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Fetal arsenic exposure appears to facilitate endocrine disruption by postnatal diethylstilbestrol in neonatal mouse adrenal.

ABSTRACT: Fetal exposure of mice to arsenic and subsequent postnatal diethylstilbestrol (DES) facilitates production of urogenital system and liver tumors in the offspring when they reach adulthood. The adrenal is a target of endocrine disruption that could influence tumor formation at other sites. Thus, we examined possible fetal arsenic-induced adrenal effects as a potential basis of arsenic enhancement of DES carcinogenesis. Pregnant CD1 mice were given drinking water containing 85 ppm arsenic as sodium arsenite or unaltered water from day 8 to day 18 of gestation and were allowed to deliver normally. Groups of offspring were subsequently injected s.c. on postpartum days 1-5 with DES (2 microg/pup/day) and killed on postnatal day 12. Total RNA was isolated from the whole adrenal glands, and the expression of various genes was analyzed by real-time RT-PCR. Fetal arsenic exposure greatly enhanced DES-induced, estrogen-linked gene expression, such as estrogen receptor-alpha and trefoil factors. Expression of genes involved with steroid metabolism and/or methionine metabolism was also increased, including genes encoding for 17beta-hydroxysteroid dehydrogenase type 5 (HSD17beta5) and androstenedione 15alpha-hydroxylase (Cyp2a4). The transcripts for homocysteine cycling genes (betaine-homocysteine methyltransferase and thioether S-methyltransferase) and developmental marker genes (alpha-fetoprotein, insulin-like growth factor 2 and IGF binding protein-1), were also higher with arsenic plus DES than either treatment alone. Thus, exposure of the mouse to arsenic during a critical period of fetal development may potentially alter adrenal genetic programming, leading to endocrine disruption and potentially enhancing tumor formation together with DES at other sites much later in life. Functional studies, such as changes in circulating steroids, would greatly support this hypothesis, and are planned.

SUBMITTER: Liu J

PROVIDER: S-EPMC7291701 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Fetal arsenic exposure appears to facilitate endocrine disruption by postnatal diethylstilbestrol in neonatal mouse adrenal.

Liu Jie J Yu Limei L Coppin Jean-Francois JF Tokar Erik J EJ Diwan Bhalchandra A BA Waalkes Michael P MP

Chemico-biological interactions 20090807 2-3

Fetal exposure of mice to arsenic and subsequent postnatal diethylstilbestrol (DES) facilitates production of urogenital system and liver tumors in the offspring when they reach adulthood. The adrenal is a target of endocrine disruption that could influence tumor formation at other sites. Thus, we examined possible fetal arsenic-induced adrenal effects as a potential basis of arsenic enhancement of DES carcinogenesis. Pregnant CD1 mice were given drinking water containing 85 ppm arsenic as sodiu ...[more]

PMID: 19665456

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Project description:BackgroundIntrauterine exposure to endocrine disrupting chemicals (EDCs) has been equivocally associated with birth weight, length and head circumference with limited attention to anthropometric endpoints such as umbilical circumference and limb lengths.ObjectiveTo explore 76 prenatal maternal plasma EDC concentrations in a healthy obstetric cohort and 7 neonatal anthropometric endpoints by maternal race/ethnicity.MethodsThe study cohort comprised 2106 (564 White, 549 Black, 590 Hispanic, 403 Asian) healthy pregnant women recruited from 12 U.S. clinical sites between 2009 and 2012 who were followed through delivery. Neonates underwent standardized anthropometric assessment (weight, length, head and umbilical circumference, and mid- upper arm and thigh length). Plasma EDC concentrations were quantified using high resolution gas chromatography-high resolution mass spectrometry and liquid chromatography-tandem mass spectrometry. EDCs were log-transformed and rescaled by their deviations (SD) when modeled relative to neonatal endpoints using linear regression adjusting for age, education, pre-pregnancy body mass index (BMI), serum cotinine, serum lipids for lipophilic chemicals, and a race/ethnicity interaction term; p-values had false discovery rate correction (<0.05).ResultsThe cohort comprised women aged 28 (SD = 5) years with normal BMIs (23.6 kg/m2, SD = 3). Maternal EDC concentrations varied by self-identified race/ethnicity and neonatal outcomes, though no specific EDC was consistently associated with neonatal anthropometric outcomes across racial/ethnic groups. For the overall cohort, perfluorooctanoic acid was negatively associated with birth length per SD increase in concentration (β = -0.23 cm; 95% CI -0.35, -0.10), while perfluorohexanesulfonic acid was negatively associated with umbilical circumference (β = -0.26 cm; 95% CI -0.40, -0.13), perfluorodecanoic acid with arm length (-0.09 cm; 95% CI -0.14, -0.04), and PCBs congeners 118/106 (-0.12 cm; 95% CI -0.20, -0.04) and 146/161 (-0.14 cm; 95% CI -0.23, -0.05) with thigh length, as were 7 other poly-and-perfluorinated alkyl substances (PFASs).ConclusionsAmong healthy pregnant women with low risk antenatal profiles and relatively low EDC concentrations, reductions in umbilical circumference and bone lengths may be a sensitive marker of intrauterine EDC exposure, particularly for PFAS.

Dataset Information

Fetal arsenic exposure appears to facilitate endocrine disruption by postnatal diethylstilbestrol in neonatal mouse adrenal.

Publications

Fetal arsenic exposure appears to facilitate endocrine disruption by postnatal diethylstilbestrol in neonatal mouse adrenal.

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