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

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.


Introduction
The mechanisms and the interaction of processes in the growth of an individual from embryonic to adult life is investigated in the field of developmental biology [1,2]. Rigorous research over the last half of a century has led to an emergence of reports that conjoin developmental biology with the areas of genetics [3], evolution [4], and epidemiology [5][6][7]. This impact on developmental biology, specifically in the area of epidemiology, has resulted in the formulation of a concept and, ultimately, a separate discipline, namely, fetal programing or the developmental origins of health and disease (DOHaD), first articulated by the human epidemiologist Dr. David Barker and colleagues [8].
The concept of the DOHaD hypothesis was not new at that time and can be traced back to the idea from the early 1800s of organic evolution, the concept that the adopted physical changes in one generation are transferable to subsequent generations via gametes, by Lamarck [9]; however, Barker was among the first to coin the term "fetal programming" or "developmental origins of health and disease". Widdowson and McCance [10] were among the first cell biologists who provided evidence that there are some critical phases in

Fetal Programming as a Multifactorial System
Although much of the research in fetal programming has focused on insults during mid-and late gestation, there is a growing interest in the earlier stages of gestation, which may "set the stage" for later programming events. Although most of the fetal size increase takes place in the last trimester, the first third of gestation is a critical period for organogenesis and tissue hyperplasia, as well as placentation [21,34,45,46], as shown in Figure 1. The prenatal growth trajectory of the conceptus is controlled by maternal nutrition either directly, by the provision of the essential nutrients; indirectly, via placental function, which regulates the transport of these nutrients [47]; or by altering the epigenetic mechanisms [48][49][50][51].  Pregnancy recognition occurs 15 to 16 days after estrous in cattle [58] and initiates maternal uterine vasculature changes to allow for the proper respiratory gas exchange and nutrient transfer to the developing embryo. Pregnancy is associated with a significant decrease in CpG methylation at the Sp1 promotor region of the KCNMB1 gene (potassium calcium-activated channel subfamily M regulatory Beta subunit 1) and an increase in the expression of large-conductance Ca +2 -activated K + channel receptors, BK Ca , causing uterine artery dilation [59]. The expression of KCNMB1 is also regulated by an increase in the expression of estrogenic receptor alpha [60] and the maintenance of membrane potential by K + and Ca +2 ions to cause pregnancy-associated relaxation by reducing the myogenic tone [61,62] (Figure 2). In addition, estrogen is a potent angiogenic factor in the uterus and is involved in systemic cardiovascular changes during pregnancy (e.g., increased cardiac output [63,64]).
Metabolites 2023, 13, x FOR PEER REVIEW 5 o Pregnancy recognition occurs 15 to 16 days after estrous in cattle [58] and initia maternal uterine vasculature changes to allow for the proper respiratory gas excha and nutrient transfer to the developing embryo. Pregnancy is associated with a signific decrease in CpG methylation at the Sp1 promotor region of the KCNMB1 gene (potassi calcium-activated channel subfamily M regulatory Beta subunit 1) and an increase in expression of large-conductance Ca +2 -activated K + channel receptors, BKCa, causing uter artery dilation [59]. The expression of KCNMB1 is also regulated by an increase in expression of estrogenic receptor alpha [60] and the maintenance of membrane poten by K + and Ca +2 ions to cause pregnancy-associated relaxation by reducing the myoge tone [61,62] (Figure 2). In addition, estrogen is a potent angiogenic factor in the uterus a is involved in systemic cardiovascular changes during pregnancy (e.g., increased card output [63,64]).

Figure 2.
Schematic overview of the role of estrogen, Ca +2 , and K + in the establishment of pregnan associated relaxation and myogenic tone reduction. Pregnancy increases the basal estrogen l and demethylate CpG at the Sp1 promotor site to increase KCNMB1 expression [61]. KCNMB1 le to opening of BKca channels, causing efflux of K + and release of Ca +2 , which further prom KCNMB1 expression [59]. Change in membrane potential of vascular smooth muscle in the ute artery by efflux of K + and release of Ca +2 results in uterine artery dilation along with pregnan induced relaxation [61]. KCNMB1, potassium calcium-activated channel subfamily M regula Beta subunit 1; BKCa, large-conductance Ca +2 -activated K + channel receptors.
