The causal relationship of human blood metabolites with the components of Sarcopenia: a two-sample Mendelian randomization analysis.

BACKGROUND: Sarcopenia is a progressive loss of muscle mass and function. Since skeletal muscle plays a critical role in metabolic homeostasis, identifying the relationship of blood metabolites with sarcopenia components would help understand the etiology of sarcopenia. METHODS: A two-sample Mendelian randomization study was conducted to examine the causal relationship of blood metabolites with the components of sarcopenia. Summary genetic association data for 309 known metabolites were obtained from the Twins UK cohort and KORA F4 study (7824 participants). The summary statistics for sarcopenia components [hand grip strength (HGS), walking pace (WP), and appendicular lean mass (ALM)] were obtained from the IEU Open GWAS project (461,089 participants). The inverse variance weighted method was used, and the MR-Egger, weighted median, and MR-PRESSO were used for the sensitivity analyses. Metabolic pathways analysis was further performed. RESULTS: Fifty-four metabolites associated with sarcopenia components were selected from 275 known metabolites pool. Metabolites that are causally linked to the sarcopenia components were mainly enriched in amino sugar and nucleotide sugar metabolism, galactose metabolism, fructose and mannose metabolism, carnitine synthesis, and biotin metabolism. The associations of pentadecanoate (15:0) with ALM, and 3-dehydrocarnitine and isovalerylcarnitine with HGS were significant after Bonferroni correction with a threshold of P < 1.82 × 10- 4 (0.05/275). Meanwhile, the association of hyodeoxycholate and glycine with the right HGS, and androsterone sulfate with ALM were significant in the sensitivity analyses. CONCLUSION: Blood metabolites from different metabolism pathways were causally related to the components of sarcopenia. These findings might benefit the understanding of the biological mechanisms of sarcopenia and targeted drugs development for muscle health.

The agreement of different techniques for muscle measurement in diagnosing sarcopenia: a systematic review and meta-analysis.

Background: The measurement or estimation of muscle mass plays an important role in the diagnosis of sarcopenia. Beside dual-energy X-ray absorptiometry (DXA), several modalities, including bioelectrical impedance analysis (BIA), ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI), have helped to provide imaging or electrical biomarkers for muscle mass. This study was aimed at summarizing the diagnostic performance of different techniques on muscle assessment for sarcopenia. Methods: Studies on the assessment of muscle mass by different techniques (compared with DXA), published from inception to 12 October, 2023 were retrieved from 4 electronic databases: the Cochrane Library, Embase, PubMed, and Web of Science. The quality assessment of included studies was conducted using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). The sensitivity, specificity, Cohen's kappa coefficient (κ), and Pearson correlation coefficient (r) with 95% confidence intervals (CIs) were pooled and presented via forest plots. The area under the curve (AUC) with 95% CI was pooled and presented via summary receiver operating characteristic (sROC) curve. Results: A total of 28 studies involving 4,926 participants were included. Compared with DXA, the pooled sensitivity and specificity, AUC, and Cohen's κ were 0.79 (95% CI: 0.71-0.86, P<0.001), 0.95 (95% CI: 0.82-0.99, P<0.001), and 0.88 (95% CI: 0.85-0.90), and 0.61 (95% CI: 0.51-0.72) for BIA. The pooled r value between DXA and BIA or US or MRI was 0.94 (95% CI: 0.92-0.96, P<0.001), 0.69 (95% CI: 0.54-0.80, P<0.001), and 0.96 (95% CI: 0.95-0.97, P=0.21), respectively. No qualified original study in relation to CT was included. Conclusions: BIA, US, and MRI would provide acceptable diagnostic accuracy for sarcopenia by evaluating muscle mass in terms of sensitivity, specificity, accuracy, and their higher correlations with DXA. Further investigation is required to elucidate the value of CT in diagnosing sarcopenia.

Nitrogen Application Can Optimize Form of Selenium in Soil in Selenium-Rich Areas to Affect Selenium Absorption and Accumulation in Black Wheat.

