Differential modulation of dibenzo[def,p]chrysene transplacental carcinogenesis: Maternal diets rich in indole-3-carbinol versus sulforaphane

Abstract

Cruciferous vegetable components have been documented to exhibit anticancer properties. Targets of action span multiple mechanisms deregulated during cancer progression, ranging from altered carcinogen metabolism to the restoration of epigenetic machinery. Furthermore, the developing fetus is highly susceptible to changes in nutritional status and to environmental toxicants. Thus, we have exploited a mouse model of transplacental carcinogenesis to assess the impact of maternal dietary supplementation on cancer risk in offspring. In this study, transplacental and lactational exposure to a maternal dose of 15 mg/Kg B.W. of dibenzo[def,p]chrysene (DBC) resulted in significant morbidity of offspring due to an aggressive T-cell lymphoblastic lymphoma. As in previous studies, indole-3-carbinol (I3C, feed to the dam at 100, 500 or 1000 ppm), derived from cruciferous vegetables, dose-dependently reduced lung tumor multiplicity and also increased offspring survival. Brussels sprout and broccoli sprout powders, selected for their relative abundance of I3C and the bioactive component sulforaphane (SFN), respectively, surprisingly enhanced DBC-induced morbidity and tumorigenesis when incorporated into the maternal diet at 10% wt/wt. Purified SFN, incorporated in the maternal diet at 400 ppm, also decreased the latency of DBC-dependent morbidity. Interestingly, I3C abrogated the effect of SFN when the two purified compounds were administered in equimolar combination (500 ppm I3C and 600 ppm SFN). SFN metabolites measured in the plasma of neonates positively correlated with exposure levels via the maternal diet but not with offspring mortality. These findings provide justification for further study of the safety and bioactivity of cruciferous vegetable phytochemicals at supplemental concentrations during the perinatal period.

Nrf2-dependent protection against acute sodium arsenite toxicity in zebrafish

“…Adverse effects of sulforaphane in combination with arsenite or other drugs have also been reported (Doudican et al, 2012;Shorey et al, 2013). Though we have no idea about the mechanism underlying this combinatorial toxic effect, some interesting aspects related to this effect were observed, e.g., less than 20 μM of sulforaphane were sufficient to induce toxicity (Fig.…”

Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type,Cyp1b1knockout, andCYP1B1humanized mice

“…m Cyp1b1 introns 1 and 2 (Suppl. Figure S2, orange) are 376 and 2591 bp in length compared to 390 and 3032 bp, respectively for h CYP1B1 . Both mRNAs are 5.2 kb and both proteins are 543 amino acids (AA) in length .…”

“…We incorporated the h CYP1B1 transgenic mouse into the in utero DBC exposure model, previously found to be susceptible to T‐ALL and lung cancer . The transgenic h CYP1B1 mouse was generated by pronuclear injection of ovulated mouse eggs on a m Cyp1b1 null background with a CYP1B1 bacterial artificial chromosome (BAC) clone as previously described .…”

“…Figure S2, orange) are 376 and 2591 bp in length compared to 390 and 3032 bp, respectively for h CYP1B1 . Both mRNAs are 5.2 kb and both proteins are 543 amino acids (AA) in length . The six substrate responsive sites (SRS) of the enzyme have a similar AA sequence and alignment as follows: SRS1, AA 116–139, 81%; SRS2, AA 224–236, 100%; SRS3, AA 259–263, 80%; SRS4, AA 330–343, 100%; SRS5, AA 392–401, 90%; SRS6, AA 503–513, 90% (Suppl.…”

“…We modified our previous transplacental DBC exposure model to include a transgenic h CYP1B1 group. All experimental transgenic null (C57BL6) and null mice (C57BL6 and 129S genetic background) were maintained and bred at OSU.…”