Exposure to low-dose arsenic in early life alters innate immune function in children

Figures & data

Table 1. Demographic and exposure characteristics of study children and mothers (N = 51).

Children
Age, (years)	4.15 ± 0.54
BMI (body mass index; kg/m^2)	14.39 ± 1.89
WAZ (weight-for-age Z-score)	−1.32 (−1.98, −0.84)
HAZ (height-for-age Z-score)	−1.11 (−2.32, −0.35)
BAZ (body-mass-index-for-age Z-score)	−0.73 (−1.29, −0.19)
Underweight, n (%)	12 (23.5%)
Stunted, n (%)	15 (29.4%)
Mothers
BMI (kg/m^2)	20.88 ± 3.36
Age (years)	23.67 ± 5.68
Mothers’ education [n (%)]
Illiterate	7 (13.7%)
Primary	5 (9.8%)
High school	33 (64.7%)
Graduate	6 (11.8%)
Arsenic (As) concentrations
Household water-As (μg/L)	43.0 (5.0, 66.0)
All children (μg/g)	39.0 (16.0, 102.0)
Boys U-As (urinary-As; μg/g)	37.0 (24.0, 111.0)
Girls U-As (μg/g)	45.0 (16.0, 80.0)
Mother U-Asconcurrent (μg/g)	114.3 (44.0, 141.5)
Mother U-Aspast (μg/g)	197.1 (81.9, 299.5)

Data shown are means (±SD) or total numbers (as percentage). Anthropometric indices and U-As values are reported as medians (with inter-quartile range in brackets).

Table 2. Multivariable adjusted linear regression analysis of the association between urinary/water As and plasma LL-37, stratified by sex and anthropometric Z-score.

LL-37 (ng/ml)	All children^a (n = 50)	Boys^b (n = 24)	Girls^b (n = 26)	Normal weight^c (n = 39)	Under weight^c (n = 12)	Normal height^c (n = 36)	Stunting^c (n = 15)
Child U-As (µg/g)	**0.17 (0.02, 0.32)	**0.21 (0.04, 0.39)	0.06 (−0.22, 0.35)	**0.22 (0.06, 0.38)	0.03 (−0.45, 0.50)	**0.21 (0.04, 0.37)	0.01 (−0.49, 0.51)
Mother U-Asconcurrent	*0.20 (0.03, 0.37)	0.20 (−0.05, 0.44)	0.17 (−0.12, 0.47)	**0.21 (0.03, 0.39)	0.01 (−0.82, 0.84)	^†0.20 (−0.01, 0.41)	0.0001 (−0.50, 0.50)
^1Mother U-Aspast	**0.27 (0.06, 0.49)	^†0.25 (−0.05, 0.54)	0.27 (−0.09, 0.63)	**0.26 (0.02, 0.51)	0.11 (−0.76, 0.98)	**0.28 (0.02, 0.54)	0.25 (−0.37, 0.87)
Water As (µg/L)	^†0.11 (−0.01, 0.22)	*0.16 (0.001, 0.32)	0.04 (−0.14, 0.22)	^†0.11 (−0.02, 0.24)	0.08 (−0.15, 0.31)	0.10 (−0.05, 0.24)	^†0.25 (−0.04, 0.54)

Data presented as beta (β) coefficient and 95% confidence interval (CI). U-As: urinary arsenic; HAZ: height-for-age Z-score; WAZ: weight-for-age Z-score. ¹U-As (past), collected 2–4 years prior. Models adjusted for child age, sex, WAZ and mothers’ BMI.

^aAdjusted by child age, sex, WAZ and mother BMI; ^bAdjusted by child age, WAZ and mother BMI. The association between plasma LL-37 and the indicated parameter (i.e. child U-As, mother U-As_concurrent, Mother U-As_past, or water-As) was significant (*p < 0.05, **p < 0.005, ^†p ≤ 0.08) as indicated.