The composition and form of selenium in the soil have significant effects on the selenium content of crops. In this study, we investigated the selenium absorption pathway in plants by studying the interaction between nitrogen fertilizer and soil selenium. Our results showed that the selenium concentration enrichment factors (CEF) varied within the same region due to nitrogen fertilizer application, where they ranged from 1.33 to 5.02. The soil selenium flow coefficient (mobility factor, MF) increased with higher nitrogen application rates. The sum of the MF values for each soil layer treated with nitrogen application rates of 192 kg hm-2 and 240 kg hm-2 was 0.70, which was 64% higher than that for the control group with no nitrogen application. In the 0-20 cm soil layer, the highest summed water-soluble and exchangeable selenium and relative percentage of total selenium (12.45%) was observed at a nitrogen application rate of 240 kg hm-2. In the 20-40 cm soil layer, the highest relative percentage content of water-soluble and exchangeable selenium and total selenium (12.66%) was observed at a nitrogen application rate of 192 kg hm-2. Experimental treatment of black wheat with various concentrations of sodium selenite showed that selenium treatment at 50 µmol L-1 significantly increased the reduced glutathione (GSH) levels in the leaves and roots of seedlings, where the GSH contents increased by 155.4% in the leaves and by 91.5% in the roots. Further analysis of the soil-black wheat system showed that nitrogen application in selenium-rich areas affected the soil selenium flow coefficient and morphological composition, thereby changing the enrichment coefficient for leaves (0.823), transport capacity from leaves to grains (-0.530), and enrichment coefficient for roots (0.38). These changes ultimately affected the selenium concentration in the grains of black wheat.

Transcriptomic Analysis of Human Skeletal Muscle in Response to Aerobic Exercise and Protein Intake.

This study aimed to provide a more comprehensive molecular insight into the effects of aerobic exercise (AE), protein intake (PI), and AE combined with PI on human skeletal muscle by comparing their transcriptomic profiles. Fourteen published datasets obtained from the Gene Expression Omnibus (GEO) database were used. The hub genes were identified in response to acute AE (ACTB, IL6), training AE (UBB, COL1A1), PI (EZH2), acute AE combined with PI (DDIT3), and training AE combined with PI (MYC). Both FOS and MYC were upregulated in response to acute AE, and they were, respectively, downregulated by higher PI and a combination of AE and PI. COL1A1 was upregulated by training AE but was downregulated by higher PI. Results from the gene set enrichment analysis (p < 0.05 and FDR < 25%) showed that AE and PI delivered their impacts on human skeletal muscle in analogous pathways, including aerobic respiration, mitochondrial complexes, extracellular matrix (ECM) remodeling, metabolic process, and immune/inflammatory responses, whereas, PI may attenuate the response of immune/inflammation and ECM remodeling which would be promoted by AE, irrespective of its types. Compared to PI alone, acute AE combined with PI would further promote protein turnover and synthesis, but suppress skeletal muscle contraction and movement.

Progress on genomics and locus of important agronomic traits in Chenopodium quinoa.

Quinoa (Chenopodium quinoa, Willd.) as a new health food in the 20th century, its comprehensive nutritional composition, stress resistance and other characteristics have been paid much of attention, and enjoys the reputation of "nutritional gold", "vegetarian king" and "food in the future" in the world. In recent years, with the rapid development of genomics and high-throughput sequencing technology, the high-quality whole genome sequence of quinoa has been completed, and the omics analysis and functional research of a series of key genes have been gradually carried out. In this review, we summarize the research progress in quinoa genomics, gene family analysis of important transcription factors, genetic map construction, QTL mapping of important traits, and genes for important agronomic and yield traits. Moreover, according to the current status of quinoa breeding, this paper also put forward five key problems in quinoa breeding, and pointed out four important directions of genetic improvement and breeding of quinoa in the future, so as to provide reference for the realization of directional genetic improvement of quinoa in the future.

Identification and characterization of QTL for spike morphological traits, plant height and heading date derived from the D genome of natural and resynthetic allohexaploid wheat.

