ILSI/HESI maternal toxicity workshop summary: maternal toxicity and its impact on study design and data interpretation

Workshops on maternal toxicity were held at the annual Society of Toxicology, Teratology Society, and European Teratology Society meetings in 2009. Speakers presented background information prior to a general discussion on this topic. The following recommendations/options are based on the outcome of the discussions at the workshops:

• 1. A comprehensive evaluation of all available data from general toxicity studies, range‐finding Developmental and Reproductive Toxicology (DART) studies, class effects, structure–activity relationships, exposure studies, etc. is essential for appropriate dose selection for definitive DART studies. The intent is to avoid marked maternal toxicity leading to mortality or decreased body weight gains of greater than 20% for prolonged periods.

• (a) Evaluate alternative endpoints for dose selection and data interpretation (e.g., target tissue effects and pharmacology) for biotherapeutics.
• (B) Evaluate additional maternal parameters based on effects and/or target organs observed in short‐term (e.g., 2‐ or 4‐week) general toxicity studies.

• 2. Evaluate all available data to determine a cause–effect relationship for developmental toxicity.

• (a) Conduct a pair‐feeding/pair‐watering study as a follow‐up.
• (b) Evaluate individual data demonstrating maternal toxicity in the mother with adverse embryo–fetal outcomes in the litter associated with the affected mother.
• (c) Conduct single‐dose studies at increasing doses as a complement to conventional embryo–fetal toxicity studies for certain classes of compounds that affect the hERG channel.

• 3. Support statements that embryo–fetal effects are caused by maternal toxicity and/or exaggerated pharmacology, especially for malformations.

• (a) Provide mechanistic or other supporting data.
• (b) Establish the relevance of the DART findings in animals for human exposures. Birth Defects Res (Part B) 92:36–51, 2010. © 2011 Wiley‐Liss, Inc.

     

Evaluating four mathematical models for nitrous oxide production by autotrophic ammonia‐oxidizing bacteria

There is increasing evidence showing that ammonia‐oxidizing bacteria (AOB) are major contributors to N₂O emissions from wastewater treatment plants (WWTPs). Although the fundamental metabolic pathways for N₂O production by AOB are now coming to light, the mechanisms responsible for N₂O production by AOB in WWTP are not fully understood. Mathematical modeling provides a means for testing hypotheses related to mechanisms and triggers for N₂O emissions in WWTP, and can then also become a tool to support the development of mitigation strategies. This study examined the ability of four mathematical model structures to describe two distinct mechanisms of N₂O production by AOB. The production mechanisms evaluated are (1) N₂O as the final product of nitrifier denitrification with NO as the terminal electron acceptor and (2) N₂O as a byproduct of incomplete oxidation of hydroxylamine (NH₂OH) to NO. The four models were compared based on their ability to predict N₂O dynamics observed in three mixed culture studies. Short‐term batch experimental data were employed to examine model assumptions related to the effects of (1) NH concentration variations, (2) dissolved oxygen (DO) variations, (3) NO accumulations and (4) NH₂OH as an externally provided substrate. The modeling results demonstrate that all these models can generally describe the NH, NO, and NO data. However, none of these models were able to reproduce all measured N₂O data. The results suggest that both the denitrification and NH₂OH pathways may be involved in N₂O production and could be kinetically linked by a competition for intracellular reducing equivalents. A unified model capturing both mechanisms and their potential interactions needs to be developed with consideration of physiological complexity. Biotechnol. Bioeng. 2013; 110: 153–163. © 2012 Wiley Periodicals, Inc.     