^cAdjusted for child age, sex and mother BMI. The association between plasma LL-37 and the indicated parameter (i.e. child U-As, mother U-As_concurrent, Mother U-As_past, or water-As) was significant (**p < 0.005, ^†p ≤ 0.08) as indicated among children with normal weight, underweight, of normal height, or stunted.

Table 3. Association of As exposure with culture supernatant cyto-/chemokine levels (n = 16).

	β-coefficient (95% CI)	p-value
	Fractalkine
Household water As	−0.06 (−0.39, 0.28)	0.72
Child U-As	*−0.47 (−0.88, −0.05)	0.03
Mother U-Asconcurrent	−0.28 (−1.61, 1.04)	0.63
Mother U-Aspast	−0.24 (−0.90, 0.41)	0.42
	IL − 13
Household water As	38.64 (−95.17, 172.45)	0.53
Child U-As	−6.97 (−212.26, 198.31)	0.94
Mother U-Asconcurrent	*463.64 (102.20, 825.07)	0.01
Mother U-Aspast	130.58 (−124.01, 385.16)	0.28
	IL − 17A
Household water As	1.35 (−3.60, 6.30)	0.56
Child U-As	1.95 (−5.52, 9.42)	0.57
Mother U-Asconcurrent	*19.31 (7.03, 31.59)	0.007
Mother U-Aspast	4.72 (−4.70, 14.14)	0.29
	IL − 7
Household water As	*−0.14 (−0.26, −0.03)	0.02
Child U-As	−0.14 (−0.34, 0.07)	0.17
Mother U-Asconcurrent	−0.14 (−0.66, 0.38)	0.55
Mother U-Aspast	*−0.27 (−0.50, −0.04)	0.03
	MIP − 1α
Household water As	0.04 (−7.56, 7.64)	0.99
Child U-As	3.84 (−7.32, 15.01)	0.47
Mother U-Asconcurrent	*24.35 (3.52, 45.18)	0.03
Mother U-Aspast	5.84 (−8.66, 20.33)	0.40
	TNFα
Household water As	−1.95 (−4.51, 0.61)	0.12
Child U-As	^†−3.30 (−7.20, 0.43)	0.08
Mother U-Asconcurrent	−5.15 (−15.23, 4.92)	0.27
Mother U-Aspast	−2.55 (−7.96, 2.85)	0.32

Regression model adjusted by child age, sex, and BMI. The association between the indicated cyto-/chemokine and specific parameter (i.e. household water-As, child U-As, mother U-As_concurrent, Mother U-As_past) was significant (*p < 0.05, ^†p ≤ 0.08) as indicated.

Figure 1. Association of tertiles of %MMA with (A) plasma LL-37, (B) MDM killing capacity, and (C) serum bactericidal antibody (SBA) response, stratified by sex. “p” was determined by multi-variate-adjusted regression analysis and the model was adjusted by child age, sex, WAZ (weight for age z-score), and mother BMI (body mass index). Plasma LL-37 concentrations in the second tertile of %MMA was significantly higher than the lowest tertile (reference group) in girls (*p = 0.05). MDM-mediated killing capacity was significantly lower (*p = 0.05) in the highest fraction of MMA compared to the lowest. SBA responses in the second tertile of %MMA was significantly lower than the first tertile in all children (*p = 0.02) and in girls (*p = 0.03). MMA: mono-methylarsonic acid; MDM: monocyte-derived macrophage; SBA: serum bactericidal antibody response.

Figure 2. Association of arsenic exposure (child U-As, mother’s concurrent U-As, mother’s past U-As, and household water arsenic) with SBA response. Analysis was performed stratifying by sex. “p” was determined by multivariate-adjusted regression analysis and the model was adjusted by child age, sex, WAZ (weight for age z-score), and mother BMI (body mass index). Significant positive associations were obtained between household W-As and SBA response in all children (*p = 0.04) and between maternal U-As_concurrent and SBA response in boys (*p = 0.02).