Fetal arsenic exposure appears to facilitate endocrine disruption by postnatal diethylstilbestrol in neonatal mouse adrenal.
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.
Liu
Jie
J
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Research Triangle Park, NC 27709, United States.
Yu
Limei
L
Coppin
Jean-Francois
JF
Tokar
Erik J
EJ
Diwan
Bhalchandra A
BA
Waalkes
Michael P
MP
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001151:Arsenic / Q000009:adverse effects*; D002273:Carcinogens / Q000008:administration & dosage / Q000494:pharmacology*; D004054:Diethylstilbestrol / Q000008:administration & dosage / Q000494:pharmacology*; D052244:Endocrine Disruptors / Q000009:adverse effects*; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D011247:Pregnancy
D002273:Carcinogens; D052244:Endocrine Disruptors; D004054:Diethylstilbestrol; D001151:Arsenic