探討高脂飲食對生殖期與懷孕期母鼠 尿液雌激素代謝產物的影響

Abstract

本實驗室過去的研究已證實，給予懷孕期母鼠攝取21天的高脂飲食，其子代罹患乳腺腫瘤的比例與子代在出生後攝取230天之高脂飲食而罹患乳腺腫瘤的比例相當，顯示懷孕期的飲食對於日後子代罹患乳癌的風險有很重要的影響。且在過去文獻指出，除了estradiol (E2) 以外，其代謝產物 (estrogen metabolites) 亦與乳癌的發生有密切相關。因此本論文主要對於生殖期 (reproductive age) 與懷孕期 (pregnancy) 之雌鼠，給予攝取高n-6脂肪酸飲食，探討飲食中脂肪酸的組成與脂肪含量的高低對尿液雌激素代謝產物之影響。實驗組別處理主要可分為三大組，分別為生殖期雌鼠給予高n-6脂肪酸飲食，並於餵食80天與120天後收集尿液作分析、 懷孕期雌鼠給予高n-9脂肪酸或高n-6脂肪酸飲食配合魚油補充，分別於懷孕第10天與第18天收集尿液作分析以及懷孕期雌鼠給予低脂與高脂飲食配合魚油補充，分別於第10天與第18天收集尿液作分析。在建立較適合的雌激素代謝產物純化方法進行純化後，以HPLC配合8個電極之電化學偵測器(ECD) 進行檢測。實驗結果顯示，給予生殖期或懷孕期母鼠攝取高n-6脂肪酸，比起給予chow diet飲食，明顯增加尿液中total estrogen metabolites、16α-OHE1、E3與2-OHE1之含量，其中又以2-OHE1增加最多，且易降低2-OCH3E/ 2-OHE與4-OCH3E/ 4-OHE，顯示高n-6脂肪酸會抑制hydroxyestrogen的甲基化。此外，給予懷孕期母鼠攝取18天高n-9脂肪酸飲食後，與高n-6脂肪酸飲食有相似的作用，易提高罹患乳癌的風險。由以上結果可知，高n-6脂肪酸會透過影響雌激素的代謝而造成罹患乳癌風險的提高。

Breast cancer is associated with high-fat intake. About two thirds of breast cancer in women are estrogen-dependent that contain estrogen receptor . It has been found that not only estrogen, the estrogen metabolites can also bind with estrogen receptor for the regulation of breast cancer development. We aimed to examine the effect of high fat diet on estrogen metabolism during reproductive age and pregnancy in rats. The urine was collected during 5-day estrus cycle in adult rats fed chow or high n-6 sunflower oil diets for 80 days, or collected at gestation day 10 or day 18 in pregnant rats fed the chow diet, high n-9 safflower oil, high n-6 sunflower oil without or with fish oil supplementation, low fat or high fat diets without or with fish oil supplementation. The 12 estrogen metabolites in urine was measured by HPLC with 8-channel electrochemical detector. We found that total estrogen metabolites, 16 -hydroxyestrone, 2-hydroxyestrone and estriol were increased in rat urine fed the high n-6 sunflower oil diet during reproductive age and in pregnancy compared with that fed chow or low fat diets. The methylation of 4-hydroxyestrogen and 2-hydroxyestrogen was decreased in rat urine fed the high n-6 sunflower oil or high n-9 safflower oil diets during reproductive age and in pregnancy compared with that fed chow or low fat diets. And this decreased effect of methylation of 2-hydroxyestrogen by high n-6 fat diet was increased back by fish oil supplementation during pregnancy. We proposed that carcinogen 16 -hydroxyestrone is increased and the anti-carcinogen 2-methoxyestrone is decreased in female rats fed high fat diet.