Para-occupational exposure to pesticides, PON1 polymorphisms and hypothyroxinemia during the first half of pregnancy in women living in a Mexican floricultural area

Abstract

Background Adequate maternal thyroxine (T4) concentrations during the first half of pregnancy are fundamental to the embryo’s or fetus’ neural development. Organophosphate pesticides (OP) can act as thyroid disruptors and genetic polymorphisms for paraoxonase 1 (PON1), an enzyme that detoxifies OP, could be involved in individual’s susceptibility to them. We assessed the association between para-occupational exposure to pesticides, including OP, during pregnancy and maternal hypothyroxinemia, as well as the potential genetic susceptibility conferred by PON1 polymorphisms. Methods We analyzed information from 381 healthy pregnant women (< 17 gestational weeks), who lived in a floricultural region of Mexico where pesticides, including OP, are routinely used. Women who were para-occupationally exposed to pesticides were those whose partner had an occupation involving contact with these products. Thyroid-Stimulating Hormone (TSH) and free T4 concentrations were determined using ELISA, and hypothyroxinemia was defined as free T4 concentrations <0.76 ng/dL. PON1192QR , PON155LM and PON1–108CT polymorphisms were determined through Polymerase Chain Reaction (PCR). The association between para-occupational exposure and genetic polymorphisms and hypothyroxinemia was estimated using logistic regression models. Results One hundred and sixty two women (42.52%) were classified as para-occupationally exposed to pesticides. Hypothyroxinemia prevalence was 54%, and it was not significantly associated with pesticide para-occupational exposure (OR: 1.21 95% CI 0.75–1.94). Independently of para-occupational exposure, the likelihood of hypothyroxinemia was higher among women who were carriers of PON155MM than in those with PON155LL genotype (OR MM vs LL : 3.03; 95%CI 1.62, 5.70). PON1192 RR (OR RR vs QQ : 1.72; 95%CI 0.93, 3.17) and PON1–108TT (OR TT vs CC : 1.60; 95%CI 0.90, 2.70) genotypes were marginally associated with hypothyroxinemia. No significant interaction was observed between pesticides para-occupational exposure and PON1 polymorphisms. Conclusions These results suggest that PON1 polymorphisms could affect thyroid function during pregnancy in women living in areas where pesticides, including OP, are routinely used. Low exposure variability in this population, could be a possible explanation for the lack of association between para-occupational exposure and thyroid function.

Pre‐clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion‐induced toxicity

“…PON-1 is a high-density enzyme that belongs to one of the classes of paraoxonases (aryldialkylphosphatases, EC 3.1.8.1), which includes the ability to hydrolyse OPs where their action is dependent on the enzyme structure and substrates among its many functions. [63][64][65] The exact mechanism of PON-1 activity is still not well understood, although it plays an important role in the detoxification of metabolites of OPs. 65 Our results showed no change in PON-1 activity of plasma rats exposed to malathion.…”

Genetic profile for the detection of susceptibility to poisoning by exposure to pesticides

“…One of its functions is the catabolism of organophosphate pesticides from which its name is derived (the first known substrate degraded by this enzyme was paraoxon due to its organophosphatase activity). PON1 also has arilesterase and lactonase activities and acts on oxidation residues in low-density lipoprotein (LDL) [35,40,41,43]. However, its activity is affected by different polymorphisms present in its gene, and PON1 activity is affected by different polymorphisms present in its gene.…”

“…In fact, around 400 polymorphisms have been identified, of which only three are of clinical relevance: one in the promoter region (rs705379; -108C/T), and two in the coding region (rs854560, A>T, L55M; rs662, A>G Q192R) [31,34,40,44]. In the promoter region, there is a change at position 108 upstream, from showing a reduced enzyme activity due to lower expression of the PON1 gene [43]. In the polymorphism of the coding region rs854560, there is an amino acid substitution in position 55 from leucine (ATG) to methionine (TTG).…”

“…The resulting 55M mutated variant expresses a lower concentration of the enzyme in the bloodstream, which also results in reduced enzyme activity. This variant is associated with the mutated allele of the 108T polymorphism in the promoter region [41,35,43,44]. In the rs662 polymorphism of the coding region, there is an amino acid change at position 192 from glutamine (CAA) to arginine (CGA), which results in a structural change in the enzyme that affects its activity, depending on the metabolized substrate (Fig.…”

“…2). For example, the 192R mutated variant has a low efficiency in metabolizing the pesticide chlorpyrifos [31,41,43,44].…”