The development of fetal organs is significantly affected by mineral availability [ Zinc deficiency or excess during pregnancy can impact the development of multiple gans, including the brain, lungs, skeleton, and heart [66][67][68][69]. In the case of brain devel ment, zinc deficiency impairs the function of Zic (Zinc finger proteins of the cerebellu genes [70], which are essential for cerebellar development [70][71][72]. Zinc supranutrit (the supplementation of more than the normal requirement but less than the maxim tolerable limit) has shown the potential to enhance the cognitive ability of offspring in by increasing the expression of the signal transducer and activator of transcriptio (STAT3) and matrix metalloproteinase-2/9 (MMP-2/9) [69]. STAT3-MMP-2/9 activity p motes the invasion and migration of placental trophoblast cells and improves neural fu tion [69,73]. In heart development, zinc deficiency alters the distribution of human natu killer-1 (HNK-1) cells and connexin 43 (Cx43) in the myocardium, contributing to the velopment of cardiovascular anomalies [74,75].
Like zinc, copper deficiency and supranutrition are associated with oxidative distr and neural degenerative disorders [76,77]. It has also been observed that both copper ficiency and the improper absorption of copper from the rumen in cattle can lead to s conditions. This can be due to the accessibility of molybdenum and sulfur, resulting in formation of thiomolybdates, which can bind with copper in the rumen leading to in propriate copper availability [78]. Copper deficiency leads to the suppression of the ac ity of a cuproenzyme, cytochrome-c oxidase, in the red nucleus region associated w large motor neurons, causing enzootic ataxia or swayback in lambs [79,80]. In addit Figure 2. Schematic overview of the role of estrogen, Ca +2 , and K + in the establishment of pregnancyassociated 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.
The development of fetal organs is significantly affected by mineral availability [65]. Zinc deficiency or excess during pregnancy can impact the development of multiple organs, including the brain, lungs, skeleton, and heart [66][67][68][69]. In the case of brain development, zinc deficiency impairs the function of Zic (Zinc finger proteins of the cerebellum) genes [70], which are essential for cerebellar development [70][71][72]. Zinc supranutrition (the supplementation of more than the normal requirement but less than the maximum tolerable limit) has shown the potential to enhance the cognitive ability of offspring in rats by increasing the expression of the signal transducer and activator of transcription 3 (STAT3) and matrix metalloproteinase-2/9 (MMP-2/9) [69]. STAT3-MMP-2/9 activity promotes the invasion and migration of placental trophoblast cells and improves neural function [69,73]. In heart development, zinc deficiency alters the distribution of human natural killer-1 (HNK-1) cells and connexin 43 (Cx43) in the myocardium, contributing to the development of cardiovascular anomalies [74,75].
Like zinc, copper deficiency and supranutrition are associated with oxidative distress and neural degenerative disorders [76,77]. It has also been observed that both copper deficiency and the improper absorption of copper from the rumen in cattle can lead to such conditions. This can be due to the accessibility of molybdenum and sulfur, resulting in the formation of thiomolybdates, which can bind with copper in the rumen leading to inappropriate copper availability [78]. Copper deficiency leads to the suppression of the activity of a cuproenzyme, cytochrome-c oxidase, in the red nucleus region associated with large motor neurons, causing enzootic ataxia or swayback in lambs [79,80]. In addition, supranutritional levels of of copper, along with zinc, cobalt, and manganese, enhance the expression of metallothionein 1A (MT1A) in the dam and Cu-Zn superoxide dismutase (CU/Zn SOD) in developing offspring of cattle [77]. The MT1A is the major transporter of metal ions and CU/Zn SOD is involved in the regulation of oxidative stress and neurodegenerative disorder [77,81].
