Estrogenic endocrine disruptive components interfere with calcium handling and differentiation of human trophoblast cells.
During development, calcium (Ca) is actively transported by placental trophoblasts to meet fetal nutritional and the skeletal mineralization needs. Maternal exposure to estrogenic pesticides, such as 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT) and methoxychlor (MTC), has been shown to result in reproductive disorders and/or abnormal fetal development. In this study, we have examined the effects of exposure of trophoblastic cells to MTC and DTT, in comparison to 17beta-estradiol (E2) and diethylstilbestrol (DES), to test the hypothesis that cellular Ca handling is a target for these endocrine disruptive components. Treatment with DDT, MTC, DES, or E2 increased cellular Ca uptake, and the expression of trophoblast-specific human Ca binding protein (HCaBP) was down-regulated by both MTC and DDT. Treatment with MTC, DDT, and DES inhibited cell proliferation, induced apoptosis, and suppressed expression of several trophoblast differentiation marker genes. These effects were reversed by overexpression of metallothionein IIa, a gene highly responsive to cadmium and other metals. These results strongly suggest that trophoblast Ca handling functions are endocrinally modulated, and that their alteration by candidate endocrine disruptors, such as MTC and DDT, constitutes a possible pathway of the harmful effects of these components on fetal development.
Derfoul
A
A
Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lin
F J
FJ
Awumey
E M
EM
Kolodzeski
T
T
Hall
D J
DJ
Tuan
R S
RS
D000251:Adenosine Triphosphatases / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003634:DDT / Q000009:adverse effects*; D004054:Diethylstilbestrol / Q000009:adverse effects*; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000009:adverse effects* / Q000031:analogs & derivatives; D005819:Genetic Markers; D006801:Humans; D008668:Metallothionein / Q000378:metabolism / Q000494:pharmacology; D008731:Methoxychlor / Q000009:adverse effects*; D011960:Receptors, Estrogen / Q000032:analysis / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000032:analysis / Q000096:biosynthesis; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D005819:Genetic Markers; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004958:Estradiol; D004054:Diethylstilbestrol; D008668:Metallothionein; D003634:DDT; D000251:Adenosine Triphosphatases; D008731:Methoxychlor; D002118:Calcium