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Neonatal Exposure to Di-(2-Ethylhexyl) Phthalate (Dehp) Through Breastfeeding Leads to Dysfunction Endocrine-metabolic Outcomes in Male Rats at Adulthood: An in Vivo and in Silico Approach

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SSRN 2025年

作者： Santos-Silva, Ana Paula Macario, Thayná M. Melo Santos, Anne R. Barbosa, Yuri Vieira Miranda-Alves, Leandro UFRJ Multidisciplinary Research Center - Xerém in Biological Sciences Brazil - NUMPEX-BIO Campus Duque de Caxias Professor Geraldo Cidade Federal University of Rio de Janeiro Brazil Federal University of Rio de Janeiro Xerem Campus Brazil Research Group on Endocrine Disruptors and Metabolic Programming Laboratory of Endocrinology and Energy Metabolism Prof. João Paulo Gabriel Camporez School of Medicine University of São Paulo Brazil Laboratory of Experimental Endocrinology - LEEx Institute of Biomedical Sciences Federal University of Rio de Janeiro Brazil

Stimuli to which the individual is exposed can influence the phenotype of the adult when they occur in phases of greater susceptibility, as defined by the DOHaD concept, developmental origin of health and disease. Endocrine disruptors (EDs) are natural and/or synthetic molecules that have the ability to influence the role of hormones, among which phthalates stand out. Obesity is a chronic, multifactorial disease, with an increase in prevalence in the population in recent years, and exposure to EDs may have an influence on this scenario. Given this, we propose to verify whether the presence of DEHP (di-2- etilhexil phtalate), in the critical phases as lactation, could influence the metabolism in adult life. Lactating Wistar rats were kept with 6 male pups and divided at groups of 100 mg/kg/day, 500 mg/kg/day, and sesame oil (control) that occurred from postnatal days (PN1D) to PND21, when half of the offspring were euthanized and the other half maintained until adulthood (PND90). In PND21, the 500DEHP group showed a decrease in weight and visceral adiposity, increase in insulin and serum T3 levels. Adult animals had an increase in visceral adiposity for the 500DEHP group, with increased cumulative food intake, reduction in serum leptin and increased serum T3 levels. In silico interation between DEHP and AS160 protein suggesting potencial mechanism of action for DEHP. This data set suggests that DEHP has the potential to influence the development of the offspring, when exposure occurs exclusively during the lactation period, with metabolic consequences associated with obesity at long-term. © 2025, The Authors. All rights reserved.

关键词： Nutrition

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White beans (Phaseolus vulgaris L.) in diet reduces hypothalamic pro-inflammatory cytokines improving insulin resistance in small litter grown rats

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Molecular and cellular endocrinology 2025年 606卷 112587页

作者： Ester Vieira Alves Tatiane Vieira Alves Lauro Sergio Barrozo Junior Marcos Vinícius de Freitas Ribeiro Adriel Felipe Freitas Nunes Camila Luiza Rodrigues Dos Santos Ricken Ingridys Regina Borkenhagen Bruno Vargas Teixeira Cavalheiro Ginislene Dias Ricardo de Oliveira Gisele Facholi Bomfim Júlio Cezar de Oliveira Research Group on Perinatal Programming of Metabolic Diseases: DOHaD Paradigm Laboratory of Metabolic and Cardiovascular Diseases Health Education and Research Center (NUPADS) Institute of Health Sciences Federal University of Mato Grosso University Campus of Sinop Sinop MT Brazil. Laboratory of Experimental Neuropsychobiology Health Education and Research Center (NUPADS) Institute of Health Sciences Federal University of Mato Grosso University Campus of Sinop Sinop MT Brazil. Research Group on Perinatal Programming of Metabolic Diseases: DOHaD Paradigm Laboratory of Metabolic and Cardiovascular Diseases Health Education and Research Center (NUPADS) Institute of Health Sciences Federal University of Mato Grosso University Campus of Sinop Sinop MT Brazil. Electronic address: julio.oliveira1@ufmt.br.

In the present study we were interested in studying the effect of white beans (Phaseolus vulgaris L.) as diet supplementation on glucose-insulin and metabolic homeostasis in early overfeeding rats. Small litter (SL) was adjusted to 3 pups on post-natal day 3, while normal litter (NL) was kept with 8 pups. The milk collection and milk intake were performed, and the rat-offspring when weaned (at 22 days old), were fed a standard (NL-SD and SL-SD groups) or a white bean (2.5 % w/w) supplemented diet (NL-WB and SL-WB groups). Body weight, food and water intake were measured from weaning until adulthood (100 days old). Glucose and insulin tolerance, and intracerebroventricular insulin (10 mmol/L) tests were performed to assess peripheral and central insulin-glucose homeostasis in adult rats. Blood, hypothalamus, visceral fat pad and lean mass were collected. Milk from SL mothers displays high content of glucose, cholesterol, triglycerides and energy (P < 0.05). Milk consumption by SL rat-offspring, in early stage of suckling, was higher than NL rats (P<0.05). At adulthood, SL-SD rats were obese, hyperphagic, dyslipidemic, hyperglycemic, glucose intolerant and IR (P < 0.05). At adulthood, SL-SD rats displayed central IR and higher hypothalamic pro-inflammatory (TNF-α, 43.5 %; IL-6, 78.5 % and IL-1β, 50.1 %, P < 0.05) cytokine. The habitual ingestion of white beans-dietary supplementation prevented all those metabolic disruptions. In summary, white beans-dietary supplementation prevented obesity and glucose-insulin homeostasis deregulation in early overfeeding rats, avoiding hypothalamic inflammatory cytokines high levels and improving insulin sensitivity.