Selenium has biological functions via selenoproteins [28,82]. A maternal Se supplementation has effects on reproduction and developmental outcomes, which may be mediated by epigenetic events [28,83]. Selenium deficiency decreases the expression of selenoproteins, such as glutathione peroxidases, including GPx1, GPx2, GPx4, and SELENOP, including Selenoprotein-P, leading to alterations in embryonic development, oxidative stress mechanisms, reproductive development, and male fertility, respectively [84,85]. Maternal Se deficiency is associated with pancreatic atrophy in the developing fetus [86]. Moreover, maternal Se deficiency causes an elevation in the selenoenzyme type II deiodinase (Dio2), which reduces thyroxine production ( Figure 3). On the other hand, supranutritional Se enhances thyroxine levels and impairs the growth hormone, insulin-like growth factor (GH-IGF) system [87,88]. The GH-IGF system impairment causes glucose intolerance and hypo-insulinemia in the fetus [86].
Metabolites 2023, 13, x FOR PEER REVIEW 7 of 20 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].  . 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]. In cattle, primary and secondary myogenesis during the early fetal period start at days 47 and 119, respectively, and establish the lifetime potential for muscle development (see Figure 1) [56,93,94]. This is why there is no net increase in the number of muscle fibers after birth. Myogenesis requires the binding of active thyroid hormones to its receptors [95,96], especially thyroid receptor α, which is predominantly expressed in skeletal muscle [97] and is involved in promoting angiogenesis [98,99]. The deficiency of selenium, zinc, and iron can cause the impairment of thyroid hormone synthesis and action [100] by decreasing the expression of glutathione peroxidase (a selenoprotein) [101], 1,5 -deiodinase [102], and thyroperoxidase [103], respectively. Iron deficiency causes iron deficiency anemia, which reduces the activity of thyroid peroxidase (a Fe-dependent enzyme), leading to the repression of thyroid hormone synthesis and myogenesis [104].
Fetal skeletal development and bone mineralization are affected by maternal mineral status. Severe hypocalcemia, hypophosphatemia [105,106], and hypomagnesemia [107,108] are associated with reduced levels of parathyroid hormone (PTH) (Figure 4). Normally, PTH acts on PTH receptor 1 (PTHR1) of the kidney, which activates cyclic adenosine monophosphate (cAMP)-associated pathways and requires Mg +2 as a cofactor [109,110] for calcitriol (1,25(OH)D) and vitamin D production. However, a decrease in PTH leads to vitamin D deficiency [111], which ultimately affects bone formation and mineralization in the developing fetus [107]. Both hypo-and hypercalcemic dams were associated with the upregulation of fatty acid binding protein 4 (FABP4), fatty acid synthase (FASN), and acetyl coenzyme A carboxylase 1 (ACC1) in the adipose tissue and liver of the offspring, leading to dyslipidemia and bone demineralization to maintain the serum level of calcium in the offspring [112].
Metabolites 2023, 13, x FOR PEER REVIEW 8 In cattle, primary and secondary myogenesis during the early fetal period st days 47 and 119, respectively, and establish the lifetime potential for muscle develop (see Figure 1) [56,93,94]. This is why there is no net increase in the number of muscle after birth. Myogenesis requires the binding of active thyroid hormones to its rece [95,96], especially thyroid receptor α, which is predominantly expressed in skeletal cle [97] and is involved in promoting angiogenesis [98,99]. The deficiency of sele zinc, and iron can cause the impairment of thyroid hormone synthesis and action [10 decreasing the expression of glutathione peroxidase (a selenoprotein) [101], 1, iodinase [102], and thyroperoxidase [103], respectively. Iron deficiency causes iron ciency anemia, which reduces the activity of thyroid peroxidase (a Fe-dependent enz leading to the repression of thyroid hormone synthesis and myogenesis [104]. Fetal skeletal development and bone mineralization are affected by maternal m status. Severe hypocalcemia, hypophosphatemia [105,106], and hypomagne [107,108] are associated with reduced levels of parathyroid hormone (PTH) (Figu Normally, PTH acts on PTH receptor 1 (PTHR1) of the kidney, which activates cyclic osine monophosphate (cAMP)-associated pathways and requires Mg +2 as a co [109,110] for calcitriol (1,25(OH)D) and vitamin D production. However, a decrea PTH leads to vitamin D deficiency [111], which ultimately affects bone formation mineralization in the developing fetus [107]. Both hypo-and hypercalcemic dams associated with the upregulation of fatty acid binding protein 4 (FABP4), fatty acid thase (FASN), and acetyl coenzyme A carboxylase 1 (ACC1) in the adipose tissue and of the offspring, leading to dyslipidemia and bone demineralization to maintain the s level of calcium in the offspring [112].  [105,111,113]. PTH is regulated by CaSR in the fetus and maternal PTHrP binds to PTHR1 kidney and activates the cAMP-associated conversion of calcitriol (1,25(OH)D), in which Mg be used as a cofactor [109][110][111]. CaSR, calcium sensing receptor; PTHrP, parathyroid hormo lated proteins; PTHR1, parathyroid hormone 1 receptor; cAMP, cyclic adenosine monophos PKA, phosphokinase activated; CREB, cAMP response element-binding protein; cal 1,25(OH)D.