KEY MESSAGE: QHd.cau-7D.1 for heading date was delimited into the physical interval of approximately 17.38 Mb harboring three CONSTANS-like zinc finger genes. Spike morphological traits, plant height and heading date play important roles in yield improvement of wheat. To reveal the genetic factors that controlling spike morphological traits, plant height and heading date on the D genome, we conducted analysis of quantitative traits locus (QTL) using 198 F7:8 recombinant inbred lines (RILs) derived from a cross between the common wheat TAA10 and resynthesized allohexaploid wheat XX329 with similar AABB genomes. A total of 23 environmentally stable QTL on the D sub-genome for spike length (SL), fertile spikelet number per spike (FSN), sterile spikelet number per spike (SSN), total spikelet number per spike (TSN), spike compactness (SC), plant height (PHT) and heading date (HD) were detected, among which eight appeared to be novel QTL. Furthermore, QHd.cau-7D.1 and QPht.cau-7D.2 shared identical confidence interval and were delimited into the physical interval of approximately 17.38 Mb with 145 annotated genes, including three CONSTANS-like zinc finger genes (TraesCS7D02G209000, TraesCS7D02G213000 and TraesCS7D02G220300). This study will help elucidate the molecular mechanism of the seven traits (SL, FSN, SSN, TSN, SC, PHT and HD) and provide a potentially valuable resource for genetic improvement.

Phenotypic characterization of the glossy1 mutant and fine mapping of GLOSSY1 in common wheat (Triticum aestivum L.).

KEY MESSAGE: A novel wax locus GLOSSY1 was finely mapped to an approximately 308.1-kbp genomic interval on chromosome 2DS of wheat. The epicuticular wax, the outermost layer of aerial organs, gives plants their bluish-white (glaucous) appearance. Epicuticular wax is ubiquitous and provides an essential protective function against environmental stresses. In this study, we identified the glossy1 mutant on the basis of its glossy glume from an EMS population in the elite wheat (Triticum aestivum L.) cultivar Jimai22. The mutant had a dramatically different profile in total wax load and composition of individual wax constituents relative to the wild type, resulting in the increased cuticle permeability of glumes. The glossy glume phenotype was controlled by a single, semidominant locus mapping to the short arm of chromosome 2D, within a 308.1-kbp genomic interval that contained ten annotated protein-coding genes. These results pave the way for an in-depth analysis of the underlying genetic basis of wax formation patterns and enrich our understanding of mechanisms regulating wax metabolism.

The semidominant mutation w5 impairs epicuticular wax deposition in common wheat (Triticum aestivum L.).

KEY MESSAGE: The semidominant EMS-induced mutant w5 affects epicuticular wax deposition and mapped to an approximately 194-kb region on chromosome 7DL. Epicuticular wax is responsible for the glaucous appearance of plants and protects against many biotic and abiotic stresses. In wheat (Triticum aestivum L.), ß-diketone is a major component of epicuticular wax in adult plants and contributes to the glaucousness of the aerial organs. In the present study, we identified an ethyl methanesulfonate-induced epicuticular wax-deficient mutant from the elite wheat cultivar Jimai22. Compared to wild-type Jimai22, the mutant lacked ß-diketone and failed to form the glaucous coating on all aerial organs. The mutant also had significantly increased in cuticle permeability, based on water loss and chlorophyll efflux. Genetic analysis indicated that the mutant phenotype is controlled by a single, semidominant gene on the long arm of chromosome 7D, which was not allelic to the known wax gene loci W1-W4, and was therefore designated W5. W5 was finely mapped to an ~ 194-kb region (flanked by the molecular markers SSR2 and STARP11) that harbored four annotated genes according to the reference genome of Chinese Spring (RefSeq v1.0). Collectively, these data will broaden the knowledge of the genetic basis underlying epicuticular wax deposition in wheat.

Elevation of soybean seed oil content through selection for seed coat shininess.

Many leguminous species have adapted their seed coat with a layer of powdery bloom that contains hazardous allergens and makes the seeds less visible, offering duel protection against potential predators 1 . Nevertheless, a shiny seed surface without bloom is desirable for human consumption and health, and is targeted for selection under domestication. Here we show that seed coat bloom in wild soybeans is mainly controlled by Bloom1 (B1), which encodes a transmembrane transporter-like protein for biosynthesis of the bloom in pod endocarp. The transition from the 'bloom' to 'no-bloom' phenotypes is associated with artificial selection of a nucleotide mutation that naturally occurred in the coding region of B1 during soybean domestication. Interestingly, this mutation not only 'shined' the seed surface, but also elevated seed oil content in domesticated soybeans. Such an elevation of oil content in seeds appears to be achieved through b1-modulated upregulation of oil biosynthesis in pods. This study shows pleiotropy as a mechanism underlying the domestication syndrome 2 , and may pave new strategies for development of soybean varieties with increased seed oil content and reduced seed dust.

