Maternal Perinatal Exposure to Dibutyl Phthalate Promotes Ovarian Dysfunction in Adult Female Offspring via Downregulation of TGF-β2 and TGF-β3

IntroductionMaternal exposure to dibutyl phthalate (DBP) may result in glucolipid dysfunction in female offspring. However, the underlying mechanisms remain elusive. We hypothesized that chronic maternal DBP exposure could induce abnormal metabolism of glucolipid.Materials and methodsSprague-Dawley rats were intraperitoneally injected with different doses of DBP, estradiol, and corn oil from gestational day 7 until the end of lactation. The weights, visceral fat percentage, serum lipid, insulin and glucose, protein levels of PI3K signal pathway in muscle were detected in F1 female offspring.ResultsAlthough the birth weight of F1 female offspring was not different among groups, the weights were heavier in DBP groups from postnatal day 7 to adult (P<0.001). The visceral adipose percentage in adult female offspring was increased by perinatal exposure to DBP (P<0.001). Decreased serum levels of triglyceride (P<0.0001), fasting glucose (P=0.004), prolactin (P=0.006), HOMA-IR (P=0.014) were found in female offspring exposed to DBP, but no difference for fasting insulin, total cholesterol, adiponectin. Increased protein levels of p-AKT, but decreased PTEN and GPR30 were observed in muscle of female offspring in DBP group, but without significant difference. None difference was observed for the protein levels of PI3K, AKT, GLUT4, InsR and IRS-1.ConclusionMaternal perinatal exposure to DBP induced obesity and accumulation of visceral adipose tissue for the adult female offspring. Serum glucolipid and local signal transduction of PTEN/PI3K/AKT pathway in muscle were not adversely affected by perinatal exposure to DBP for adult female offspring.

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Developmental exposure to DDT or DDE alters sympathetic innervation of brown adipose in adult female mice

Environmental Health ◽

10.1186/s12940-021-00721-2 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Annalise N. vonderEmbse ◽

Sarah E. Elmore ◽

Kyle B. Jackson ◽

Beth A. Habecker ◽

Katherine E. Manz ◽

...

Keyword(s):

Adult Female ◽

Sympathetic Neurons ◽

Sympathetic Innervation ◽

Female Offspring ◽

Perinatal Exposure ◽

Female Mice ◽

Cl 316,243 ◽

Brown Adipose ◽

Increased Risk ◽

Sympathetic Regulation

Abstract Background Exposure to the bioaccumulative pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) has been associated with increased risk of insulin resistance and obesity in humans and experimental animals. These effects appear to be mediated by reduced brown adipose tissue (BAT) thermogenesis, which is regulated by the sympathetic nervous system. Although the neurotoxicity of DDT is well-established, whether DDT alters sympathetic innervation of BAT is unknown. We hypothesized that perinatal exposure to DDT or DDE promotes thermogenic dysfunction by interfering with sympathetic regulation of BAT thermogenesis. Methods Pregnant C57BL/6 J mice were administered environmentally relevant concentrations of DDTs (p,p’-DDT and o,p’-DDT) or DDE (p,p’-DDE), 1.7 mg/kg and 1.31 mg/kg, respectively, from gestational day 11.5 to postnatal day 5 by oral gavage, and longitudinal body temperature was recorded in male and female offspring. At 4 months of age, metabolic parameters were measured in female offspring via indirect calorimetry with or without the β3 adrenergic receptor agonist, CL 316,243. Immunohistochemical and neurochemical analyses of sympathetic neurons innervating BAT were evaluated. Results We observed persistent thermogenic impairment in adult female, but not male, mice perinatally exposed to DDTs or p,p’-DDE. Perinatal DDTs exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDTs nor p,p’-DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDTs-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDTs, but not p,p’-DDE, and 48 and 43% fewer synapses in stellate ganglia of mice exposed to either DDTs or p,p’-DDE, respectively, compared to control. Conclusions These data demonstrate that perinatal exposure to DDTs or p,p’-DDE impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT. Graphical abstract

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Correction: Perinatal Exposure of Mice to the Pesticide DDT Impairs Energy Expenditure and Metabolism in Adult Female Offspring

PLoS ONE ◽

10.1371/journal.pone.0107332 ◽

2014 ◽

Vol 9 (9) ◽

pp. e107332

Author(s):

Keyword(s):

Energy Expenditure ◽

Adult Female ◽

Female Offspring ◽

Perinatal Exposure

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Perinatal Exposure of Mice to the Pesticide DDT Impairs Energy Expenditure and Metabolism in Adult Female Offspring

PLoS ONE ◽

10.1371/journal.pone.0103337 ◽

2014 ◽

Vol 9 (7) ◽

pp. e103337 ◽

Cited By ~ 76

Author(s):

Michele La Merrill ◽

Emma Karey ◽

Erin Moshier ◽

Claudia Lindtner ◽

Michael R. La Frano ◽

...

Keyword(s):

Energy Expenditure ◽

Adult Female ◽

Female Offspring ◽

Perinatal Exposure

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Effects of exogenous adiponectin supplementation in early pregnant PCOS mice on the metabolic syndrome of adult female offspring

Journal of Ovarian Research ◽

10.1186/s13048-020-00755-z ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Meng Zuo ◽

Guotao Liao ◽

Wenqian Zhang ◽

Dan Xu ◽

Juan Lu ◽

...

