Background Several studies have suggested a population-wide decline in the quality of semen over the past 50 years, but clear evidence of decreasing semen quality in recent decades is lacking. Methods From 1973 through 1992 we measured the volume of seminal fluid, the sperm concentration, and the percentages of motile and morphologically normal spermatozoa in 1351 healthy fertile men. The data on the semen samples were collected at one sperm bank in Paris. The data in each calendar year were analyzed as a function of the year of donation, the age of each patient, the year of birth, and the duration of sexual abstinence before semen collection. Results There was no change in semen volume during the study period. The mean concentration of sperm decreased by 2.1 percent per year, from 89 ×106 per milliliter in 1973 to 60×106 per milliliter in 1992 (P<0.001). During the same period the percentages of motile and normal spermatozoa decreased by 0.6 percent and 0.5 percent per year, respectively (both P<0.001). ...

Decline in Semen Quality Among Fertile Men in Paris During the Past 20 Years

Note: Suppl. 18C Reference UPRAD-ARTICLE-1994-003 URL: ://A1994MY17500184 Record created on 2006-12-05, modified on 2017-05-12

The Transcription Factor Mtf-1 Is Essential for Basal and Heavy Metal-Induced Metallothionein-I Gene-Expression

The biological half-life (t1/2) of perfluorooctanoic acid (PFOA) in male rats is 70 times longer than that in female rats. The difference is mainly due to the difference in renal clearance (CL(R)), which was significantly reduced by probenecid, suggesting that PFOA is excreted by organic anion transporter(s). Castration of male rats caused a 14-fold increase in the CL(R) of PFOA, which made it comparable with that of female rats. The elevated PFOA CL(R) in castrated males was reduced by treating them with testosterone. Treatment of male rats with estradiol increased the CL(R) of PFOA. In female rats, ovariectomy caused a significant increase in CL(R) of PFOA, which was reduced by estradiol treatment. Treatments of female rats with testosterone reduced the CL(R) of PFOA as observed in castrated male rats. To identify the transporter molecules that are responsible for PFOA transport in rat kidney, renal mRNA levels of organic anion transporter 1 (OAT1), OAT2, OAT3, organic anion transporting polypeptide 1 (oatp1), oatp2 and kidney specific organic anion transporter (OAT-K) were determined in male and female rats under various hormonal states and compared with the CL(R) of PFOA. The level of OAT2 mRNA in male rats was only 13% that in female rats. Castration or estradiol treatment increased the level of OAT2 mRNA whereas treatment of castrated male rats with testosterone reduced it. In contrast to OAT2, mRNA levels of both oatp1 and OAT-K were significantly higher in male rats compared with female rats. Castration or estradiol treatment caused a reduction in the levels of mRNA of oatp1 and OAT-K in male rats. Ovariectomy of female rats significantly increased the level of OAT3 mRNA. Multiple regression analysis suggests that the change in the CL(R) of PFOA is, at least in part, due to altered expression of OAT2 and OAT3.

Sex hormone-regulated renal transport of perfluorooctanoic acid (KIDNEYS AND URINARY EXCRETION SYSTEM) (GENERAL SESSION BY POSTER PRESENTATION) (Proceedings of the 30th Annual Meeting)

The long half-time for methylmercury in the neonatal rats is explained by the neonatal liver's inability to secrete the toxin into bile, which in adults is the main route of elimination. The ability to secrete mercury into bile develops between 2 and 4 weeks of age and is correlated with the increasing ability of the developing liver to secrete glutathione into bile.

Developmental changes in the biliary excretion of methylmercury and glu-tathione

Practical Clinical Chemistry

Safety assessment of drug metabolites in the development of pharmaceuticals was discussed in January 2007 at the kick-off meeting of a "Drug Evaluation Forum", with reference to the views of clinicians and other academic representatives. Safety evaluation of metabolites cannot readily be based on a single theoretical framework, and basically a case-by-case approach is called for. These evaluations should be performed precisely and an accurate profile secured taking into account adverse reactions that are unpredictable from the parent compound administered in clinical studies and any signs or symptoms that may be associated with the metabolites. In addition, elimination of scientifically meaningless metabolite safety assessment studies is essential for prompt supply of high-quality drugs to the medical frontline. Preparation of an outline concept paper would be useful for achievement of shared understanding of issues of this type. Collective viewpoints obtained in this fashion are also relevant to the discussion on the need for guidance, and given a degree of flexibility may also be helpful for drug development and, in turn, society at large.

Current opinion: safety evaluation of drug metabolites in development of pharmaceuticals.

Safety assessment of biopharmaceuticals in preclinical studies is guided by the ICH S6 guideline issued in 1997. Along with enormous experiences and knowledge on safety assessment of some classes of biopharmaceuticals over the last decade, the necessity and feasibility of updating the guideline has been discussed. According to a recommendation by safety experts at the ICH meeting in Chicago in 2006, regional discussions of ICH S6 were held in the USA, EU and Japan. The meeting to clarify the values, challenges and recommendations for ICH S6 from Japanese perspective was held as a part of the first Drug Evaluation Forum in Tokyo on August 10, 2007. Of utmost importance, the "case-by-case" approach must be preserved as the basic principle of the ICH S6 guideline. It is our opinion that oligonucleotides, siRNA, aptamers and related molecules should be excluded from ICH S6 and may be more appropriate for separate guidance. However, based on experiences and accumulated knowledge, there are a number of issues that can be updated including new types of biopharmaceuticals such as bioconjugates, use of homologous proteins and transgenic animals, reproductive/developmental toxicity studies in non-human primates, in vitro cardiac ion channel assay and alternative approaches for carcinogenicity assessment. Preliminary recommendations for some of these topics were outlined at the meeting. The overall Japanese recommendation is that the ICH S6 guideline should be updated to address these topics.

Safety assessment of biopharmaceuticals : Japanese perspective on ICH S6 guideline maintenance

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Current opinion: safety evaluation of drug metabolites in development of pharmaceuticals.

Safety assessment of biopharmaceuticals : Japanese perspective on ICH S6 guideline maintenance