A novel allele of TaGW2-A1 is located in a finely mapped QTL that increases grain weight but decreases grain number in wheat (Triticum aestivum L.).

KEY MESSAGE: A novel TaGW2-A1 allele was identified from a stable, robust QTL region, which is pleiotropic for thousand grain weight, grain number per spike, and grain morphometric parameters in wheat. Thousand grain weight (TGW) and grain number per spike (GNS) are two crucial determinants of wheat spike yield, and genetic dissection of their relationships can help to fine-tune these two components and maximize grain yield. By evaluating 191 recombinant inbred lines in 11 field trials, we identified five genomic regions on chromosomes 1B, 3A, 3B, 5B, or 7A that solely influenced either TGW or GNS, and a further region on chromosome 6A that concurrently affected TGW and GNS. The QTL of interest on chromosome 6A, which was flanked by wsnp_BE490604A_Ta_2_1 and wsnp_RFL_Contig1340_448996 and designated as QTgw/Gns.cau-6A, was finely mapped to a genetic interval shorter than 0.538 cM using near isogenic lines (NILs). The elite NILs of QTgw/Gns.cau-6A increased TGW by 8.33%, but decreased GNS by 3.05% in six field trials. Grain Weight 2 (TaGW2-A1), a well-characterized gene that negatively regulates TGW and grain width in wheat, was located within the finely mapped interval of QTgw/Gns.cau-6A. A novel and rare TaGW2-A1 allele with a 114-bp deletion in the 5' flanking region was identified in the parent with higher TGW, and it reduced TaGW2-A1 promoter activity and expression. In conclusion, these results expand our knowledge of the genetic and molecular basis of TGW-GNS trade-offs in wheat. The QTLs and the novel TaGW2-A1 allele are likely useful for the development of cultivars with higher TGW and/or higher GNS.

Impurity Compensation Effect Induced by Tin Valence Change in α-Ga1.4Sn0.6O3 Thin Films.

Corundum-structured α-phase Ga1.4Sn0.6O3 thin films have been deposited on m-plane Al2O3(300) substrates using laser molecular beam epitaxy technology. With increasing of the oxygen partial pressure, the crystal lattice of Ga1.4Sn0.6O3 films expands due to tin ions valence changes from Sn4+ to Sn2+. The resistivity of the film deposited under 3 × 10-5 Pa is 3.54 × 104 Ω·cm, which decreases by about 2 orders of magnitude than that fabricated under 3 × 10-1 Pa. The mixture valence of Sn2+ and Sn4+ ions leads to the impurity altitude compensation effect. The deep ultraviolet photodetector based on α-phase Ga1.4Sn0.6O3 thin films was fabricated. With the oxygen partial pressure reducing gradually, the dark current and the photocurrent increase, and the relaxation time constants diminish, respectively.

Fine mapping and candidate gene analysis of two loci conferring resistance to Phytophthora sojae in soybean.

KEY MESSAGE: RpsUN1 and RpsUN2 were fine mapped to two genomic regions harboring disease resistance-like genes. The haplotypes and instability of the regions and candidate genes for the two resistance loci were characterized. Phytophthora root and stem rot caused by Phytophthora sojae, is one of the most destructive diseases of soybean. Deploying soybean cultivars carrying race-specific resistance conferred by Rps genes is the most practical approach to managing this disease. Previously, two Rps genes, RpsUN1 and RpsUN2 were identified in a landrace PI 567139B and mapped to a 6.5 cM region on chromosome 3 and a 3.0 cM region on chromosome 16, corresponding to 1387 and 423 kb of the soybean reference genome sequences. By analyzing recombinants defined by genotypic and phenotypic screening of the 826 F2:3 families derived from two reciprocal crosses between the two parental lines, RpsUN1 and RpsUN2, were further narrowed to a 151 kb region that harbors five genes including three disease resistance (R)-like genes, and a 36 kb region that contains four genes including five R-like genes, respectively, according to the reference genome. Expressional changes of these nine genes before and after inoculation with the pathogen, as revealed by RNA-seq, suggest that Glyma.03g034600 in the RpsUN1 region and Glyma.16g215200 and Glyma.16g214900 in the RpsUN2 region of PI 567139B may be associated with the resistance to P. sojae. It is also suggested that unequal recombination between/among R-like genes may have occurred, resulting in the formation of two recombinants with inconsistent genotypic and phenotypic observations. The haplotype variation of genomic regions where RpsUN1 and RpsUN2 reside in the entire soybean germplasm deposited in the US soybean germplasm collection suggests that RpsUN1 and RpsUN2 are most likely novel genes.

