Background:At a time of increasing disconnectedness from nature, scientific interest in the potential health benefits of nature contact has grown. Research in recent decades has yielded substantial evidence, but large gaps remain in our understanding.Objectives:We propose a research agenda on nature contact and health, identifying principal domains of research and key questions that, if answered, would provide the basis for evidence-based public health interventions.Discussion:We identify research questions in seven domains: a) mechanistic biomedical studies; b) exposure science; c) epidemiology of health benefits; d) diversity and equity considerations; e) technological nature; f) economic and policy studies; and g) implementation science.Conclusions:Nature contact may offer a range of human health benefits. Although much evidence is already available, much remains unknown. A robust research effort, guided by a focus on key unanswered questions, has the potential to yield high-impact, consequential public health insights. https://doi.org/10.1289/EHP1663

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Obesity is frequently associated with systemic insulin resistance, glucose intolerance, and hyperlipidemia. Impaired insulin action in muscle and paradoxical diet/ insulin-dependent overproduction of hepatic lipids are important components of obesity, but their pathogenesis and inter-relationships between muscle and liver are uncertain. We studied two murine obesity models, moderate high-fatfeeding and heterozygous muscle-specific PKC-l knockout, in both of which insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but conserved in liver. In both models, activation of hepatic sterol receptor element binding protein-1c (SREBP-1c) and NFkB (nuclear factorkappa B), major regulators of hepatic lipid synthesis and systemic insulin resistance, was chronically increased in the fed state. In support of a critical mediatory role of aPKC, in both models, inhibition of hepatic aPKC by adenovirally mediated expression of kinase-inactive aPKC markedly diminished diet/insulin-dependent activation of hepatic SREBP-1c and NFkB, and concomitantly improved hepatosteatosis, hypertriglyceridemia, hyperinsulinemia, and hyperglycemia. Moreover, in high-fat-fed mice, impaired insulin signaling to IRS-1-dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle and hyperinsulinemia were largely reversed. In obesity, conserved hepatic aPKC-dependent activation of SREBP-1c and NFkB contributes importantly to the development of hepatic lipogenesis, hyperlipidemia, and systemic insulin resistance. Accordingly, hepatic aPKC is a potential target for treating obesityassociated abnormalities. Supplementary key words atypical protein kinase C • high fatObesity, particularly when accompanied by systemic insulin resistance, glucose intolerance, and hyperlipidemia (i.e., a "metabolic syndrome") is a global health problem and a frequent forerunner of type 2 diabetes mellitus. Whereas both exogenous/diet-induced and genetically determined obesity can produce insulin resistance and metabolic syndrome features, vice versa, systemic insulin resistance can produce obesity and metabolic syndrome features. However, mechanisms underlying lipid abnormalities and insulin resistance in these situations, and the critical interplay between muscle and liver, are poorly understood.The high-fat-fed (HFF) mouse model is useful for studying diet-induced obesity-related insulin resistance. In our experience, feeding mice a Western-type 20% milk highfat diet for 3-4 weeks leads to diminished insulin activation of phosphatidylinositol (PI) 3-kinase (PI3K) effectors, atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt) in muscle (1, 2), with little or no effect on hepatic aPKC and PKB/Akt activation (1). In this HFF model, we have observed no increases in basal (unstimulated) activities of conventional (a,b2) or novel (y,y) PKCs in liver, despite observing increases in muscle (unpublished). Accordingly, our HFF model may partly differ from others wherein higher dietary fat was used, thereby activating hepatic novel ...

