Are there sex differences in interactive associations of environmental exposure to Lead (Pb), Mercury (Hg), and Manganese (Mn) with GST Genes (GSTP1, GSTT1, and GSTM1) in relation to ASD in Jamaican children?

Background: Male preponderance is well-established in children with autism spectrum disorder (ASD). Glutathione S-transferase (GST) genes play a crucial role in suppressing oxidative stress triggered by environmental stressors.Objective: To determine whether the association between metals and ASD differs by sex and by GST genes.Methods: Using data from 344 pairs of sex-and age-matched cases and controls, we assessed the association of each metal with ASD or ASD severity, by applying conditional logistic regression (CLR) or general linear models (GLM). Sex was assessed as an effect modifier in separate GST genetic models.Results: For Pb exposure, using a recessive model for the GSTP1 Ile105Val polymorphism, CLR revealed significant overall interaction between sex and GSTP1 (P = 0.04). However, sex-specific matched odds ratios revealed marginally lower odds of the Val/Val genotype among ASD cases than controls in females (MORfemales= 0.23 (95 % CI): 0.05-1.11, P = 0.06), but not among males (MORmales= 1.18 (95 % CI): 0.66-2.16, P = 0.57) in the adjusted model. GLMs for Hg exposure detected significant overall interactions in GSTP1 co-dominant and recessive genetic models. For example, the mean difference in ASD severity among children with Val/Val genotype compared to those with Ile/Ile or Ile/Val were MORfemales=-0.26 and MORmales= 1.30, respectively, in the adjusted model.Conclusion: The association of Pb and Hg with ASD significantly differed by sex under the GSTP1 co-dominant and recessive genetic models. Such findings reflect potential sex differences in metal detoxification mechanisms. Replication is warranted due to the limited sample size of female participants.