein 1 (RKIP-1) and its orthologs are conserved throughout evolution and widely expressed in eukaryotic organisms. In its non-phosphorylated form RKIP-1 negatively regulates the Raf/MEK/ERK pathway by interfering with the activity of Raf-1. In its phosphorylated state, RKIP-1 dissociates from Raf-1 and inhibits GRK-2, a negative regulator of G-protein coupled receptors (GPCRs). Available data indicate that the phosphorylation of RKIP-1 by PKC can stimulate both the Raf/MEK/ERK and GPCR pathways. RKIP-1 has also been implicated as a negative regulator of the NF-kappaB pathway. Recent studies have shown that phosphorylated RKIP-1 binds to the centrosomal and kinetochore regions of metaphase chromosomes, where it may be involved in regulating the partitioning of chromosomes and the progression through mitosis. The collective evidence indicates that RKIP-1 regulates the activity and mediates the crosstalk between several important cellular signaling pathways. A variety of ablative interventions suggest that reduced RKIP-1 function may influence metastasis, angiogenesis, resistance to apoptosis, and genome integrity. Attenuation of RKIP-1 may also affect cardiac and neurological functions, spermatogenesis, sperm decapacitation, and reproductive behavior. In this review, the role of RKIP-1 in cellular signaling, and especially its functions revealed using a mouse knockout model, are discussed.

Hepatic transporters play a vital role in the disposition of endogenous compounds and xenobiotics in the liver. The current study investigates the expression and regulation of hepatic efflux transporters in response to treatment with the peroxisome proliferator-activated receptor (PPAR)␣ agonist clofibrate (CFB). Changes in mRNA and protein levels for several hepatic transporters were assessed in male CD-1 mice after 10 days of CFB dosing (500 mg/kg i.p.). Administration of CFB up-regulated mRNA levels for breast cancer resistance protein (Bcrp) and multidrug resistance-associated proteins 3 and 4 (Mrp3 and Mrp4, respectively). Western blot analysis confirmed that CFB enhances protein expression of liver Bcrp, Mrp3, and Mrp4 in CD-1 mice. To further characterize the regulation of these hepatic transporters, CFB-mediated changes in transporter mRNA levels were assessed in wild-type (sv/129) and PPAR␣-null male mice. Wild-type mice treated with CFB showed similar changes in mRNA levels for all of these transporters, whereas the PPAR␣-null mice did not. Although protein expression of Mrp3 and Mrp4 in the wild-type mice correlated well with changes in mRNA levels, Bcrp protein was not upregulated by CFB treatment. These results show that PPAR␣ activation by CFB coordinately regulates the hepatic efflux transporters Mrp3 and Mrp4. Induction of Mrp3 and Mrp4 by CFB may alter the disposition of toxicants and xenobiotics that are substrates for these transporters.