The Roles of Minerals in Fetal Genome Regulation
Epigenomic regulation in the fetus is affected by the insufficiency of maternal ents, including minerals. In a recent study in cattle, the authors reported that ess micronutrient supplementation and the dietary plane of nutrition (as assessed by th of bodyweight gain) during early gestation can affect the neonatal immune respons  [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.

The Roles of Minerals in Fetal Genome Regulation
Epigenomic regulation in the fetus is affected by the insufficiency of maternal nutrients, including minerals. In a recent study in cattle, the authors reported that essential micronutrient supplementation and the dietary plane of nutrition (as assessed by the rate of bodyweight gain) during early gestation can affect the neonatal immune response and the availability of mineral reserves for postnatal development [114,115]. In addition, the expression of genes associated with cholesterol synthesis, ion homeostasis, and nutrient transport was altered in the developing placenta [116,117]. To explain the epigenomic regulation of these pathways based on maternal mineral homeostasis and their effects on fetal programming, different studies have been conducted in model organisms (see Table 2). Can alter placentation and growth in postnatal life by impairing growth hormone secretion [125] The transcriptomics of the developing fetus can be regulated either by changing the methylation pattern of specific DNA regions or by repressing mRNA expression based on the adequacy of maternal mineral nutrition. For example, Zn is transported in the blood by forming a complex with metallothionein-2 (MT2) [126]. In a mouse model, Zn deficiency was associated with a polymorphism in MT2 at rs1610216 (MT2A-209A/G) along with histone modification and hypermethylation of a metal-responsive element (MRE) in the promotor region of MT2 [123], and similar changes are seen in human [127]. Furthermore, the mRNA expression of zinc transporter 1 (ZnT1) in a zebrafish model [128], as well as zinc importing protein (ZIP14) in a rat model [75], and divalent metal transporter 1 (DMT1) in human cell lines [129] is associated with the availability of zinc. The impairment of the expression of these genes affects zinc availability to the developing fetus and, subsequently, organogenesis [66,67].
Selenium deficiency affects the expression of selenoenzymes such as GPx1, GPx2, and GPx4 and selenoproteins (i.e., Selenoproteins-P, SELENOP), which are involved in not only fetal reproductive development and the regulation of oxidative stress [84,85] but also the overall DNA methylation pattern. Selenium availability affects the concentration of S-adenosyl homocysteine (a potential inhibitor of DNA methyltransferases) and the availability of S-adenosyl methionine (the methyl-donor for all methylation reactions) in the methionine-homocysteine cycle [130][131][132][133]. In a rainbow trout model, selenium availability affected the differentially methylated cytosines of more than 6500 differentially methylated genes associated with immune modulations and neural signaling [124].
Like zinc and selenium deficiency, maternal iron deficiency in pregnancy is critical as it can permanently affect brain development [120,121]. Iron deficiency is associated with histone modification and DNA methylation at the brain-derived neurotrophic factor IV (BDNF-IV) promotor region in the hippocampus of the developing fetus, which affects cognitive response and hippocampal plasticity, as observed in a rat model [120]. Additionally, iron deficiency causes a reduction in the expression of DMT1 (a major transporter) in rats, which leads to impaired manganese availability to the developing fetus [134,135]. Copper deficiency can also impair DMT1 expression and affect the availability of iron and manganese to the fetus [136] (Figure 5). In a study of copper availability and DNA methylation changes in fetuses during pregnancy in humans, the most robust negatively associated, differentially methylated region was found in a zinc-finger gene, ZNF197, which was correlated with birth weight [125].
