Preeclampsia is a major pregnancy complication with potential short- and long-term consequences for both mother and fetus. Understanding its pathogenesis and causative biomarkers is likely to yield insights for prediction and treatment. Herein, we provide evidence that transthyretin, a transporter of thyroxine and retinol, is aggregated in preeclampsia and is present at reduced levels in sera of preeclamptic women, as detected by proteomic screen. We demonstrate that transthyretin aggregates form deposits in preeclampsia placental tissue and cause apoptosis. By using in vitro approaches and a humanized mouse model, we provide evidence for a causal link between dysregulated transthyretin and preeclampsia. Native transthyretin inhibits all preeclampsia-like features in the humanized mouse model, including new-onset proteinuria, increased blood pressure, glomerular endotheliosis, and production of anti-angiogenic factors. Our findings suggest that a focus on transthyretin structure and function is a novel strategy to understand and combat preeclampsia.

Lumpy skin disease (LSD) is a re-emerging transboundary viral disease of cattle and buffaloes with severe economic impact and listed as a notifiable disease by the World Organization for Animal Health (OIE, 2017). The severity of clinical signs of LSD varies from subclinical to fatal depending on the virulence of the strains and the cattle breed's susceptibility. Generally, LSD tends to have a mortality of <10% and a morbidity of 0%-90% (OIE, 2017;Sprygin et al., 2018). LSD, first detected in Zambia (1929), was historically restricted and endemic to southern and eastern Africa (Beard, 2016). The first LSD outbreak outside sub-Saharan Africa occurred in Egypt and Israel

A variety of environmental chemicals may possess the potential to interact with various endocrine factors and consequently cause adverse effects on the reproductive, central nervous, and immune systems via the endocrine system(s). In this study, we used the GH3 cell line as an in vitro model to determine the effects of potential endocrine disruptors (EDs) on the induction of calbindin-D9k (CaBP-9k), a useful biomarker for detecting the estrogenic activities of EDs. A rat pituitary cell line, GH3, was treated with octyl-phenol (OP), nonyl-phenol (NP), and bisphenol A (BPA) in a dose-dependent manner (10(-5), 10(-6), and 10(-7)M) for 24 h. To determine the time dependency, the cells were exposed to a high concentration (10(-5)M) of OP, NP, and BPA and harvested at different time points (1, 3, 6, 12, and 24 h). An antiestrogen, ICI 182,780, was used to examine the potential involvement of the estrogen receptor (ER) in the induction of CaBP-9k by EDs via an ER-mediated pathway. Treatment with OP, NP, and BPA induced a significant increase in CaBP-9k expression at both the transcriptional and translational levels in a dose-dependent manner. Interestingly, ED exposure caused a significant increase in CaBP-9k messenger RNA (mRNA) expression at 6 h, whereas induction of CaBP-9k protein was observed as early as 1 h after treatment. However, both CaBP-9k mRNA and protein expression peaked at 24 h following treatment. The differential response of CaBP-9k mRNA and protein to EDs may be explained by translational efficiency. Cotreatment with ICI 182,780 significantly reversed ED-induced CaBP-9k expression in GH3 cells, suggesting that EDs may trigger the induction of CaBP-9k via an ER-mediated pathway in these cells. Taken together, these results demonstrate for the first time that a single in vitro exposure to OP, NP, or BPA results in an increase in CaBP-9k expression in GH3 cells, after 24 h. These results may contribute to our understanding of the relationship between the molecular events evoked by ED exposure and its biological effects on the pituitary gland in humans and animals. This in vitro model, in combination with a single injection in vivo method developed by us, may be important for elucidating additional details of the mode of action of xenoestrogens and may provide reliable tests for screening estrogenic agonists and antagonists.

Polybrominated diphenyl ethers (PBDEs), a class of organic brominated flame retardants, have been increasing in the environment and in the tissues and milk of animals, including humans. To date, 209 PBDE congeners have been reported. Among these, 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) is the dominant congener found in humans and animals. A number of studies have suggested that BDE 47 possesses the potential to disrupt the endocrine system, as well as reproductive functions. This suggests that BDE 47 may act as a developmental neurotoxin and endocrine disruptor. In this study, we employed immature rats as a developmental model to examine the potential involvement of BDE 47 in the induction of calbindin-D9k (CaBP-9k), which is a novel biomarker for screening estrogenic compounds. Beginning on postnatal day 16, BDE 47 was administered to immature rats in a dose- and time-dependent manner for 3 days. The biological effects of BDE 47 on the induction of CaBP-9k mRNA and protein were examined by semiquantitative RT-PCR and western blotting, respectively. In addition, the physiological role of the estrogen receptor (ER) in BDE 47-induced CaBP-9k expression was examined in vivo. Treatment with a high dose of BDE 47 (200 mg/kg body weight [BW]/day) resulted in a significant increase in CaBP-9k mRNA and protein 24 h after injection, whereas a modest increase was observed with low and medium doses (50 and 100 mg/kg BW/day). Additionally, treatment with the high dose of BDE 47 induced a clear uterotrophic response. Cotreatment with ICI 182,780, an ER antagonist, completely reversed the BDE 47-induced increases in uterine wet weight and CaBP-9k mRNA and protein. Taken together, these results demonstrate that BDE 47 exposure results in increases in CaBP-9k mRNA and protein in the uteri of immature rats. The biochemical pathway for BDE 47-induced activity may involve the ER-mediated signaling pathway. These results provide new insights into the estrogenic effects of BDE 47 at a critical developmental stage of the female reproductive system.

