ABSTRACT
Evidence has emerged that endocrine-disrupting chemicals (EDCs) can produce adverse effects, even at low doses that are assumed safe. However, systemic reviews and meta-analyses focusing on human studies, especially of EDCs with short half-lives, have demonstrated inconsistent results. Epidemiological studies have insuperable methodological limitations, including the unpredictable net effects of mixtures, non-monotonic dose-response relationships, the non-existence of unexposed groups, and the low reliability of exposure assessment. Thus, despite increases in EDC-linked diseases, traditional epidemiological studies based on individual measurements of EDCs in bio-specimens may fail to provide consistent results. The exposome has been suggested as a promising approach to address the uncertainties surrounding human studies, but it is never free from these methodological issues. Although exposure to EDCs during critical developmental periods is a major concern, continuous exposure to EDCs during non-critical periods is also harmful. Indeed, the evolutionary aspects of epigenetic programming triggered by EDCs during development should be considered because it is a key mechanism for developmental plasticity. Presently, living without EDCs is impossible due to their omnipresence. Importantly, there are lifestyles which can increase the excretion of EDCs or mitigate their harmful effects through the activation of mitohormesis or xenohormesis. Effectiveness of lifestyle interventions should be evaluated as practical ways against EDCs in the real world.
ABSTRACT
Evidence has emerged that endocrine-disrupting chemicals (EDCs) can produce adverse effects, even at low doses that are assumed safe. However, systemic reviews and meta-analyses focusing on human studies, especially of EDCs with short half-lives, have demonstrated inconsistent results. Epidemiological studies have insuperable methodological limitations, including the unpredictable net effects of mixtures, non-monotonic dose-response relationships, the non-existence of unexposed groups, and the low reliability of exposure assessment. Thus, despite increases in EDC-linked diseases, traditional epidemiological studies based on individual measurements of EDCs in bio-specimens may fail to provide consistent results. The exposome has been suggested as a promising approach to address the uncertainties surrounding human studies, but it is never free from these methodological issues. Although exposure to EDCs during critical developmental periods is a major concern, continuous exposure to EDCs during non-critical periods is also harmful. Indeed, the evolutionary aspects of epigenetic programming triggered by EDCs during development should be considered because it is a key mechanism for developmental plasticity. Presently, living without EDCs is impossible due to their omnipresence. Importantly, there are lifestyles which can increase the excretion of EDCs or mitigate their harmful effects through the activation of mitohormesis or xenohormesis. Effectiveness of lifestyle interventions should be evaluated as practical ways against EDCs in the real world.
Subject(s)
Humans , Epidemiologic Studies , Epidemiology , Epigenomics , Life Style , PlasticsABSTRACT
Behavioral profiles are influenced by both positive and negative experiences as well as the genetic disposition. Traditionally, accumulating adversity over lifetime is considered to predict increased anxiety-like behavior ("allostatic load"). The alternative "mismatch hypothesis" suggests increased levels of anxiety if the early environment differs from the later-life environment. Thus, there is a need for a whole-life history approach to gain a deeper understanding of how behavioral profiles are shaped. The aim of this study was to elucidate the effects of life history on the behavioral profile of mice varying in serotonin transporter (5-HTT) genotype, an established mouse model of increased anxiety-like behavior. For this purpose, mice grew up under either adverse or beneficial conditions during early phases of life. In adulthood, they were further subdivided so as to face a situation that either matched or mismatched the condition experienced so far, resulting in four different life histories. Subsequently, mice were tested for their anxiety-like and exploratory behavior. The main results were: (1) Life history profoundly modulated the behavioral profile. Surprisingly, mice that experienced early beneficial and later escapable adverse conditions showed less anxiety-like and more exploratory behavior compared to mice of other life histories. (2) Genotype significantly influenced the behavioral profile, with homozygous 5-HTT knockout mice displaying highest levels of anxiety-like and lowest levels of exploratory behavior. Our findings concerning life history indicate that the absence of adversity does not necessarily cause lower levels of anxiety than accumulating adversity. Rather, some adversity may be beneficial, particularly when following positive events. Altogether, we conclude that for an understanding of behavioral profiles, it is not sufficient to look at experiences during single phases of life, but the whole life history has to be considered.
ABSTRACT
OBJECTIVE: Epidemiological studies have established that low birth weight offspring, when faced with a nutritional mismatch in postnatal life, have an increased risk of developing the metabolic syndrome. Our laboratory and others have demonstrated that maternal protein restriction (MPR) leads to high cholesterol and insulin resistance in the offspring due to impaired liver function, though the underlying molecular mechanisms remain elusive. Recent in vitro studies have associated decreased phosphorylation of Akt1 (Serine 473), a marker of insulin sensitivity, with increased phosphorylation of eukaryotic initiation factor (eIF)-2α (Serine 51), a key regulator of protein translation attenuation. The main aim of the study was to determine whether nutritional mismatch in MPR offspring leads to elevated phospho-eIF2α (Ser51) levels in the liver. MATERIALS/METHODS: To investigate if this occurs long-term in MPR offspring, pregnant Wistar rats were fed a control (20%) protein diet (control) or a low (8%) protein diet during pregnancy and postnatal life (LP1), or during pregnancy and lactation (LP2). RESULTS: At postnatal day 130, LP2 offspring exhibited increases in hepatic phosphorylation of eIF2α (Ser51) concomitant with decreases in the phosphorylation of Akt1 (Ser473), while LP1 offspring exhibited the converse relationship. Interestingly, in embryonic day 19 livers derived from control or MPR pregnancy, no changes in eIF2α (Ser51) or Ak1 (Ser473) phosphorylation were observed. CONCLUSION: Collectively, our data provide robust evidence that phosphorylation of eIF2α (Ser51) is inversely correlated with phosphorylated Akt1 (Ser473) in vivo. Moreover, this study demonstrates that this inverse relationship is adversely influenced in these MPR offspring by a mismatch in the postnatal nutritional environment.