关键词： Breastfeeding Early obesity Functional food metabolic syndrome Overfeeding Phaseolus vulgaris

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Fetal programming of immune function and respiratory disease

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Clinical & Experimental Allergy 2006年第12期27卷

作者： S. LANGLEY-EVANS Metabolic and Molecular Programming Group Department of University Medicine Level D South Block Southampton General Hospital Tremona Road Southampton S016 6YD UK

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Fetal growth and insulin resistance in adult life: Relationship between glycogen synthase activity in adult skeletal muscle and birthweight

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DIABETIC MEDICINE 1996年第4期13卷 325-329页

作者： Phillips, DIW Borthwick, AC Stein, C Taylor, R Metabolic Programming Group MRC Environmental Epidemiology Unit Southampton General Hospital Southampton UK Department of Medicine Medical School Newcastle upon Tyne UK Metabolic Programming Group MRC Environmental Epidemiology Unit Southampton General Hospital Southampton UK Department of Medicine Medical School Newcastle upon Tyne UK

Growth retardation during fetal life is associated with insulin insensitivity and an increased prevalence of impaired glucose tolerance in adult life. Because insulin-mediated stimulation of glycogen synthase may be an important rate-limiting step for insulin action at the cellular level, we have sought to determine whether impaired activation of muscle glycogen synthase is linked with early growth retardation. Postprandial glycogen synthase activity was therefore measured in muscle biopsies from a group of 27 women with normal glucose tolerance aged around 50 who were born in Preston, Lancashire, whose birthweight and body size at birth were recorded. Glycogen synthase activity measured at 0.1 mmol 1(-1) glucose-6-phosphate correlated with insulin sensitivity as measured by a short insulin tolerance test (r=0.42, p<0.05) and the waist to hip ratio (r=-0.48, p<0.01), but not body mass index, body fat percentage or age. Within the group of women with normal glucose tolerance there was no relationship between intra-uterine growth as evidenced by birthweight or body size at birth and the response to insulin of skeletal muscle glycogen synthase in adult life. Thus we found no evidence for a direct link between fetal growth and insulin sensitivity in this pathway.

关键词： type 2 (non-insulin dependent) diabetes insulin resistance fetal growth glycogen synthase programming

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The relation of fetal growth to insulin secretion in young men

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DIABETIC MEDICINE 1996年第8期13卷 773-774页

作者： Wills, J Watson, JM Hales, CN Phillips, DIW MRC Metabolic Programming Group University of Southampton Southampton General Hospital Southampton SO16 6YD UK

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FETAL GROWTH AND INSULIN-RESISTANCE IN ADULT LIFE - ROLE OF PLASMA TRIGLYCERIDE AND NONESTERIFIED FATTY-ACIDS

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DIABETIC MEDICINE 1995年第9期12卷 796-801页

作者： PHILLIPS, DIW MCLEISH, R OSMOND, C HALES, CN Metabolic Programming Group University of Southampton UK MRC Environmental Epidemiology Unit University of Southampton UK Department of Clinical Biochemistry Addenbrooke' Hospital Cambridge UK

Reduced fetal growth is associated with insulin resistance and a high prevalence of glucose intolerance in adult life. Because babies who are growth retarded have elevated levels of triglyceride and non-esterified fatty acids (NEFA), and because similar abnormalities are observed in subjects with the insulin resistance syndrome, impaired regulation of lipid metabolism could be one of the mechanisms explaining the link between reduced fetal growth and insulin resistance, We have, therefore, measured fasting plasma triglyceride and NEFA, and the insulin-mediated suppression of NEFA during an oral glucose tolerance test in 93 men and women aged 50, born in Preston, whose birthweight and body size at birth had been recorded. Elevated fasting plasma triglycerides and reduced NEFA suppression during the oral glucose tolerance test were associated with the male sex, glucose intolerance, central obesity as indicated by a high waist to hip ratio and insulin resistance as measured by a short insulin tolerance test. However there were no statistically significant relationships between the birth measurements and the circulating lipid levels. Moreover in regression analyses the relationships between thinness at birth and insulin resistance or glucose intolerance in adult life were unaffected by the addition of triglyceride or NEFA in the models. These results suggest that the link between reduced fetal growth and insulin resistance in the adult is not mediated by an abnormal regulation of lipid metabolism.