(MRE) in the promotor region of MT2 [123], and similar changes are seen in human [127]. Furthermore, the mRNA expression of zinc transporter 1 (ZnT1) in a zebrafish model [128], as well as zinc importing protein (ZIP14) in a rat model [75], and divalent metal transporter 1 (DMT1) in human cell lines [129] is associated with the availability of zinc. The impairment of the expression of these genes affects zinc availability to the developing fetus and, subsequently, organogenesis [66,67].
Selenium deficiency affects the expression of selenoenzymes such as GPx1, GPx2, and GPx4 and selenoproteins (i.e., Selenoproteins-P, SELENOP), which are involved in not only fetal reproductive development and the regulation of oxidative stress [84,85] but also the overall DNA methylation pattern. Selenium availability affects the concentration of Sadenosyl homocysteine (a potential inhibitor of DNA methyltransferases) and the availability of S-adenosyl methionine (the methyl-donor for all methylation reactions) in the methionine-homocysteine cycle [130][131][132][133]. In a rainbow trout model, selenium availability affected the differentially methylated cytosines of more than 6500 differentially methylated genes associated with immune modulations and neural signaling [124].
Like zinc and selenium deficiency, maternal iron deficiency in pregnancy is critical as it can permanently affect brain development [120,121]. Iron deficiency is associated with histone modification and DNA methylation at the brain-derived neurotrophic factor IV (BDNF-IV) promotor region in the hippocampus of the developing fetus, which affects cognitive response and hippocampal plasticity, as observed in a rat model [120]. Additionally, iron deficiency causes a reduction in the expression of DMT1 (a major transporter) in rats, which leads to impaired manganese availability to the developing fetus [134,135]. Copper deficiency can also impair DMT1 expression and affect the availability of iron and manganese to the fetus [136] (Figure 5). In a study of copper availability and DNA methylation changes in fetuses during pregnancy in humans, the most robust negatively associated, differentially methylated region was found in a zinc-finger gene, ZNF197, which was correlated with birth weight [125]. 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.
In terms of macrominerals, maternal magnesium deficiency and calcium deficiency affect the methylation of CpG island regions of hydroxysteroid 11-beta dehydrogenase 2 (Hsd11b2) [119] and hydroxysteroid 11-beta dehydrogenase 1 (Hsd11b1) [118], respectively, leading to the impairment of glucocorticoid metabolism in the developing fetus. The hepatic glucocorticoid concentration was altered in rats [119], which affects the GH-IGF system, leading to a reduction in postnatal skeletal development and myogenesis [95,96]. Due to sex-specific modifications, however, the effects of insulin resistance were minimal in later F2 and F3 generations, although insulin production was still dysregulated [140,141].

Feto-Maternal Crosstalk
After attachment/implantation, fetomaternal crosstalk and the transport of nutrients (including minerals) are completely dependent on the placenta. Before placental vascularization is completed (the first 50 d of gestation in cattle), histotrophic nutrition (via uterine secretions) is the main source of nutrients to the fetus [21]. However, after placental circulation is established, hemotrophic nutrition is the primary pathway involved in the transfer of nutrients to the fetus. In ruminants, chorionic development begins at about day 20 of pregnancy, and placental development along with the interdigitation of fetomaternal villi completes at day 50 [46]. The establishment of pregnancy requires minerals and is especially associated with membrane potential as regulated by estrogen, K + , and Ca +2 [61,62]. In ewes, Ca +2 and Na + levels increase in histotroph on post-fertilization from days 13 to 16, suggesting their role in placental development and implantation [142]. During pregnancy, estrogen binds to the SP1 site in the promotor of the KCNMB1 gene, which causes upregulation in the expression of BK Ca [61]. The opening of BK Ca channels results in the efflux of K + and the sarcoplasmic release of Ca +2 to further enhance KCNMB1 expression and BK Ca channels [59], which causes the pregnancy-induced relaxation of uterine vascular smooth muscle. This hypothesis was further strengthened in cattle models by one recent study in which sarcoplasmic reticulum Ca +2 -ATPase 3 (ATP2A3) and ATPase subunit beta-1 (ATP1B1) were found to be upregulated in caruncles of the mineral-supplemented group compared to the non-supplemented one, indicating the intracellular sarcoplasmic Ca +2 release through these ATPase pumps [116].
