Control F1 Research Articles

Systemic alterations play a dominant role in epigenetic predisposition to breast cancer in offspring of obese fathers and is transmitted to a second generation

We previously showed that environmentally-induced epigenetic inheritance of cancer occurs in rodent models. For instance, we reported that paternal consumption of an obesity-inducing diet (OID) increased breast cancer susceptibility in the offspring (F1). Nevertheless, it is still unclear whether programming of breast cancer in daughters is due to systemic alterations or mammary epithelium-specific factors and whether the breast cancer predisposition in F1 progeny can be transmitted to subsequent generations. In this study, we show that mammary glands from F1 control (CO) female offspring exhibit enhanced growth when transplanted into OID females compared to CO mammary glands transplanted into CO females. Similarly, carcinogen-induced mammary tumors from F1 CO female offspring transplanted into OID females has a higher proliferation/apoptosis rate. Further, we show that granddaughters (F2) from the OID grand-paternal germline have accelerated tumor growth compared to CO granddaughters. This between-generation transmission of cancer predisposition is associated with changes in sperm tRNA fragments in OID males. Our findings indicate that systemic and mammary stromal alterations are significant contributors to programming of mammary development and likely cancer predisposition in OID daughters. Our data also show that breast cancer predisposition is transmitted to subsequent generations and may explain some familial cancers, if confirmed in humans.

Exposure to Copper Oxide Nanoparticles and Arsenic Causes Intergenerational Effects on Rice (Oryza sativa japonica Koshihikari) Seed Germination and Seedling Growth.

Offspring generation (F1) rice (Oryza sativa japonica Koshihikari) seed germination and seedling growth tests were conducted for 18 d to investigate intergenerational effects of arsenic (As) and copper oxide nanoparticles (nCuO), with seeds harvested from a life cycle study exposed to As (0 and 10 mg/kg) and nCuO (0, 0.1, 1.0, 10, 50, and 100 mg/L). Seed germination and seedling growth of F1 plants were influenced by treatments experienced by parent generation (F0) plants (p < 0.05). Seeds produced from plants in F0 treatment with nCuO 50 mg/L had the lowest germination percentage and shortest seedling shoot length and root length in F1 control (F1C) and As at 10 mg/kg (F1As) alone treatments (p < 0.05). The shoot length and root length were decreased, whereas the number of root branches was increased in F1As treatment compared with F1C (p < 0.001). Interaction of As and nCuO also caused differential seed germination and seedling growth at various nCuO concentrations in quasi-F0 treatment (seeds receiving the same exposure as F0 plants; p < 0.05). Copper and As uptake in F1C seedlings were not affected by seeds' F0 exposure; this indicated that the transgenerational effects on rice seedling growth were not dependent on total Cu or As uptake in seedlings. The enhanced effects on seedlings from quasi-F0 treatment were influenced by additional exposure to nCuO and As that also interacted to affect Cu and As uptake in seedlings. Environ Toxicol Chem 2019;38:1978-1987. © 2019 SETAC.

Intergenerational impact of maternal overnutrition and obesity throughout pregnancy in sheep on metabolic syndrome in grandsons and granddaughters

We previously reported that maternal overnutrition and obesity (MO) throughout pregnancy and lactation in sheep (MOF0) decreases term fetal pancreatic β-cell numbers and increases perirenal adiposity producing hyperphagia, increased adiposity and insulin resistance in adult female offspring (MOF1) fed ad libitum. Pregnant female MOF1 exhibited increased blood glucose from mid to late gestation vs control F1 (CTRF1) though both groups ate only to NRC recommendations. MOF1 ewes delivered female offspring (F2) who like their MOF1 mothers exhibited increased abdominal adiposity and absent neonatal leptin surge. In the current work, we determined if adult MOF2 exhibited metabolic syndrome components when fed ad libitum. After weaning, MOF2 males (n = 5), MOF2 females (n = 6), CTRF2 males (n = 5), and CTRF2 females (n = 6) were fed to NRC requirements until 19 mo followed by 12-wk ad libitum feeding. Body weight and % fat increased (P < 0.01) in all F2 during this feeding trial. MOF2 males were heavier (P < 0.01) than CTRF2 males and females, and MOF2 females throughout the trial. By wk 8, baseline blood glucose concentrations increased (P < 0.001) in MOF2 females, but not other groups, remaining elevated throughout the trial. Baseline insulin was similar through wk 6, increasing (P < 0.05) at wk 8 in MOF2 females only. MOF2 female insulin returned to CTRF2 female levels during wk 10 and 12. The progressive increase of plasma glucose on wk 8 in association with increased insulin in MOF2 females but not other groups demonstrated a diet-induced increase (P < 0.001) in MOF2 female insulin resistance. The subsequent decline in insulin during wk 10 and 12 despite elevated glucose in MOF2 females is consistent with a decrease in glucose-stimulated pancreatic β-cell function. These data indicate that ad libitum feeding exceeds the pancreatic secretory response predisposing MOF2 females to hyperglycemia. Furthermore, there was a sex difference where MOF2 males increased body mass and MOF2 females displayed insulin/glucose dysregulation.