Botryticides affect grapevine leaf photosynthesis without inducing defense mechanisms

The effects of the two botryticides, fludioxonil (fdx) and fenhexamid (fhd), were investigated on grapevine leaves (Vitis vinifera L. cv. Pinot noir) following photosynthesis and defense mechanisms. Treatments were carried out in vineyard at the end of flowering. Phytotoxicity of both fungicides was evaluated by measuring variations of leaf photosynthetic parameters and correlated expression of photosynthesis-related genes. Results demonstrated that similar decrease in photosynthesis was caused by fdx and fhd applications. Moreover, the mechanism leading to photosynthesis alteration seems to be the same for both fungicides. Stomatal limitation to photosynthetic gas exchange did not change following treatments indicating that inhibition of photosynthesis was mostly attributed to non-stomatal factors. Nevertheless, fungicides-induced depression of photosynthesis was related neither to a decrease in Rubisco carboxylation efficiency and in the capacity for regeneration of ribulose 1,5-bisphosphate nor to loss in PSII activity. However, fdx and fhd treatments generated repression of genes encoding proteins involved in the photosynthetic process. Indeed, decreased photosynthesis was coupled with repression of PsbP subunit of photosystem II (psbP1), chlorophyll a/b binding protein of photosystem I (cab) and Rubisco small subunit (rbcS) genes. A repression of these genes may participate in the photosynthesis alteration. To our knowledge, this is the first study of photosynthesis-related gene expression following fungicide stress. In the meantime, defense responses were followed by measuring chitinase activity and expression of varied defense-related genes encoding proteins involved in phenylpropanoid synthesis (PAL) or octadecanoid synthesis (LOX), as well as pathogenesis-related protein (Chi4C). No induction of defense was observed in botryticides-treated leaves. To conclude, the photosynthesis is affected without any triggering of plant defense responses.     

絮凝酵母吸附Cr(VI)的机理

絮凝酵母SPSC01为酿酒酵母Saccharomyces cerevisiae和粟酒裂殖酵母Schizosaccharomyces pombe的融合菌株,用其吸附水溶液中的重金属Cr(VI),可以大大降低生物吸附的固液分离成本。为了探讨SPSC01菌体絮凝蛋白对Cr(VI)还原吸附的影响,对SPSC01与其亲本菌株的吸附行为进行了比较。结果表明,SPSC01和其具有絮凝性状的亲本S.pombe的Cr(VI)去除速率基本同步,远优于无絮凝性状的亲本S.cerevisiae;达到吸附平衡时,S.pombe、SPSC01和S.cerevisiae对总Cr去除率分别达68.8%、48.6%和37.5%;从而证明了絮凝有利于Cr(VI)的还原、吸附,絮凝蛋白在Cr(VI)的还原吸附过程中起促进作用。通过化学屏蔽方法和傅立叶变换红外光谱(FTIR)分析,对SPSC01菌体表面吸附Cr(VI)的机理进行了研究,结果表明SPSC01菌体表面吸附Cr(VI)起主要作用的基团是氨基、羧基和酰胺基。     

三裂叶豚草锈菌侵染寄主叶片的显微和超微观察

【背景】三裂叶豚草是我国重要的外来入侵植物之一,其传播速度快,已给我国造成巨大的经济损失。近年来发现的三裂叶豚草锈菌是一种对其具有生物防治潜力的病原菌。【方法】本文利用显微技术研究了三裂叶豚草锈菌的侵染过程及其对寄主结构的影响。【结果】三裂叶豚草锈菌菌丝可从多处侵入同一个叶肉细胞,胞间菌丝与叶肉细胞相接触可使部分细胞壁增厚。锈菌侵染使三裂叶豚草叶脉末梢导管分枝增多,造成三裂叶豚草水分代谢失调;叶片细胞内膜系统破碎化,细胞器结构受到不同程度的破坏,导致细胞内膜系统紊乱,细胞器结构稳定性降低。【结论与意义】豚草锈菌侵染破坏了三裂叶豚草叶片的细胞结构。本研究为深入研究豚草锈菌的致病机理奠定了基础。     

The molecular mechanisms of interactions between bioactive peptides and angiotensin-converting enzyme

The ability of milk protein derived Ile-Pro-Ala (IPA), Phe-Pro (FP) and Gly-Lys-Pro (GKP) peptides to inhibit angiotensin I-converting enzyme (ACE), a protein with an important role in blood-pressure regulation, were verified in vitro and in vivo. This work elucidates the modes and molecular mechanisms of the interaction of IPA, FP and GKP with ACE, including mechanisms that bind the peptides to the cofactor Zn²⁺. It was observed that the best docking poses obtained for IPA, FP and GKP were at the ACE catalytic site with very similar modes of interaction, including the interaction with Zn²⁺. The interactions, including H-bonds, hydrophobic, hydrophilic, and electrostatic interactions, as well as the interaction with Zn²⁺, were responsible for the binding between the bioactive peptides and ACE.     