Inhibition of unintentional extra carriers by Mn valence change for high insulating devices.

For intrinsic oxide semiconductors, oxygen vacancies served as the electron donors have long been, and inevitably still are, attributed as the primary cause of conductivity, making oxide semiconductors seem hard to act as high insulating materials. Meanwhile, the presence of oxygen vacancies often leads to a persistent photoconductivity phenomenon which is not conducive to the practical use in the fast photoelectric response devices. Herein, we propose a possible way to reduce the influence of oxygen vacancies by introducing a valence change doping in the monoclinic ß-Ga2O3 epitaxial thin film. The unintentional extra electrons induced by oxygen vacancies can be strongly suppressed by the change valence of the doped Mn ions from +3 to +2. The resistance for the Mn-doped Ga2O3 increases two orders of magnitude in compared with the pure Ga2O3. As a result, photodetector based on Mn-doped Ga2O3 thin films takes on a lower dark current, a higher sensitivity, and a faster photoresponse time, exhibiting a promising candidate using in high performance solar-blind photodetector. The study presents that the intentional doping of Mn may provide a convenient and reliable method of obtaining high insulating thin film in oxide semiconductor for the application of specific device.

Epitaxial growth and magnetic properties of ultraviolet transparent Ga2O3/(Ga1-xFex)2O3 multilayer thin films.

Multilayer thin films based on the ferromagnetic and ultraviolet transparent semiconductors may be interesting because their magnetic/electronic/photonic properties can be manipulated by the high energy photons. Herein, the Ga2O3/(Ga1-xFex)2O3 multilayer epitaxial thin films were obtained by alternating depositing of wide band gap Ga2O3 layer and Fe ultrathin layer due to inter diffusion between two layers at high temperature using the laser molecular beam epitaxy technique. The multilayer films exhibits a preferred growth orientation of crystal plane, and the crystal lattice expands as Fe replaces Ga site. Fe ions with a mixed valence of Fe(2+) and Fe(3+) are stratified distributed in the film and exhibit obvious agglomerated areas. The multilayer films only show a sharp absorption edge at about 250 nm, indicating a high transparency for ultraviolet light. What's more, the Ga2O3/(Ga1-xFex)2O3 multilayer epitaxial thin films also exhibits room temperature ferromagnetism deriving from the Fe doping Ga2O3.

Coordination of MicroRNAs, PhasiRNAs, and NB-LRR Genes in Response to a Plant Pathogen: Insights from Analyses of a Set of Soybean Rps Gene Near-Isogenic Lines.

Disease-related genes, particularly the nucleotide binding site (NB)-leucine-rich repeat (LRR) class of R plant genes can be triggered by microRNAs (miRNAs) to generate phased small interfering RNAs (phasiRNAs), which could reduce the transcript levels of their targets. However, how global changes in NB-LRR transcript levels coordinate with changes in miRNA and phasiRNA levels in defense responses remains largely unknown. Here, we investigated changes in the relative abundance of small RNAs (sRNAs), with a focus on miRNAs and phasiRNAs and their potential targets in response to the pathogen Phytophthora sojae in the susceptible soybean [Glycine max (L.) Merr.] 'Williams' and nine resistant near-isogenic lines (NILs), each carrying a unique resistance to P. sojae (Rps) gene. In total, 369 distinct miRNAs, including 78 new ones, were identified in the 10 soybean lines. The majority of miRNAs were downregulated by the pathogen. Of the 525 NB-LRR genes found in the soybean reference genome, 257 were predicted to be the targets of eight abundant miRNA families and 126 (dubbed phasi-NB-LRRs or pNLs) were predicted to have produced phasiRNAs. Upregulation of 15 phasi-NB-LRRs was associated with downregulation of their corresponding phasiRNAs in the NILs; these phasiRNAs were predicted to regulate 75 additional NB-LRRs in trans. In addition, we identified putative 24-nucleotide (nt) phasiRNAs from transposons, possibly representing a novel general epigenetic mechanism for regulation of transposon activity under biotic stresses. Together, these observations suggest that miRNAs and phasiRNAs play an important role in response to plant pathogens through complex, multiple layers of post-transcriptional regulation.

