Plastics have transformed everyday life; usage is increasing and annual production is likely to exceed 300 million tonnes by 2010. In this concluding paper to the Theme Issue on Plastics, the Environment and Human Health, we synthesize current understanding of the benefits and concerns surrounding the use of plastics and look to future priorities, challenges and opportunities. It is evident that plastics bring many societal benefits and offer future technological and medical advances. However, concerns about usage and disposal are diverse and include accumulation of waste in landfills and in natural habitats, physical problems for wildlife resulting from ingestion or entanglement in plastic, the leaching of chemicals from plastic products and the potential for plastics to transfer chemicals to wildlife and humans. However, perhaps the most important overriding concern, which is implicit throughout this volume, is that our current usage is not sustainable. Around 4 per cent of world oil production is used as a feedstock to make plastics and a similar amount is used as energy in the process. Yet over a third of current production is used to make items of packaging, which are then rapidly discarded. Given our declining reserves of fossil fuels, and finite capacity for disposal of waste to landfill, this linear use of hydrocarbons, via packaging and other short-lived applications of plastic, is simply not sustainable. There are solutions, including material reduction, design for end-of-life recyclability, increased recycling capacity, development of bio-based feedstocks, strategies to reduce littering, the application of green chemistry life-cycle analyses and revised risk assessment approaches. Such measures will be most effective through the combined actions of the public, industry, scientists and policymakers. There is some urgency, as the quantity of plastics produced in the first 10 years of the current century is likely to approach the quantity produced in the entire century that preceded.

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Plastics, the environment and human health: current consensus and future trends.

Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Modifications of the hypothalamo-pituitary-adrenal axis and associated changes in circulating levels of glucocorticoids form a key component of the response of an organism to stressful challenges. Increased levels of glucocorticoids promote gluconeogenesis, mobilization of amino acids, and stimulation of fat breakdown to maintain circulating levels of glucose necessary to mount a stress response. In addition to profound changes in the physiology and function of multiple tissues, stress and elevated glucocorticoids can also inhibit reproduction, a logical effect for the survival of self. Precise levels of glucocorticoids are required for proper gonadal function; where the balance is disrupted, so is fertility. Glucocorticoids affect gonadal function at multiple levels in hypothalamo-pituitary-gonadal axis: 1) the hypothalamus (to decrease the synthesis and release of gonadotropin-releasing hormone [GnRH]); 2) the pituitary gland (to inhibit the synthesis and release of luteinizing hormone [LH] and follicle stimulating hormone [FSH]); 3) the testis/ovary (to modulate steroidogenesis and/or gametogenesis directly). Furthermore, maternal exposure to prenatal stress or exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal function and stress-related behaviors in offspring. Glucocorticoids are vital to many aspects of normal brain development, but fetal exposure to superabundant glucocorticoids can result in life-long effects on neuroendocrine function. This review focuses on the molecular mechanisms believed to mediate glucocorticoid inhibition of reproductive functions and the anatomical sites at which these effects take place.

Glucocorticoids, stress, and fertility.

proposed that steroids play a key role in the hormonal modulation of social plasticity. Here, we propose a reciprocal model for the action of androgens on short-term behavioral plasticity and review a set of studies conducted in our laboratory using an African cichlid fish (Oreochromis mossambicus) that provide support for it. Androgens are shown to be implicated as physiological mediators in a wide range of social phenomena that promote social competence, namely by adjusting the behavioral response to the nature of the intruder and the presence of third parties (dear enemy and audience effects), by anticipating territorial intrusions (bystander effect and conditioning of the territorial response), and by modifying future behavior according to prior experience of winning (winner effect). The rapid behavioral actions of socially induced short-term transient changes in androgens indicate that these effects are most likely mediated by nongenomic mechanisms. The fact that the modulation of rapid changes in behavior is open to the influence of circulating levels of androgens, and is not exclusively achieved by changes in central neuromodulators, suggests functional relevance of integrating body parameters in the behavioral response. Thus, the traditional view of seeing neural circuits as unique causal agents of behavior should be updated to a brain–body–environment perspective, in which these neural circuits are embodied and the behavioral performance (and outcomes as fitness) depends on a dynamic relationship between the different levels. In this view hormones play a major role as behavioral modulators.

Social behavior in context: Hormonal modulation of behavioral plasticity and social competence

Phthalates: European regulation, chemistry, pharmacokinetic and related toxicity

Phthalates, the most abundantly produced plasticizers, leach out from polyvinyl chloride plastics and disrupt androgen action. Male rats that are exposed to phthalates in utero develop symptoms characteristic of the human condition referred to as testicular dysgenesis syndrome (TDS). Environmental influences have been suspected to contribute to the increasing incidence of TDS in humans (i.e. cryptorchidism and hypospadias in newborn boys and testicular cancer and reduced sperm quality in adult males). In this review, we discuss the recent findings that prenatal exposure to phthalates affects Leydig cell function in the postnatal testis. This review also focuses on the recent progress in our understanding of how Leydig cell factors contribute to phthalate-mediated TDS.

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Phthalate-induced testicular dysgenesis syndrome: Leydig cell influence.

Testicular Leydig cells are the primary source of testosterone in males. Adult Leydig cells have been shown to arise from stem cells present in the neonatal testis. Once established, adult Leydig cells turn over only slowly during adult life, but when these cells are eliminated experimentally from the adult testis, new Leydig cells rapidly reappear. As in the neonatal testis, stem cells in the adult testis are presumed to be the source of the new Leydig cells. As yet, the mechanisms involved in regulating the proliferation and differentiation of these stem cells remain unknown. We developed a unique in vitro system of cultured seminiferous tubules to assess the ability of factors from the seminiferous tubules to regulate the proliferation of the tubule-associated stem cells, and their subsequent entry into the Leydig cell lineage. The proliferation of the stem Leydig cells was stimulated by paracrine factors including Desert hedgehog (DHH), basic fibroblast growth factor (FGF2), platelet-derived growth factor (PDGF), and activin. Suppression of proliferation occurred with transforming growth factor β (TGF-β). The differentiation of the stem cells was regulated positively by DHH, lithium- induced signaling, and activin, and negatively by TGF-β, PDGFBB, and FGF2. DHH functioned as a commitment factor, inducing the transition of stem cells to the progenitor stage and thus into the Leydig cell lineage. Additionally, CD90 (Thy1) was found to be a unique stem cell surface marker that was used to obtain purified stem cells by flow cytometry.

https://www.pnas.org/content/pnas/113/10/2666.full.pdf

Qing-Quan Lian

Papers

Phthalate-induced testicular dysgenesis syndrome: Leydig cell influence.

Regulation of seminiferous tubule-associated stem Leydig cells in adult rat testes

Rapid mechanisms of glucocorticoid signaling in the Leydig cell.

Environmental inhibitors of 11β-hydroxysteroid dehydrogenase type 2.

Inutero exposure to diisononyl phthalate caused testicular dysgenesis of rat fetal testis.