Endocrine-disrupting chemicals and their effects on puberty.

peer reviewedSexual maturation in humans is characterized by a unique individual variability. Pubertal onset is a highly heritable polygenic trait but it is also affected by environmental factors such as obesity or endocrine disrupting chemicals. The last 30 years have been marked by a constant secular trend toward earlier age at onset of puberty in girls and boys around the world. More recent data, although more disputed, suggest an increased incidence in idiopathic central precocious puberty. Such trends point to a role for environmental factors in pubertal changes. Animal data suggest that the GnRH-neuronal network is highly sensitive to endocrine disruption during development. This review focuses on the most recent data regarding secular trend in pubertal timing as well as potential new epigenetic mechanisms explaining the developmental and transgenerational effects of endocrine disrupting chemicals on pubertal timing

Perinatal exposure to known endocrine disrupters alters ovarian development and systemic steroid hormone profile in rats

peer reviewe

Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats

IntroductionEstrogenic endocrine disrupting chemicals (EDCs) such as diethylstilbestrol (DES) are known to alter the timing of puberty onset and reproductive function in females. Accumulating evidence suggests that steroid synthesis inhibitors such as ketoconazole (KTZ) or phthalates may also affect female reproductive health, however their mode of action is poorly understood. Because hypothalamic activity is very sensitive to sex steroids, we aimed at determining whether and how EDCs with different mode of action can alter the hypothalamic transcriptome and GnRH release in female rats.DesignFemale rats were exposed to KTZ or DES during perinatal (DES 3-6-12μg/kg.d; KTZ 3-6-12mg/kg.d), pubertal or adult periods (DES 3-12-48μg/kg.d; KTZ 3-12-48mg/kg.d).ResultsEx vivo study of GnRH pulsatility revealed that perinatal exposure to the highest doses of KTZ and DES delayed maturation of GnRH secretion before puberty, whereas pubertal or adult exposure had no effect on GnRH pulsatility. Hypothalamic transcriptome, studied by RNAsequencing in the preoptic area and in the mediobasal hypothalamus, was found to be very sensitive to perinatal exposure to all doses of KTZ before puberty with effects persisting until adulthood. Bioinformatic analysis with Ingenuity Pathway Analysis predicted “Creb signaling in Neurons” and “IGF-1 signaling” among the most downregulated pathways by all doses of KTZ and DES before puberty, and “PPARg” as a common upstream regulator driving gene expression changes. Deeper screening ofRNAseq datasets indicated that a high number of genes regulating the activity of the extrinsic GnRH pulse generator were consistently affected by all the doses of DES and KTZ before puberty. Several, including MKRN3, DNMT3 or Cbx7, showed similar alterations in expression at adulthood.ConclusionnRH secretion and the hypothalamic transcriptome are highly sensitive to perinatal exposure to both DES and KTZ. The identified pathways should be exploredfurther to identify biomarkers for future testing strategies for EDC identification and when enhancing the current standard information requirements in regulation

Congenital ablation of Tacr2 reveals overlapping and redundant roles of NK2R signaling in the control of reproductive axis

peer reviewe

Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause-effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman's reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause-effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.Peer reviewe

Multi- and Transgenerational Outcomes of an Exposure to a Mixture of Endocrine-Disrupting Chemicals (EDCs) on Puberty and Maternal Behavior in the Female Rat.

peer reviewedBACKGROUND: The effects of endocrine-disrupting chemicals (EDCs) on fertility and reproductive development represent a rising concern in modern societies. Although the neuroendocrine control of sexual maturation is a major target of EDCs, little is known about the potential role of the hypothalamus in puberty and ovulation disruption transmitted across generations. OBJECTIVES: We hypothesized that developmental exposure to an environmentally relevant dose of EDC mixture could induce multi- and/or transgenerational alterations of sexual maturation and maternal care in female rats through epigenetic reprograming of the hypothalamus. We investigated the transmission of a disrupted reproductive phenotype via the maternal germline or via nongenomic mechanisms involving maternal care. METHODS: Adult female Wistar rats were exposed prior to and during gestation and until the end of lactation to a mixture of the following 13 EDCs: di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), vinclozolin, prochloraz, procymidone, linuron, epoxynaxole, dichlorodiphenyldichloroethylene, octyl methoxynimmate, 4-methylbenzylidene camphor (4-MBC), butylparaben, and acetaminophen. Perinatally exposed offspring (F1) were mated with unexposed males to generate germ cell (F2) and transgenerationally exposed (F3 and F4) females. Sexual maturation, maternal behavior, and hypothalamic targets of exposure were studied across generations. RESULTS: Germ cell (F2) and transgenerationally (F3) EDC-exposed females, but not F1, displayed delayed pubertal onset and altered folliculogenesis. We reported a transgenerational alteration of key hypothalamic genes controlling puberty and ovulation (Kiss1, Esr1, and Oxt), and we identified the hypothalamic polycomb group of epigenetic repressors as actors of this mechanism. Furthermore, we found a multigenerational reduction of maternal behavior (F1-F3) induced by a loss in hypothalamic dopaminergic signaling. Using a cross-fostering paradigm, we identified that the reduction in maternal phenotype was normalized in EDC-exposed pups raised by unexposed dams, but no reversal of the pubertal phenotype was achieved. DISCUSSION: Rats developmentally exposed to an EDC mixture exhibited multi- and transgenerational disruption of sexual maturation and maternal care via hypothalamic epigenetic reprogramming. These results raise concerns about the impact of EDC mixtures on future generations. https://doi.org/10.1289/EHP8795