Bisphenol A: developmental toxicity from early prenatal exposure.

Bisphenol A (BPA) exposure has been documented in pregnant women, but consequences for development are not yet widely studied in human populations. This review presents research on the consequences for offspring of BPA exposure during pregnancy. Extensive work in laboratory rodents has evaluated survival and growth of the conceptus, interference with embryonic programs of development, morphological sex differentiation, sex differentiation of the brain and behavior, immune responsiveness, and mechanism of action. Sensitive measures include RAR, aryl hydrocarbon receptor, and Hox A10 gene expression, anogenital distance, sex differentiation of affective and exploratory behavior, and immune hyperresponsiveness. Many BPA effects are reported at low doses (10-50 µg/kg d range) by the oral route of administration. At high doses (>500,000 µg/kg d) fetal viability is compromised. Much of the work has centered around the implications of the estrogenic actions of this agent. Some work related to thyroid mechanism of action has also been explored. BPA research has actively integrated current knowledge of developmental biology, concepts of endocrine disruption, and toxicological research to provide a basis for human health risk assessment.

Reduced water intake: Implications for rodent developmental and reproductive toxicity studies.

In developmental and reproductive toxicity studies, drinking water is a common means of delivering the test agent. Reduced consumption of toxicant-containing water raises questions about indirect effects of reduced maternal fluid consumption resulting from unpalatability, versus direct effects of the test compound. Issues to consider include: objective assessment of dehydration and thirst, the relative contributions of innate and learned behaviors to drinking behavior and flavor preference, and the objective assessment of physiologic stress. Not only do lab animals under ad lib conditions consume more water than the minimum required to maintain fluid balance, animals faced with water restriction have substantial physiologic capacity for protection of metabolic processes. Measures of blood biochemistry can provide quantifiable, objective indications of fluid balance, but changes in these parameters could result from other causes such as effects of a test toxicant. Consummatory behaviors in response to perceived need are highly influenced by learning. Hence, the drinking behavior, water intake, and flavor acceptance/preference of animals used in toxicology experiments could be subject to learning experiences with the test compound. Physiological symptoms of stress produced by water deprivation may be distinguishable from the symptoms associated with other generalized stressors, such as food deprivation, but doing so may be beyond the scope of most developmental or reproductive toxicity studies. Use of concurrent controls, paired to test groups for water consumption, could help distinguish between the direct effects of a test toxicant as opposed to effects of reduced water consumption alone.

Cancer mortality in a Chinese population exposed to hexavalent chromium in drinking water.

BACKGROUND: In 1987, investigators in Liaoning Province, China, reported that mortality rates for all cancer, stomach cancer, and lung cancer in 1970-1978 were higher in villages with hexavalent chromium (Cr+6)-contaminated drinking water than in the general population. The investigators reported rates, but did not report statistical measures of association or precision. METHODS: Using reports and other communications from investigators at the local Jinzhou Health and Anti-Epidemic Station, we obtained data on Cr+6 contamination of groundwater and cancer mortality in 9 study regions near a ferrochromium factory. We estimated: (1) person-years at risk in the study regions, based on census and population growth rate data, (2) mortality counts, based on estimated person-years at risk and previously reported mortality rates, and (3) rate ratios and 95% confidence intervals. RESULTS: The all-cancer mortality rate in the combined 5 study regions with Cr+6-contaminated water was negligibly elevated in comparison with the rate in the 4 combined study regions without contaminated water (rate ratio = 1.13; 95% confidence interval = 0.86-1.46), but was somewhat more elevated in comparison with the whole province (1.23; 0.97-1.53). Stomach cancer mortality in the regions with contaminated water was more substantially elevated in comparison with the regions without contaminated water (1.82; 1.11-2.91) and the whole province (1.69; 1.12-2.44). Lung cancer mortality was slightly elevated in comparison with the unexposed study regions (1.15; 0.62-2.07), and more strongly elevated in comparison with the whole province (1.78; 1.03-2.87). Mortality from other cancers combined was not elevated in comparison with either the unexposed study regions (0.86; 0.53-1.36) or the whole province (0.92; 0.58-1.38). CONCLUSIONS: While these data are limited, they are consistent with increased stomach cancer risk in a population exposed to Crz=6 in drinking water.