AMP-activated protein kinase (AMPK) is the central component of a cellular signaling system that regulates multiple metabolic enzymes and pathways in response to reduced intracellular energy levels. The transcription factor hepatic nuclear factor 4␣ (HNF4␣) is an orphan nuclear receptor that regulates the expression of genes involved in energy metabolism in the liver, intestine, and endocrine pancreas. Inheritance of a single null allele of HNF4␣ causes diabetes in humans. Here we demonstrate that AMPK directly phosphorylates HNF4␣ and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4␣ on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. These results demonstrate that HNF4␣ is a downstream target of AMPK and raise the possibility that one of the effects of AMPK activation is reduced expression of HNF4␣ target genes.The transcription factor HNF4␣ 1 (NR2A1), a member of the nuclear receptor superfamily, plays a key role in regulating the expression of metabolic genes in multiple tissues including the liver, intestine, kidney, and endocrine pancreas (for review see Ref. 1). In humans, a nonsense mutation in a single allele of the HNF4␣ gene causes an inherited form of diabetes known as maturity onset diabetes of the young (MODY) (for a review see Ref. 2). This syndrome is characterized by insufficient insulin secretion (3, 4), indicating a significant defect in pancreatic function. Surprisingly, there is not a major deficit in liver function, despite the important role of HNF4␣ in hepatic gene expression (5). These observations suggest that HNF4␣ regulates pancreatic genes involved in glucose sensing and/or insulin production. This hypothesis is supported by experiments demonstrating that HNF4␣ regulates expression of genes encoding enzymes of glucose metabolism and insulin secretion (6 -8). Because MODY1 patients have a single null allele that does not produce a dominant-negative acting protein (9), the physiological abnormalities in these patients must be caused by a relatively mild (ϳ50%) decrease in the amount of HNF4␣ protein. Taken together, these observations raise the possibility that any modification of HNF4␣ that causes a reduction in its transcriptional activity could have significant effects on pancreatic function.HNF4␣ has also been shown recently to play an important role in the regulation of hepatic glucose output, a key component of the maintenance of plasma glucose levels. Yoon et al. (10) recently demonstrated that the transcriptional regulation of gene for the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase by cAMP was mediated by the transcriptional co-activator PGC-1 acting through HNF4␣. These findings suggest that HNF4␣ may play a role in the transcriptional response of the liver to metabolic hormones and that factors regulating the activity of HNF4␣ could have an effect on hepatic glucose output.AMPK is the mammalian homolog of the yeast SNF1 pr...

English sole (Parophrys vetulus) are susceptible to the development of hepatic disease, including neoplasia, as a result of environmental exposure to polycyclic aromatic hydrocarbons (PAHs). The metabolism of PAHs, believed to be an essential factor in the development of neoplasia, has received considerable study in English sole, except that xenobiotic metabolizing enzymes (XMEs) have not been well-studied in this species. In the present work, the activities of hepatic aryl hydrocarbon hydroxylase (AHH), glutathione-S-transferase (GST), and epoxide hydrolase (EH) were measured in English sole exposed to several organic xenobiotics. These studies included an examination of the effects of captivity, the short-term responses of hepatic XME activities to several xenobiotic compounds, and detailed studies of the time- and dose-responses of hepatic XME activities to both a representative carcinogenic PAH (benzo[a]pyrene) and to a complex mixture of contaminants extracted from a sediment collected from a polluted area of Puget Sound, WA. Additionally, during the captivity and time- and dose-response studies, the levels of fluorescent aromatic compounds (FACs) were measured in the bile of the fish, both to provide an estimation of contaminant exposure and to evaluate the time- and dose-responses of this measure. The results of the captivity studies showed that the levels of FACs in bile were most affected by captivity, primarily as a result of changes in feeding status. The results of the exposure studies showed that xenobiotic metabolism, as reflected in hepatic activities of XMEs and levels of FACs in the bile, is altered by exposure to environmental contaminants. Whereas hepatic AHH activity could be rapidly and substantially increased by such exposure, activities of GST and EH were not affected, even up to 42 days after exposure. Moreover, because fish were exposed to a wide range of doses of chemicals or mixtures of chemicals which are known to be present in contaminated estuaries, and the responses of the hepatic AHH system and the levels of FACs in bile were measured at several time periods after exposure, the results provided substantial validation for the use of these two measures as bioindicators of exposure to environmental contamination in benthic fish.