Multisectoral Climate Impact Hotspots in a Warming World

The impacts of global climate change on different aspects of humanity's diverse life-support systems are complex and often difficult to predict. To facilitate policy decisions on mitigation and adaptation strategies, it is necessary to understand, quantify, and synthesize these climate-change impacts, taking into account their uncertainties. Crucial to these decisions is an understanding of how impacts in different sectors overlap, as overlapping impacts increase exposure, lead to interactions of impacts, and are likely to raise adaptation pressure. As a first step we develop herein a framework to study coinciding impacts and identify regional exposure hotspots. This framework can then be used as a starting point for regional case studies on vulnerability and multifaceted adaptation strategies. We consider impacts related to water, agriculture, ecosystems, and malaria at different levels of global warming. Multisectoral overlap starts to be seen robustly at a mean global warming of 3 degC above the 1980-2010 mean, with 11% of the world population subject to severe impacts in at least two of the four impact sectors at 4 degC. Despite these general conclusions, we find that uncertainty arising from the impact models is considerable, and larger than that from the climate models. In a low probability-high impact worst-case assessment, almost the whole inhabited world is at risk for multisectoral pressures. Hence, there is a pressing need for an increased research effort to develop a more comprehensive understanding of impacts, as well as for the development of policy measures under existing uncertainty

Perturbation neuroendocrinienne de la maturation sexuelle après exposition postnatale précoce au Diéthylstilbestrol ou au Bisphénol A.

Notre société fait face actuellement à un problème de santé publique grandissant lié à la production et la présence croissantes de produits chimiques synthétiques qui peuvent interférer avec notre système endocrinien. Ces substances sont appelées perturbateurs endocriniens (PEs). L’organisme en développement possède une plasticité qui lui permet la mise en place de processus d’adaptation à l’environnement qui s’exprimeront toute la vie. Le développement de nombreuses fonctions physiologiques dépend de l’action d’hormones et la perturbation précoce de cette action peut conduire au développement à long terme de maladies. Ce concept est connu sous le nom de DOHaD pour « Developmental Origins of Health and Disease ».C’est dans ce contexte que s’inscrit le but de ce travail qui vise à déterminer l’impact de l’exposition précoce à deux PEs, le diéthylstilbestrol (DES) ou le bisphénol A (BPA) sur la maturation sexuelle du rat femelle et l’implication de mécanismes neuroendocriniens. Ce travail a révélé qu’une exposition durant les cinq premiers jours de vie au DES peut à la fois avancer ou retarder l’âge de l’ouverture vaginale en fonction de la dose. C’est la 1re étude révélant un retard pubertaire suite à l’exposition au DES. De plus, ce retard est associé à une perturbation neuroendocrinienne avec une sécrétion de GnRH ralentie et une diminution de l’expression hypothalamique de la kisspeptine. Par ailleurs, nous avons également identifié que la combinaison de cette exposition postnatale au DES avec une restriction alimentaire prénatale supprime l’effet stimulant de la leptine sur la sécrétion de GnRH. Concernant le BPA, ce travail révèle également qu’en fonction de la dose, le BPA induit un retard ou une avancée de maturation sexuelle. Le retard est dû à une dose environnementale de BPA de 25 ng/kg/j qui est 160 fois inférieure au seuil de sécurité fixé par l’EFSA. Nous avons mis en évidence que ces effets sur le timing pubertaire sont associés à une perturbation de la neurotranmission GABAergique qui est également affectée dans des sens opposés en fonction de la dose de BPA. Ce modèle d’exposition au BPA nous a par ailleurs, conduit à l’identification d’un GPCR orphelin, GPR151, comme acteur potentiel du réseau des neurones à GnRH. Nous avons observé l’expression de ce récepteur dans les terminaisons des neurones à GnRH et constaté que l’expression de son ARNm augmente particulièrement au moment de l’établissement de la puberté. In vitro, la surexpression de ce récepteur dans des neurones à GnRH immortalisés augmente la libération de GnRH par ces cellules

Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats

Raw and additional data for the article : "Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats  "</p