Page 116 - Read Online

Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37 Page 19

twins had a BW of ≥ 2500 g, a 500 g increase in BW was associated with an increased risk of PCa within
dizygotic twin pairs [odds ratio (OR) = 1.41, 95%CI: 1.02-1.57)], but not within monozygotic twin pairs (OR
[578]
= 1.06, 95%CI: 0.61-1.84) . Especially, BW ≥ 4250 g was associated with significantly higher PCa incidence
[576]
[62% (CI: 4%-151%)] and PCa mortality [82% (CI: 3%-221%)] than BW 3001-4249 g . High BW is related
to increased risks of total and aggressive/lethal PCa , underlining that intrauterine exposures may
[577]
enhance PCa risk and course. In fact, the Malmö Diet and Cancer Study reported a protective effect of lower
BW on risk of total and aggressive PCa .
[579]

Remarkably, maternal milk consumption but not the intake of fermented milk products (cheese) was
associated with fetal weight gain and higher BW [580,581] , as subsequently confirmed by systematic
reviews [582-584] . In contrast to fermented milk with degraded MEX , raw and pasteurized milk delivers MEX
[425]
and MEX miR-21 [418,422,424,451] , which in murine models reach the placenta and peripheral tissues [420,437] and
have been related with placental weight and fetal overgrowths (macrosomia) [585,586] . Milk protein-derived
essential amino acids and MEX-derived miRs, especially miR-21 and miR-148a, promote mTORC1 activity.
Increased trophoblast mTORC1 activity determines placental-fetal transfer of amino acids and glucose and
thus fetal growth and BW [587-591] . Of note, mTORC1 signaling regulates the expression of trophoblast genes
involved in ribosome and protein synthesis, mitochondrial function, lipid metabolism, nutrient transport,
and angiogenesis, representing novel links between mTORC1 signaling and multiple placental functions
[592]
critical for fetal growth and development . It is worth mentioning that other nutritional factors unrelated
to milk intake, such as total animal protein intake during pregnancy as well as other nutritional factors such
as ω-3 fatty acid intake and folic acid supplementation, have an influence on BW, which are not discussed in
this review. Taken together, epidemiological and translational evidence supports the view that maternal
milk consumption during pregnancy modifies fetal mTORC1-driven growth trajectories that determine BW
and may also affect early prostate development and morphogenesis.

Height during puberty and PCa risk
According to the Copenhagen School Health Records Register and the Danish Cancer Registry, childhood
height at age 13 years showed a positive association with PCa-specific mortality [593-596] . The PCa-promoting
effect of height at 13 years was not entirely dependent on adult height, suggesting different modes of
action . These findings implicate late childhood and adolescence are critical exposure windows of interest
[596]
[593]
that underlie the association between height and PCa . According to the Longitudinal Studies of Child
Health and Development, fat and animal protein intake during childhood was positively related with height
[597]
at age 13 and adult height . Notably, an earlier age at peak height velocity was associated with a diet high
in fat and animal protein and low in vegetable protein during childhood . Childhood diet and accelerated
[597]
growth thus influence earlier pubertal timing and taller attained height in males, supporting their
contribution in the pathogenesis of PCa .
[597]

Notably, The NHANES 1999-2002 study reported that consumption of milk, in contrast to other dairy
products, is related to height among US preschool children . The frequency of milk consumption and
[598]
[599]
[600]
milk intake were identified as significant predictors of height at 12-18 years . Almon et al. , who
explored the potential relationship among the LCT (lactase) C>T-13910 polymorphism, milk consumption,
and height in a sample of Swedish preadolescents and adolescents, reported a positive association between
milk consumption and height in preadolescents and adolescents. In fact, increased consumption of cow
milk, which leads to higher levels of IGF-1 in circulation, promotes increased velocity of linear growth [261,264] .

[168]
In a population-based cohort of 8894 men born between 1907 and 1935, Torfadottir et al. studied the
effects of early-life residency in Iceland and differences in milk intake in relation to the risk of PCa later in