The placental transport of other micro-and macrominerals is required for fetal developmental programming. Zinc is maternally transported by ZnT1 in the form of the Zn-MT complex [126] and binds to ZIP14 in placental trophoblast. It is further transported to the fetus by ZnT2 and DMT1 [126] (Figure 5). When zinc and copper supplementation and cobalt and manganese in beef cattle were examined together, MT1A expression was found upregulated in the dams and Cu/Zn SOD levels were upregulated in their successive offerings [77]. This explains the maternal pathway for zinc transport, but the transport mechanism of zinc in the fetus still needs validation in the cattle model. The cattle model study, however, recently showed evidence supporting fetal transport. It was found that the metallothionein coding genes MT1A, MT2A, and MT1E are upregulated, while ZnT10 is differentially expressed in mineral-supplemented fetal groups compared to non-supplemented groups [117].
Selenium and iodine deficiency can impair fetal development by influencing the GH-IGF system [87,91]. In the maternal liver, selenium in the presence of selenophosphate synthetase and SEPSECS (Sep [O-Phosphoserine]) TRNA:Sec ([Selenocysteine TRNA Synthase]) is converted into selenophosphate and selenocyctenyl tRNA, respectively. Selenocyctenyl tRNA in the presence of SBP (selenocysteine binding protein 2) produces selenoproteins, such as SELENOP, and deiodinases [89]. SELENOP binds to ApoER2 (Apolipoprotein E Receptor-2) in the placental trophoblast and is transported to the fetus [85,90]. The production of Dio2 converts the Thyroxine-4 (T4) to active triiodothyronine (T3) [89]. T3 and T4 are produced in the fetal thyroid gland by thyroglobulin produced from iodine and tyrosine [91]. Free T3 increases the expression of Dio3 in placental trophoblast, which will convert T3 back to inactive T4 in the fetus. This mechanism is associated with low active T3 in the fetus and, thus, prevents fetal hyperthyroidism [92] (Figure 3). The proposed mechanism of selenium feto-maternal transport based on lab animal data was not validated in a lamb model, and no changes in fetal T3:T4 were identified when ewes were supplemented with selenium [88]. This puts a question mark on the role of Dio3 in the interconversion of T3 to T4 in fetuses, indicating the current lack of understanding regarding fetal selenium transport.
Placental transporters are regulated by minerals, including manganese, iron, and copper, as shown in Figure 5. Manganese or iron in blood serum forms a complex with transferrin (Tf ) proteins. This complex interacts with the transferrin 1 receptor (TfR1) at the placental microvillous membrane and is endocytosed in vesicle form [135,137]. This proposed pathway of the manganese/iron-Tf complex binding to TfR1 for vesicular endocytosis was also supported in a recent cattle model study, in which TfR1 was differentially expressed in the minerals-supplemented group compared to the non-supplemented group [117]. The acidification of these vesicles causes the release of either manganese or iron, which is further transported to the fetus by DMT1 [135,137,139,143,144]. The fetal uptake of Cu is performed by the binding of Cu +2 from maternal plasma to a high-affinity copper transporter protein 1, CTR1, at the placental trophoblast [145]. The transfer of Cu from CTR1 to a chaperon protein, ATOX1, is associated with the transport to either the fetus by the ATPase ATP7A or back to the dam and then the maternal liver by the ATPase ATP7B [138,139]. Copper supplementation data in a cattle model have shown that, rather than CTR1, MTIA and Cu/Zn SOD can be the maternal and fetal transporters of copper, respectively [77,146], emphasizing the need for further research on copper deficiency in a cattle model.