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Abstract. Endocrine disruptors (EDs) with androgenic and anti-androgenic effects may alter reproductive function by binding to androgenic receptors (AR) and inducing or modulating AR-dependent responses in the male reproductive system. However, the molecular mechanism(s) underlying these events remains unclear. In the present study, pregnant Sprague Dawley (SD) rats were treated with testosterone propionate (TP), flutamide (Flu) and di-(2-ethylhexyl) phthalate (DEHP) from gestation days (GD) 11 to 21. Interestingly, maternal exposure to Flu or DEHP caused fluctuations in the neonatal levels of serum testosterone (T) and luteinizing hormone (LH). Serum testosterone and LH were upregulated by Flu, but these hormones were down-regulated by DEHP. The anogenital distances (AGD) of male newborns were determined at post-neonatal days (PND) 1, 21 and 63. Male rats treated prenatally with DEHP (100 mg/kg mother's body weight) or Flu showed an AGD shorter than that of control rats. At PND 63, sperm concentration, viability and motility were reduced in the maternal DEHP and Flu-treated groups. The numbers of seminiferous tubules were reduced in the Flu and DEHP-treated offspring when compared with the vehicle-and TPtreated groups, and the tubules of the testes at PND 63 were disrupted by a high dose of Flu. In addition, we found differential gene expression patterns by microarray analysis following ED exposure, particularly in sex determinationrelated genes. Although Flu and DEHP are considered to be identical with regard to their anti-androgenic effects, their effects on developing male reproductive organs were distinct, suggesting that Flu competes with endogenous T, while DEHP influences a different step in androgenesis. Key words: Flutamide, Male reproduction, Phthalate (J. Reprod. Dev. 55: [400][401][402][403][404][405][406][407][408][409][410][411] 2009) ecently, environmental, anti-androgenic compounds have been recognized as endocrine disruptors (EDs) because of their hormone-like activities. Anti-androgenic chemicals have the potential to interfere with male reproductive development and function in humans and animals. The EDs are thought to act via many mechanisms, such as by decreasing androgen synthesis, exerting effects on the pituitary-gonadal axis and/or blocking the androgen receptor (AR) [1,2]. The consequences of these actions may cause abnormal hormonal regulation and gene expression.It has been demonstrated that the AR plays a critical role in control of male sexual differentiation. During mammalian sex differentiation, the androgens, testosterone (T) and its metabolite dihydrotestosterone (DHT), produced by the fetal/neonatal male during sexual differentiation are critical factors in the male phenotype [3]. Sex development continues postnatally with the onset of secondary sexual characteristics at puberty and the acquisition of reproductive capacity. In addition, the differentiation of the Wolffian structures (e.g., the epididymis, vas deferens and seminal vesicles) appears to be T-mediated, while ma...

We previously demonstrated that the androgenic and anti-androgenic effects of endocrine disruptors (EDs) alter reproductive function and exert distinct effects on developing male reproductive organs. To further investigate these effects, we used an immature rat model to examine the effects of di-(2 ethylhexyl) phthalate (DEHP) and flutamide (Flu) on the male reproductive system. Immature male SD rats were treated daily with DEHP and Flu on postnatal days (PNDs) 21 to 35, in a dose-dependent manner. As results, the weights of the testes, prostate, and seminal vesicle and anogenital distances (AGD) decreased significantly in response to high doses of DEHP or Flu. Testosterone (T) levels significantly decreased in all DEHP- treated groups, whereas luteinizing hormone (LH) plasma levels were not altered by any of the two treatments at PND 36. However, treatment with DEHP or Flu induced histopathological changes in the testes, wherein degeneration and disorders of Leydig cells, germ cells and dilatation of tubular lumen were observed in a dose-dependent manner. Conversely, hyperplasia and denseness of Leydig, Sertoli and germ cells were observed in rats given with high doses of Flu. The results by cDNA microarray analysis indicated that 1,272 genes were up-regulated by more than two-fold, and 1,969 genes were down-regulated in response to DEHP, Flu or both EDs. These genes were selected based on their markedly increased or decreased expression levels. These genes have been also classified on the basis of gene ontology (e.g., steroid hormone biosynthetic process, regulation of transcription, signal transduction, metabolic process, biosynthetic process...). Significant decreases in gene expression were observed in steroidogenic genes (i.e., Star, Cyp11a1 and Hsd3b). In addition, the expression of a common set of target genes, including CaBP1, Vav2, Plcd1, Lhx1 and Isoc1, was altered following exposure to EDs, suggesting that they may be marker genes to screen for the anti-androgenic or androgenic effects of EDs. Overall, our results demonstrated that exposure to DEHP, Flu or both EDs resulted in a alteration of gene expression in the testes of immature male rats. Furthermore, the toxicological effects of these EDs on the male reproductive system resulted from their anti-androgenic effects. Taken together, these results provide a new insight into the molecular mechanisms underlying the detrimental impacts of EDs, in regards to anti-androgenic effects in humans and wildlife.

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