Hypospadias risk is increased with maternal residential exposure to hormonally active hazardous air pollutants

Abstract

Background: With the increasing birth prevalence of hypospadias, there is growing concern for pollutant exposure interfering with normal penile development. We assess the association between hypospadias and hormonally active hazardous air pollutants (HAHAPs) through a nationwide database of hazardous air pollutants and the Texas Birth Defects Registry (TBDR). Methods: Using the TBDR, we identified 8,981 nonsyndromic isolated hypospadias cases from 1999 to 2008. Birth certificate controls were matched for birth year at a 10:1 ratio to cases. Estimated HAHAP concentrations from the 2005 U.S. EPA National–Scale Air Toxics Assessment were used to assign exposure based on maternal residence at birth. Exposure levels were categorized as quintiles based on the distribution in controls. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each increasing exposure category of selected HAHAPs. Results: Of the 10 HAHAPs studied, seven were significantly associated with hypospadias risk. The HAHAP that was most strongly associated with hypospadias was phenol, which was associated with risk in all groups except the high exposure group. Cumulative HAHAP exposure demonstrated a modest increase in hypospadias risk (OR 1.15, 95% CI: 1.07–1.24, p < 0.001) in the medium and medium–high quintiles. Conclusions: While maternal exposure to some HAHAPs was significantly associated with the risk of hypospadias in male offspring, the effects were modest, and no dose–response effects were observed. Future work should employ biomarkers of exposure to better delineate the relationship.

Hypospadias Risk from Maternal Residential Exposure to Heavy Metal Hazardous Air Pollutants

“…Logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence interval (CI) between hypospadias and each increasing maternal exposure category of selected HMHAPs, as well as selected covariates. Maternal race/ethnicity was chosen as a confounder in the final model based on the epidemiology of hypospadias, previous assessments of these exposures and related outcomes [41,42,43]. Birth year was included as a covariate since it was used to match cases and controls.…”

“…Birth year was included as a covariate since it was used to match cases and controls. p -values for trend were then calculated for the adjusted logistic regression models in order to assess relative differences between increasing exposure of the specific HMHAPs and hypospadias prevalence [42,43,44,45,46]. Associations between each HMHAP exposure quintile and non-syndromic isolated hypospadias cases were considered significant when p < 0.05.…”

Association between prenatal air pollution exposure and risk of hypospadias in offspring: a systematic review and meta-analysis of observational studies

“…Sixteen studies (three cohort and thirteen case-control studies) were published between 1998 and 2020, with 21,701 hypospadias cases and 1,465,364 participants. Eight studies were conducted in Europe [ 10 , 17 , 22 – 26 , 29 ], six in North America [ 18 , 19 , 21 , 27 , 28 , 30 ], and two in Asia [ 20 , 31 ]. The exposure windows ranged from 3 months before conception to seven days after delivery.…”

“…Due to the lack of basic information provided for the control group, two studies [ 10 , 25 ] were assessed as “possibly high” risk for selection bias (comparison group). Two studies [ 21 , 30 ] received a “probably high” risk of bias for attrition/exclusion bias (outcome data complete) because the absence of some important data/populations affected the evaluation of the subsequent results. Two studies [ 21 , 30 ] were also rated as “probably high” risk in terms of detection bias (exposure characterization) due to more than 25 percent of data missing.…”

Variants in ALX4 and their association with genitourinary defects

“…A subset of these defects can be linked to environmental and hormonal signal perturbation. [5][6][7] A small subset of genes has been established as important for the development of the lower GU tract. 1,[8][9][10][11][12] Although the common GU defects such as hypospadias and cryptorchidism are not life-threatening, they must be repaired surgically and can carry potential long-term sequelae such as infertility, cancer, and, possibly, because of underlying pleiotropic causes, an increased risk for neurodevelopmental disorders, including autism.…”