The transport and regulation of some macrominerals such as magnesium, calcium, and phosphorous are interlinked and are affected by the availability of each in the maternal diet ( Figure 4). Calcium from blood plasma interacts with the calcium-sensing receptor (CaSR) at the placenta and increases the expression of placental parathyroid hormonerelated proteins (PTHrP) and the release of parathyroid hormone (PTH) from the fetal parathyroid gland [105,113]. PTHrP expression increases in the maternal mammary tissues of humans; thus, both calcium-associated mechanisms run parallel in the fetal and maternal systems [111]. Both PTH and PTHrP from the fetus and PTHrP from the dam act on PTH receptor 1 (PTHR1) of the kidney both in the fetus and dam, which activates cyclic adenosine monophosphate (cAMP)-associated pathways and requires Mg +2 as a cofactor [109,110]. The cAMP-associated pathways increase the expression of 25(OH)D(3)-1-α hydroxylase, which then increases calcitriol production from 25(OH)D3, resulting in calcium and phosphorous absorption from the intestine [110,111]. Based on these mechanisms, the deficiency of any of these minerals-magnesium, calcium, or phosphorous-will affect the availability of each other and, ultimately, affect bone mineralization and development in the fetal and maternal systems.

Final Considerations
The potential regulatory roles of maternal mineral intake in developmental programming, from conception to birth, indicate that the excess or deficiency of minerals can lead to pre-and postnatal metabolic disorders and growth abnormalities [147]. The limitation of the studies we have cited is that most are based primarily on laboratory animal models. Although there is a need to validate these observations more extensively and in other species, basic epigenomic regulation involves similar patterns in most species, and, as such, similar responses are expected in cattle and other livestock models [148][149][150]. Recent studies using cattle as experimental models [18,19,[114][115][116] have provided evidence that maternal nutrition during early pregnancy affects the deposition of minerals for postnatal development, metal ion homeostasis, growth regulatory pathways (e.g., the GH-IGF and thyroid hormone pathways), and, in particular, the overall metabolomics of the developing fetus. Based on animal models, and despite the limited evidence from livestock models [116,117], we believe that the proposed mechanisms are very likely to be valid but still need to be examined in livestock models of mineral deficiency or excess. Moreover, the literature concerning sheep [88] and cattle [77,146] models still brings into question the accepted pathways of feto-maternal transport, especially for selenium, zinc, and copper.
Another major limitation is that the available data are mostly based on mRNA, which is insufficient to make conclusions about epigenomic regulation and its role in fetal programming. In this review, we have presented some key genomic/molecular regulatory pathways involved in the effects of minerals on the epigenetic regulation of fetal and placental development. However, much more information and a much better understanding of the alterations in gene expression and their association with epigenetic signals (i.e., non-coding RNAs, histone modifications, and DNA methylation patterns) are needed in other species models. Recent reviews have done a good job explaining the role of epigenetic signals in the effects of maternal and paternal stressors on the developing embryo and fetus [34,151]. The effects of these stressors, however, across the offspring's lifetime and across subsequent generations warrant further investigation. In addition, many of the mineral deficiencies regulate the GH-IGF and thyroid hormone systems; however, the compensatory adaptations of subsequent generations to maternal and postnatal stressors in terms of epigenetic signal inheritance need to be explored further [140].
Future studies are needed to address these abovementioned limitations in the available data to gain a better understanding of maternal mineral nutrition and its role in the epigenetic regulation of the developing fetus and offspring. Furthermore, we also need to identify efficient ways to correlate the epigenomic signaling data (i.e., the DNA methylation pattern, histone modifications, or non-coding RNAs) with genomic regulation, so that we can effectively translate the effects of maternal nutrition and other prenatal stressors across generations by delineating the cascade of minerals and mineral transporters involved in feto-maternal crosstalk. However, based on the available literature from animal models (including livestock species), humans, and cell lines, we have discussed our current understanding of the genomic regulatory roles of the following:

•
Calcium in dyslipidemia and insulin resistance; • Zinc in neural, cardiac, and general organ development and trace mineral transport; • Selenium in reproductive function, the regulation of the GH-IGF system, and the thyroid hormone system; • Magnesium in glucocorticoid metabolism; • Copper in oxidative stress, the regulation of the GH-IGF system, and placental development; • Calcium and potassium in the establishment of pregnancy and the regulation of placental vascular tone; • Selenium and iron in growth hormone metabolism and myogenesis; • Magnesium, calcium, and phosphorous in skeletal development and parathyroid hormone and vitamin D metabolism.