"Natural" progesterone: information on fetal effects.

BACKGROUND: A variety of progestational agents have been used therapeutically and evaluated for adverse effects over the last 50 years. However, progesterone itself has come into use as a therapeutic agent only recently with the development of an orally bioavailable "micronized" preparation. METHODS: The current review examines progesterone adverse effects as identified in the larger literature on the toxicity of progestational agents and pharmacokinetics. RESULTS: Progesterone has cytoplasmic and membrane receptors in a variety of reproductive and nonreproductive tissues including the brain and is a potent inhibitor of GnRH. Limited information is available on progesterone receptors and actions in the fetus. Concern about exogenous progestagen effects on fetal reproductive tract development have led to considerable human research over the years, but this literature review demonstrates that contemporary developmental toxicology research on progesterone is lacking. CONCLUSIONS: Progesterone is a potent, multi-faceted endocrine agent with an expanding therapeutic profile and a minimal scientific database for evaluating safe use during pregnancy.

Review on testicular development, structure, function, and regulation in common marmoset.

BACKGROUND: The common marmoset (Callithrix jacchus) is a New World primate that has been used increasingly in toxicological evaluations including testing for testicular toxicity of pharmaceutical and environmental chemicals. Information on structural and functional characteristics of the testis in common marmosets ("marmoset" in this review) is critical for designing experiments, interpreting data collected, and determining relevance to humans in risk assessment. METHODS: This study provides a comprehensive review on testicular development, structure, function, and regulation in common marmosets. RESULTS: There is little information regarding testicular formation and development during gestation. Based on the overall pattern of embryonic development in marmosets, it is postulated that gonadal formation and testicular differentiation most likely takes place during gestational Week 6-12. After birth, the neonatal period of the first 2-3 weeks and the pubertal period from Months 6-12 are critical for establishment of spermatogenesis in the adult. In the adult, a nine-stage model has been used to describe the organization of seminiferous epithelium and multiple stages per tubular cross-section have been observed. Seminiferous epithelium is organized in a wave or partial-wave manner. There are on average two stages per cross-section of seminiferous tubules in adult marmoset testis. Sertoli cells in the marmoset have a uniform morphology. Marmoset spermatogenesis has a high efficiency. The prime determinant of germ cell production is proliferation and survival of spermatogonia. Sertoli cell proliferation during the neonatal period is regulated by follicle-stimulating hormone (FSH), but chorionic gonadotropin (CG), instead of luteinizing hormone (LH), is the only gonadotropin with luteinizing function in marmoset. The receptor gene for CG in marmoset is unique in that it does not have exon 10. Marmosets have a "generalized steroid hormone resistance," i.e., relatively high levels of steroid hormones in circulation and relatively low response to exogenous steroids. Blockage of FSH, CG, and testosterone production during the first 3 months after birth does not cause permanent damage to the male reproductive system. Initiation of spermatogenesis in the marmoset requires unique factors that are probably not present in other mammals. Normal male marmosets respond to estradiol injection positively (increased LH or CG levels), a pattern seen in normal females or castrated males, but not usually in normal males of other mammalian species. CONCLUSIONS: It seems that the endocrine system including the testis in marmosets has some unique features that have not been observed in rodents, Old World primates, and humans, but detailed comparison in these features among these species will be presented in another review. Based on the data available, marmoset seems to be an interesting model for comparative studies. However, interpretation of experimental findings on the testicular effects in marmosets should be made with serious caution. Depending on potential mode of testicular actions of the chemical under investigation, marmoset may have very limited value in predicting potential testicular or steroid hormone-related endocrine effects of test chemicals in humans.