媒介昆虫—病毒—植物互作加剧生物入侵的过程和生理机制

烟粉虱(Bemisia tabaci)及其传播的双生病毒是全球性重大入侵生物,给农业生产造成了严重损失。媒介昆虫—病毒—植物互作是决定病害流行和昆虫种群动态的重要因子,但其在生物入侵中所起的作用一直未受到关注。入侵烟粉虱与双生病毒通过寄主植物所形成的间接互惠共生关系可能是其广泛入侵并取代土著近缘生物的一个重要生态机制。现已从植物生理变化、昆虫共生细菌生理功能和昆虫生理反应三个方面综合探讨这种互惠共生关系的生理机制及分子机制,以期深入揭示媒介昆虫与病毒互作在生物入侵中的作用,为发展高效的预警和治理技术体系提供理论基础。     

空心莲子草在我国的适应性及入侵机制

空心莲子草是入侵我国的重要杂草之一,它在我国能广泛传播和迅速蔓延,与其自身特有的形态生理适应性、强大的繁殖特性和竞争力,以及传入地缺乏自然控制机制密切相关.空心莲子草从其原产地过渡到新的侵入地的过程中,在生态环境适应方面发生重大变化,产生一系列的形态结构、生理过程,以求适应陆地生活条件.其表型可塑性使得空心莲子草有更宽的生态幅,可利用的潜在资源范围也随之扩展;强大的营养繁殖能力,使其迅速产生大量的后代,在失去自然天敌调控的情况下,尤为适应其侵入种的生长、繁殖、发展和传播,种群数量的激增又会加速其传播扩散速度,导致空心莲子草爆发成灾.在综述空心莲子草在形态、生理、繁殖的适应性特征及天敌因素和入侵特性的基础上,根据前人的有关论述,分析了空心莲子草在我国的适应性特征及入侵机制,指出了空心莲子草在我国适应性及入侵机制应着重研究的方向,提出了综合治理和充分利用空心莲子草的对策.     

天然反义转录物及其调控基因的表达机制

天然反义转录(NATs)是一组编码蛋白质或非编码蛋白质的RNAs, 与其他(有义)转录物具有互补序列, 可以调节有义链的表达。这种调节可以发生在转录水平或转录后水平, 调节方式有转录干扰、RNA封闭、双链依赖机制或染色质重建(修饰)等。正义链和反义链分别加工成小RNAs调节基因表达, 也是NATs调节基因表达的重要方式, 如piRNAs的“乒乓机制”。实验或计算机研究已经证明了NATs在生物中广泛存在, 是一种重要的基因表达调节方式。文章论述了NATs的重要作用和机理, 重点论述了NATs的调节机制和相关的小RNAs。     

Dietary flavonoids enhance conspicuousness of a melanin‐based trait in male blackcaps but not of the female homologous trait or of sexually monochromatic traits

Signalling theory predicts that signals should fulfil three fundamental requirements: high detectability, discriminability and, most importantly, reliability. Melanins are the most common pigments in animals. Correlations between genotypic and phenotypic qualities of the sender and size and morph of melanin‐based traits are known, but it is contentious whether melanin‐based colouration may signal any quality. We examined the effect of supplementing blackcaps (Sylvia atricapilla) with flavonoids, potent plant antioxidants, on plumage colouration. We demonstrate that melanin‐based colour can fulfil all requirements of signals of phenotypic condition. As predicted by sexual selection theory, flavonoid supplementation influenced only the sexually dichromatic black cap of males, whereas the female homologous trait and the sexually monochromatic back colouration remained unaffected. Using avian vision models we show that birds can estimate male flavonoid intake from colouration of males’ black cap. Because flavonoid ingestion can increase immune responsiveness in blackcaps, melanin head colouration may signal environmentally determined immune condition.