Keyword(s):

Adult Female ◽

Early Pregnancy ◽

Testosterone Level ◽

Metabolic Disorders ◽

Serum Testosterone ◽

Female Offspring ◽

Metabolic Phenotype ◽

Serum Testosterone Level ◽

The Metabolic Syndrome ◽

Pcos Group

Abstract Objective PCOS is a heterogeneous endocrine disorder with both reproductive and metabolic abnormalities. At present, PCOS has been confirmed to have a certain genetic background. Compared with healthy women, the vast majority of PCOS patients have hyperandrogenemia, and this excessive androgen exposure during pregnancy may affect the development of female fetuses. The aim of the current study was to investigate the effect of adiponectin intervention during early pregnancy of obese mice with PCOS on the metabolic phenotype of adult female offspring. Methods After the PCOS model was established, C57BL/6J mice were divided into maternal-control, maternal-PCOS, and maternal-PCOS + APN groups. DHEA-induced PCOS mice were supplemented with adiponectin (10 mg/kg/day) in the early pregnancy in order to eliminate adverse hormone exposure and then traced for endocrine indicators in their adult female offspring, which were observed for metabolism syndrome or endocrine disturbance and exhibited the main effects of APN. To further explore the underlying mechanism, the relative expressions of phosphorylated AMPK, PI3K, and Akt were detected in the ovaries of offspring mice. Results The serum testosterone level of the maternal-PCOS + APN group in early pregnancy was significantly lower than that of the maternal-PCOS group (p < 0.01). The serum testosterone level in the offspring-PCOS + APN group was significantly lower than in the offspring-PCOS group (p <0.05), the diestrus time characterized by massive granulocyte aggregation in the estrus cycle was significantly shorter than in the offspring-PCOS group (p<0.05), and the phenotypes of PCOS-like reproductive disorders and metabolic disorders, such as obesity, insulin resistance, impaired glucose tolerance, and hyperlipidemia, were also significantly improved in the offspring-PCOS + APN group (p < 0.05). Compared with the control group, the expression levels of phosphorylated AMPK, PI3K, and Akt in the offspring-PCOS group were significantly decreased (p < 0.05), while those in the offspring-PCOS + APN group were significantly increased (p < 0.05). Conclusions APN intervention in early pregnancy significantly reduced the adverse effects of maternal obesity and high androgen levels during pregnancy on female offspring and corrected the PCOS-like endocrine phenotype and metabolic disorders of adult female offspring. This effect may be caused by the activation of the AMPK/PI3K-Akt signaling pathway in PCOS offspring mice.

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MATERNAL EXPOSURE TO DDE MAY INCREASE WEIGHT AND BODY-MASS IN ADULT FEMALE OFFSPRING

Epidemiology ◽

10.1097/00001648-200407000-00299 ◽

2004 ◽

Vol 15 (4) ◽

pp. S117-S118 ◽

Cited By ~ 2

Author(s):

Wilfried Karmaus ◽

Ihuoma Eneli

Keyword(s):

Body Mass ◽

Adult Female ◽

Female Offspring ◽

Maternal Exposure

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Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00421.2012 ◽

2012 ◽

Vol 303 (11) ◽

pp. E1373-E1385 ◽

Cited By ~ 52

Author(s):

Miao Sun ◽

Manuel Maliqueo ◽

Anna Benrick ◽

Julia Johansson ◽

Ruijin Shao ◽

...

Keyword(s):

Lipid Metabolism ◽

Insulin Sensitivity ◽

Fatty Liver ◽

Adult Female ◽

Late Pregnancy ◽

Free Testosterone ◽

Estrogen Receptor Α ◽

Female Offspring ◽

Adipocyte Size ◽

Nonalcoholic Fatty Liver

Here, we tested the hypothesis that excess maternal androgen in late pregnancy reduces placental and fetal growth, increases placental steroidogenesis, and adversely affects glucose and lipid metabolism in adult female offspring. Pregnant Wistar rats were randomly assigned to treatment with testosterone (daily injections of 5 mg of free testosterone from gestational days 16 to 19) or vehicle alone. In experiment 1, fetal and placental weights, circulating maternal testosterone, estradiol, and corticosterone levels, and placental protein expression and distribution of estrogen receptor-α and -β, androgen receptor, and 17β-hydroxysteroid dehydrogenase 2 were determined. In experiment 2, birth weights, postnatal growth rates, circulating testosterone, estradiol, and corticosterone levels, insulin sensitivity, adipocyte size, lipid profiles, and the presence of nonalcoholic fatty liver were assessed in female adult offspring. Treatment with testosterone reduced placental and fetal weights and increased placental expression of all four proteins. The offspring of testosterone-treated dams were born with intrauterine growth restriction; however, at 6 wk of age there was no difference in body weight between the offspring of testosterone- and control-treated rats. At 10–11 wk of age, the offspring of the testosterone-treated dams had less fat mass and smaller adipocyte size than those born to control rats and had no difference in insulin sensitivity. Circulating triglyceride levels were higher in the offspring of testosterone-treated dams, and they developed nonalcoholic fatty liver as adults. We demonstrate for the first time that prenatal testosterone exposure alters placental steroidogenesis and leads to dysregulation of lipid metabolism in their adult female offspring.

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