Prenatal cadmium exposure alters proliferation in mouse CD4+ T cells via LncRNA Snhg7

Prenatal cadmium (Cd) exposure leads to immunotoxic phenotypes in the offspring. Long non-coding RNAs (lncRNAs) are integral to T cell regulation. Here, we identified genes and pathways altered in CD4+ T cell by prenatal Cd exposure. We investigated the role of long non-coding RNA small nucleolar RNA hostgene 7 (lncSnhg7) in T cell proliferation: LncSnhg7 expression increases in CD4+ T cells following stimulation with anti-CD3/CD28 beads. LngSnhg7 and a downstream protein, GALNT7, are upregulated in T cells from offspring exposed to Cd during gestation. Overexpression of miR-34a, a regulator of lnhcSnhg7 and GALNT7, suppresses GALNT7 protein levels in primary T cells, but not in a mouse T lymphocyte cell line. The T cells isolated from Cd-exposed offspring exhibit increased proliferation after activation in vitro, but Treg suppression and CD4+ T cell apoptosis are not affected by prenatal Cd exposure. In conclusion, prenatal Cd exposure alters the expression of lncRNAs during T cell activation. The induction of lncSnhg7 is enhanced in splenic T cells from Cd offspring resulting in the upregulation of GALNT7 protein and increased proliferation following activation. miR-34a overexpression decreased GALNT7 expression suggesting that the lncSnhg7/miR-34a/GALNT7 is an important pathway in primary CD4+ T cells. These data highlight the need to understand the consequences of environmental exposures on lncRNA functions in non-cancerous cells. Male and female C.Cg-Foxp3tm2Tch/J mice were mated with continuous exposure to 10 ppm CdCl2 (or unspiked water for the controls) via their drinking water. Female mice were exposed throughout pregnancy. Spiked water was replaced with normal water within 12 hours of the birth of the pups. Control and Cd-exposed offspring were aged to 8 weeks. CD4 T Cells were isolated from the splenocytes using negative selection. CD4 T cells were stimulated in vitro with anti-CD3/CD28 beads for 16h. RNA were purified from the unstimulated and stimulated cells. Gene expression was analyzed by RNA-Sequencing.