Maternal high fructose diet exacerbates cadmium-induced reproductive toxicity across two generations of male offspring
Citation:
Yoo, Brendan R., Colette N. Miller, Lillian F. Strader, Gail M. Nelson, Kaberi P. Das, Makala L. Moore, Rachel D. Grindstaff, W. Padgett, W. Winnik, Janice A. Dye, C. Lau, AND Gary R. Klinefelter. Maternal high fructose diet exacerbates cadmium-induced reproductive toxicity across two generations of male offspring. Triangle Consortium for Reproductive Biology, Raleigh, NC, March 06, 2026.
Impact/Purpose:
This study set out to ask whether a common dietary pattern can change how a widespread pollutant affects fertility across generations. In an experimental model, combining a high fructose diet with cadmium exposure produced greater, longer lasting reproductive harm than either factor alone, pointing to powerful diet-environment interactions. The work highlights that real world “mixtures” matter: maternal nutrition can amplify pollutant effects and leave a molecular footprint in reproductive cells that may influence offspring.
Description:
Exposure to cadmium (Cd) both in adulthood and during developmental stages is associated with poorer fertility. However, there is increasing recognition that components of food may modify the toxicity of environmental pollutants by altering the absorption of such chemicals, or through other mechanisms. Herein, we investigated the multigenerational reproductive toxicity of exposure to Cd, utilizing a high fructose diet (HFrD) as a modulatory dietary factor. F0 CD-1 female mice were exposed to Cd (0.0 or 5.0 ppm) ± HFrD (59%) for two weeks prior to gestation and throughout pregnancy and lactation. Fertility-related endpoints, as well as RNA sequencing (RNAseq), were then assessed across two generations of male offspring (F1 and F2). Testosterone production was suppressed in F1 males from the Cd + HFrD group, which was evident at gestation day 18 and persisted until puberty, when levels then normalized in adulthood. Exposure to Cd + HFrD resulted in impaired fertility (15.1% decrease) at postnatal day (PND) 120. This outcome persisted in the F2 generation at PND 140 (16.5% decrease). While this effect was largely independent of sperm motility, RNAseq of the sperm revealed a similar observation when both factors were combined. A total of 46 differentially expressed genes (DEGs) were detected in the F1 sperm of the Cd + HFrD group, compared to 39 and 18 in the Cd or HFrD groups, respectively. The testis reflected like outcomes, with the most robust gene changes measured in male F1 offspring from the Cd + HFrD group (1,260). On the other hand, HFrD alone had a greater impact on sperm RNAs in the F2 generation (80), followed by Cd + HFrD (32), and Cd alone (23). While Cd and HFrD independently altered ~100 genes in the F2 testis, again, the most robust number of DEGs were present in Cd + HFrD males (2,903). Collectively, this work suggests that F0 exposure to both Cd and HFrD results in greater impairment in fecundity than either factor alone, effects that were largely mirrored with RNAseq of reproductive tissues. Further characterization of the sperm proteome and DNA methylation status is underway to understand the potential biological mechanisms that may have contributed to such multigenerational outcomes.