Maternal Mineral Nutrition Regulates Fetal Genomic Programming in Cattle: A Review

Abstract

Maternal mineral nutrition during the critical phases of fetal development may leave lifetime impacts on the productivity of an individual. Most research within the developmental origins of the health and disease (DOHaD) field is focused on the role of macronutrients in the genome function and programming of the developing fetus. On the other hand, there is a paucity of knowledge about the role of micronutrients and, specifically, minerals in regulating the epigenome of livestock species, especially cattle. Therefore, this review will address the effects of the maternal dietary mineral supply on the fetal developmental programming from the embryonic to the postnatal phases in cattle. To this end, we will draw a parallel between findings from our cattle model research with data from model animals, cell lines, and other livestock species. The coordinated role and function of different mineral elements in feto-maternal genomic regulation underlies the establishment of pregnancy and organogenesis and, ultimately, affects the development and functioning of metabolically important tissues, such as the fetal liver, skeletal muscle, and, importantly, the placenta. Through this review, we will delineate the key regulatory pathways involved in fetal programming based on the dietary maternal mineral supply and its crosstalk with epigenomic regulation in cattle.

Keywords: developmental biology; epigenetics; epigenome; essential nutrients; genetics; macrominerals; microminerals; restricted nutrition.

Figure 1

Timeline indicating organogenesis and development of different structures during gestation in cattle [45,46,52,53,54,55,56,57,58].

Figure 2

Schematic overview of the role of estrogen, Ca⁺², and K⁺ in the establishment of pregnancy-associated relaxation and myogenic tone reduction. Pregnancy increases the basal estrogen level and demethylate CpG at the Sp1 promotor site to increase KCNMB1 expression [61]. KCNMB1 leads to opening of BKca channels, causing efflux of K⁺ and release of Ca⁺², which further promote KCNMB1 expression [59]. Change in membrane potential of vascular smooth muscle in the uterine artery by efflux of K⁺ and release of Ca⁺² results in uterine artery dilation along with pregnancy-induced relaxation [61]. KCNMB1, potassium calcium-activated channel subfamily M regulatory Beta subunit 1; BK_Ca, large-conductance Ca⁺²-activated K⁺ channel receptors.

Figure 3

Proposed mechanism of fetal–maternal transport of selenium and iodine and their role in thyroxine metabolism in cattle. Maternal selenium concentration impacts the expression of selenoproteins, i.e., SEPP1 and Dio2 in dam’s liver [89]. SEPP1 will be transported to fetus by ApoER2, and Dio2 will affect thyroxines interconversion across fetal–maternal tissues [85,89,90,91,92]. SEPSECS, (Sep (O-Phosphoserine) TRNA:Sec (Selenocysteine) TRNA Synthase); SBP2, selenocysteine binding protein 2; SEPP1, Selenoprotein-P; Dio2, TypeII Deiodinase; ApoER2, Apolipoprotein E Receptor-2; Dio3, TypeIII Deiodinase; T3, Triiodothyronine-3; T4, Thyroxine-4.

Figure 4

Proposed mechanism of feto-maternal transport of Ca, P, Mg, and iodine and their roles in regulating molecular mechanism of parathyroid hormone (PTH) and calcitriol (1,25-dihydroxycholecalciferol, 1,25(OH)2D) in cattle. Maternal Ca⁺² concentration causes a change in the expression of PTHrP in placenta and mammary tissue along with the expression of CaSR in placenta [105,111,113]. PTH is regulated by CaSR in the fetus and maternal PTHrP binds to PTHR1 in the kidney and activates the cAMP-associated conversion of calcitriol (1,25(OH)D), in which Mg⁺² will be used as a cofactor [109,110,111]. CaSR, calcium sensing receptor; PTHrP, parathyroid hormone related proteins; PTHR1, parathyroid hormone 1 receptor; cAMP, cyclic adenosine monophosphate; PKA, phosphokinase activated; CREB, cAMP response element-binding protein; calcitriol, 1,25(OH)D.

Figure 5

Proposed mechanism of fetomaternal transport of Fe, Mn, Zn, and Cu in cattle. Iron or manganese can form complexes with transferrin and bind to TfR1 in the placenta, which transports Fe or Mn to the fetus [135,137]. Cu and Zn are also transported by placental transporters CTR1 or Cu-Zn SOD [77,81,138,139] and ZIP14 [75], respectively. All these mentioned minerals are in the divalent form and, in the fetus, are transported via DMT1 [129,134,135,136]. ZnT1, zinc transporter 1; MT1A, metallothionine-1A; ZIP14, zinc-importing protein; DMT1, divalent metal transporter 1; CTR1, copper transporter protein 1; Cu-Zn SOD, copper zinc superoxide dismutase; ATOX1, antioxidant 1 copper chaperone; ATP7A, ATPase copper-transporting alpha; TfR1, transferrin 1 receptor.