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Peroxisome proliferators cause a rapid and coordinated transcriptional activation of genes encoding the enzymes of the peroxisomal beta-oxidation pathway in rats and mice. Cis-acting peroxisome proliferator responsive elements (PPREs) have been identified in the 5'-flanking region of H202-producing rat acyl-CoA oxidase (ACOX) gene and in other genes inducible by peroxisome proliferators. To gain more insight into the purported nonresponsiveness of human liver cells to peroxisome volume density and in the activity of the beta-oxidation enzyme system, we have previously cloned the human ACOX gene, the first and rate-limiting enzyme of the peroxisomal beta-oxidation system. We now present information on a regulatory element for the peroxidase proliferator-activated receptor (PPAR)/retinoid X receptor (RXR) heterodimers. The PPRE, consists of AGGTCA C TGGTCA, which is a direct repeat of hexamer half-sites interspaced by a single nucleotide (DR1 motif). It is located at -1918 to -1906 base pairs upstream of the transcription initiation site of this human ACOX gene. This PPRE specifically binds to baculovirus-expressed recombinant rat PPAR alpha/RXR alpha heterodimers. In transient transfection experiments, the maximum induction of luciferase expression by ciprofibrate and/or 9-cis-retinoic acid is dependent upon cotransfection of expression plasmids for PPAR alpha and RXR alpha. The functionally of this human ACOX promoter was further demonstrated by linking it to a beta-galactosidase reporter gene or to a rat urate oxidase cDNA and establishing stably transfected African green monkey kidney (CV1) cell lines expressing reporter protein. The human ACOX promoter has been found to be responsive to peroxisome proliferators in CV1 cells stably expressing PPAR alpha, whereas only a basal level of promoter activity is detected in stably transfected cells lacking PPAR alpha. The presence of a PPRE in the promoter of this human peroxisomal ACOX gene and its responsiveness to peroxisome proliferators suggests that factors other than the PPRE in the 5'-flanking sequence of the human ACOX gene may account for differences, if any, in the pleiotropic responses of humans to peroxisome proliferators.

1988. Contaminant effects on ovarian development in English sole (Parophrys vetulus) from Puget Sound, Washington. Can. 8. Fish. Aquat. Sci. 45: 21 33-2146.In a study evaluating the effects sf exposure to xenobiotic compounds on ovarian development in English sole (Parophrys V~~UIUS), prespawni ng females were sampled from four sites in Puget Sound, Washington, during the 1986 and 1987 spawning seasons. Two sampling sites had high concentrations sf xenobiotic compounds in the sediment, while the other sites were less contaminated. The following factors associated with ovarian maturation were measured: ovarian developmental stage, ovarian atresia, gonadosornatic index, plasma estradiol, and plasma vitellsgenin as estimated from alkali-labile phosphorus. contaminant exposure was assessed by measuring concentrations of fluorescent aromatic compounds in the bile, hepatic aryl hydrocarbon hydrowytase (AHH) activity, and hepatic polychlorinated biphenyl levels, and liver tissue was examined histologically for the presence sf suspected towicopathic lesions. Female English sole from the heavily csntaminated sites were significantly less likely to undergo gonadal recrudescence and had lower mean levels of plasma estradiol than females From the less contaminated sites. The risk sf inhibited gonadal recrudescence was significantly increased in sole with elevated hepatic AHH activity, and AHH activity was also significantly negatively correlated with plasma estradiol level. These findings suggest that contaminant exposure may interfere with ovarian development in female English sole.Dans le cadre de lt6valuation des effets sur le developpernent ovarien de la sole anglaise (Parophrys vetulus) de I'exposition 21 des composes x6wobiotiques, des femelles au stade prefrai ont kt6 prelevees en quatre endroits du detrsit Puget (Washington) au cours des saisons de frai de 1986 et 1987. Les s6diments de deux des sites de prelevements presentaient des concentrations elevkes de csrnpss6s w6nobistiques, ceuw des deux autres sites &ant moins contatmines. Les facteurs lies 2 la maturation ovarienne mesurbes snt 6t6 : \'&ape de develsppement svarien, IPatr6sie ovarienne, I'indice gonadssomatique, la teneur en estradiol plasmatique et la teneur en vitellogenine plasmatique estirnee 2 partir du phssphsre labile era milieu alcalin. L'expssitisn aux contaminants a etk determinee par la mesure des eesncentrations des compss6s arsmatiques Fluorescents prksents dans la bile, de l'activite de Bfaryl-hydroxylase des hydrscarbures EAHH) du foie et des teneurs en biphenyles polyehlor~s du fsie et par urn examen kistslogique des tissus hkpatiques pour la recherche de Iksions toxicopathiques. bes soles anglaises femelles des sites forternent contarnines prksentaient, de fasesn significative, un rktablissement gsnadique moins important et des teneurs rnoyennes en estradisl plasmatique inferieures cornparativement aux femelles des sites moins contaminks. Le risque d'une inhibition du rktablissement gonadique etait significativement accru chez les soles p...