关键词： INSULIN RESISTANCE TRIGLYCERIDES NONESTERIFIED FATTY ACIDS FETAL GROWTH programming

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RELATION OF FETAL GROWTH TO ADULT MUSCLE MASS AND GLUCOSE-TOLERANCE

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DIABETIC MEDICINE 1995年第8期12卷 686-690页

作者： PHILLIPS, DIW Metabolic Programming Group MRC Environmental Epidemiology Unit (University of Southampton) Southampton General Hospital Southampton UK.

Recent studies show reduced fetal growth is associated with insulin resistance and a raised prevalence of glucose intolerance in adult life. Because early growth retardation in animal models leads to permanent changes in body composition and a reduction in the mass of muscle, a major insulin sensitive tissue, reduced adult muscle mass could explain the link between impaired fetal growth and glucose intolerance. To investigate this hypothesis, muscle mass has been determined in a group of men and women aged around 50 who were born in Preston, Lancashire and compared with their birthweight or body size at birth and their current insulin resistance and glucose tolerance. Subjects who had lower birthweights were shorter and lighter but their weight adjusted for height (BMI) was similar to that of other subjects. Much of the difference in weight was accounted for by a reduction in muscle mass. Muscle mass as estimated by the urinary creatinine excretion rose from 18.8 % of body weight in women who had birthweights of 2.5 kg or less to 24.7% of bodyweight in those with birthweights of 3.4 kg or more. Trends in men were similar. Regression analysis showed that adult muscle mass was predicted by low birthweight (p = 0.004), low placental weight (p= 0.02), and small head circumference (p = 0.02) but not, however, by thinness at birth, the birth measurement most predictive of insulin resistance. In addition there were no significant relationships between muscle mass and insulin resistance or glucose tolerance in either men or women. These results may be explained by the existence of two populations of babies both characterized by low birthweight. Babies who are symmetrically small at birth have reduced muscle mass in adult life. They do not, however, have increased insulin resistance or a tendency to develop glucose intolerance. Thin babies have a normal adult muscle mass;their tendency to develop insulin resistance or glucose intolerance is not explained by alterations in mu

关键词： TYPE 2 DIABETES FETAL GROWTH BODY COMPOSITION MUSCLE MASS programming

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The 30 minute insulin incremental response in an oral glucose tolerance test as a measure of insulin secretion

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Diabetic medicine : a journal of the British Diabetic Association 1995年第10期12卷 931页

作者： N J Wareham D I Phillips C D Byrne C N Hales Department of Community Medicine Department of Clinical Biochemistry University of Cambridge Metabolic Programming Group MRC Environmental Epidemiology Unit Southampton

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UNDERSTANDING ORAL GLUCOSE-TOLERANCE - COMPARISON OF GLUCOSE OR INSULIN MEASUREMENTS DURING THE ORAL GLUCOSE-TOLERANCE TEST WITH SPECIFIC MEASUREMENTS OF INSULIN-RESISTANCE AND INSULIN-SECRETION

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DIABETIC MEDICINE 1994年第3期11卷 286-292页

作者： PHILLIPS, DIW CLARK, PM HALES, CN OSMOND, C Metabolic Programming Group Southampton General Hospital Southampton Department of Clinical Biochemistry University of Cambridge Cambridge UK MRC Environmental Epidemiology Unit (University of Southampton) Southampton General Hospital Southampton

The extent to which the oral glucose tolerance test can be used to estimate insulin secretion and insulin resistance has been evaluated by comparing glucose and insulin concentrations during an oral glucose tolerance test with specific measurements of insulin secretion and insulin resistance in 85 normoglycaemic subjects and 23 subjects with impaired glucose tolerance (IGT). Insulin secretion was measured by the first phase insulin response to intravenous glucose and insulin resistance by the insulin tolerance test which measures the decline of plasma glucose after the injection of a bolus of insulin. The best measure of insulin secretion was the ratio of the 30 min increment in insulin concentration to the 30 min increment in glucose concentration following oral glucose loading. This correlated with the first phase insulin release following intravenous glucose (r = 0.61, p < 0.001) but not insulin resistance (r = -0.05, p > 0.05). Insulin resistance could be estimated by the fasting insulin, proinsulin, or split proinsulin concentrations. However, fasting split proinsulin appeared to discriminate best between insulin resistance (r = -0.53, p < 0.001) and insulin secretion (r = 0.07, p > 0.05). Relative insulin resistance estimated by homeostasis model assessment (HOMA), also correlated well with insulin resistance (r = -0.57, p < 0.001) but not insulin secretion (r = 0.01, p > 0.05). We conclude that the oral glucose tolerance test can be used to derive estimates of the relative roles of insulin secretion and insulin resistance in population studies of glucose tolerance.

关键词： ORAL GLUCOSE TOLERANCE INSULIN RESISTANCE INSULIN SECRETION

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TWIN STUDIES IN MEDICAL-RESEARCH - CAN THEY TELL US WHETHER DISEASES ARE GENETICALLY-DETERMINED

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LANCET 1993年第8851期341卷 1008-1009页

作者： PHILLIPS, DIW Metabolic Programming Group Medical Research Council Environmental Epidemiology Unit Southampton General Hospital Southampton SO9 4XY UK

The classic twin study must now be regarded as an unreliable method of estimating the genetic component in most of the common diseases of adult life.

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